Anti-Cocaine Vaccine Based on Coupling a Cocaine Analog to a Disrupted Adenovirus

PubMed Central

Koob, George; Hicks, Martin J.; Wee, Sunmee; Rosenberg, Jonathan B.; De, Bishnu P.; Kaminksy, Stephen M.; Moreno, Amira; Janda, Kim D.; Crystal, Ronald G.

2012-01-01

The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans, we hypothesized that linking a cocaine hapten to Ad capsid proteins would elicit high-affinity, high-titer antibodies against cocaine, sufficient to sequester systemically administered cocaine and prevent access to the brain, thus suppressing cocaine-induced behaviors. Based on these concepts, we developed dAd5GNE, a disrupted E1−E3− serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In pre-clinical studies, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies, and was highly effective in blocking cocaine-induced hyperactivity and cocaine self-administration behavior in rats. Future studies will be designed to expand the efficacy studies, carry out relevant toxicology studies, and test dAd5GNE in human cocaine addicts. PMID:22229312

Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence.

PubMed

Hall, W; Carter, L

2004-08-01

A "cocaine vaccine" is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

Cocaine abuse versus cocaine dependence: cocaine self-administration and pharmacodynamic response in the human laboratory.

PubMed

Walsh, Sharon L; Donny, Eric C; Nuzzo, Paul A; Umbricht, Annie; Bigelow, George E

2010-01-01

Cocaine has high abuse liability but only a subset of individuals who experiment with it develop dependence. The DSM-IV (APA. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-R. American Psychiatric Association, Washington, DC, 2000) provides criteria for diagnosing cocaine abuse and cocaine dependence as distinct disorders- the latter characterized by additional symptoms related to loss of control over drug use. In this study, two groups of cocaine users (n=8/group), matched on demographic factors and length of cocaine use history and meeting criteria for either cocaine abuse (CocAb) or cocaine dependence (CocDep), were compared on (1) measures related to impulsivity and sensation seeking, (2) response to experimenter-administered cocaine (0, 12.5, 25 and 50mg/70 kg, i.v.), and (3) cocaine self-administration using a Relapse Choice and a Progressive Ratio Procedure (0, 12.5 and 25mg/70 kg, i.v.). Groups did not differ on impulsivity or sensation seeking scores. After experimenter-administered cocaine, the CocAb group reported feeling more suspicious and observers rated them significantly higher on unpleasant effects (e.g., irritability, difficulty concentrating). In contrast, the CocDep group reported significantly greater desire for cocaine, which was sustained over the course of the study, and gave higher street value estimates for cocaine (p<0.05). While cocaine self-administration was dose-related and generally comparable across the two procedures, the CocDep users chose to take significantly more cocaine than the CocAb users. These data suggest that, while regular long-term users of cocaine with cocaine abuse or dependence diagnoses cannot be distinguished by trait measures related to impulsivity, they do exhibit significant differences with regard to cocaine-directed behavior and response to cocaine administration. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation.

PubMed

You, Zhi-Bing; Wang, Bin; Zitzman, Dawnya; Wise, Roy A

2008-09-03

Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to approximately 160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 microM VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.

A randomized, double-blind, placebo-controlled trial of RBP-8000 in cocaine abusers: pharmacokinetic profile of rbp-8000 and cocaine and effects of RBP-8000 on cocaine-induced physiological effects.

PubMed

Nasser, Azmi F; Fudala, Paul J; Zheng, Bo; Liu, Yongzhen; Heidbreder, Christian

2014-01-01

RBP-8000 is a double mutant cocaine esterase that rapidly metabolizes cocaine. This study was conducted to assess the pharmacokinetics of cocaine and cocaine-induced physiological effects in the absence (placebo) or presence of RBP-8000. Twenty-nine cocaine abusers were randomized 1:1 (active: placebo) to 4 sequences and 2 treatment periods. In the presence of RBP-8000, cocaine plasma exposures dropped by 90% within 2 min; cocaine-induced physiological effects were significantly reduced with higher extent and faster decrease in systolic blood pressure and pulse rate compared to placebo. This study provides strong evidence in support to use RBP-8000 as a pharmacotherapy for cocaine intoxication.

N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

PubMed

Levi Bolin, B; Alcorn, Joseph L; Lile, Joshua A; Rush, Craig R; Rayapati, Abner O; Hays, Lon R; Stoops, William W

2017-09-01

Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues. Copyright © 2017 Elsevier B.V. All rights reserved.

Cocaine Use: 2002 and 2003. The NSDUH Report

ERIC Educational Resources Information Center

Substance Abuse and Mental Health Services Administration, 2005

2005-01-01

Cocaine, including crack cocaine, was responsible for 12.8 percent of admissions to substance abuse treatment services in 2002.1 The National Survey on Drug Use and Health (NSDUH) asks persons aged 12 or older to report their use of illicit drugs, including cocaine. NSDUH defines cocaine use as use of cocaine in any form, including crack cocaine.…

Extended Access Cocaine Self-Administration Results in Tolerance to the Dopamine-Elevating and Locomotor-Stimulating Effects of Cocaine

PubMed Central

Calipari, Erin S.; Ferris, Mark J.; Jones, Sara R.

2013-01-01

Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine self-administration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self-administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Further, we report reductions in cocaine-induced uptake inhibition as measured by fast scan cyclic voltammetry, and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (Ki) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine-induced DA overflow as measured by microdialysis. Additionally, cocaine-induced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self-administration. Here we demonstrate both neurochemical and behavioral cocaine tolerance in an extended-access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts. PMID:24102293

The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-administration, but does not occasion cocaine-like levels of generalization

PubMed Central

Batman, Angela M.; Dutta, Aloke K.; Reith, Maarten E. A.; Beardsley, Patrick M.

2010-01-01

A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED50 value of 3.13 (1.54-6.34) mg/kg, and reduced response rates with an ED50 value of 20.39 (7.24-57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine lever responding, while reducing response rates with lower potency than cocaine (ED50=30.94 (12.34-77.60) mg/kg). Pretreatment with D-84 (9.6-30.4 mg/kg) significantly (P<0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self-administration tests with D-84 (0.1-1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pre-treatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine abusing patients. PMID:20840845

Comparative behavioral pharmacology and toxicology of cocaine and its ethanol-derived metabolite, cocaine ethyl-ester (cocaethylene)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katz, J.L.; Terry, P.; Witkin, J.M.

The present study compared the behavioral and toxic effects of cocaine and its ethanol derived metabolite, cocaine ethyl-ester (cocaethylene). Both drugs produced qualitatively similar psychomoter stimulant effects. Cocaine and cocaethylene increased locomotor activity in mice, with cocaine approximately four times more potent than cocaethylene. The durations of action of ED{sub 75} doses of each of the drugs were comparable. Each of the drugs also produced stimulation of operant responding in rats. In rats and squirrel monkeys trained to discriminate cocaine injections from saline, cocaine was approximately three to five times more potent than cocaethylene in producing these cocaine-like interoceptive effects.more » In contrast to the behavioral effects, cocaine and cocaethylene were equipotent in producing convulsions, and cocaethylene was more potent than cocaine in producing lethality. These results suggest that the conversion of cocaine to cocaethylene with simultaneous cocaine and alcohol use may produce an increased risk of toxicity due to a decrease in the potency of cocaethylene in producing psychomotor stimulant effects, and its increased potency in producing toxicity.« less

AAVrh.10-mediated expression of an anti-cocaine antibody mediates persistent passive immunization that suppresses cocaine-induced behavior.

PubMed

Rosenberg, Jonathan B; Hicks, Martin J; De, Bishnu P; Pagovich, Odelya; Frenk, Esther; Janda, Kim D; Wee, Sunmee; Koob, George F; Hackett, Neil R; Kaminsky, Stephen M; Worgall, Stefan; Tignor, Nicole; Mezey, Jason G; Crystal, Ronald G

2012-05-01

Cocaine addiction is a major problem affecting all societal and economic classes for which there is no effective therapy. We hypothesized an effective anti-cocaine vaccine could be developed by using an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain. To accomplish this, we constructed AAVrh.10antiCoc.Mab, an AAVrh.10 gene transfer vector expressing the heavy and light chains of the high affinity anti-cocaine monoclonal antibody GNC92H2. Intravenous administration of AAVrh.10antiCoc.Mab to mice mediated high, persistent serum levels of high-affinity, cocaine-specific antibodies that sequestered intravenously administered cocaine in the blood. With repeated intravenous cocaine challenge, naive mice exhibited hyperactivity, while the AAVrh.10antiCoc.Mab-vaccinated mice were completely resistant to the cocaine. These observations demonstrate a novel strategy for cocaine addiction by requiring only a single administration of an AAV vector mediating persistent, systemic anti-cocaine passive immunity.

Effects of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) on cocaine vs. food choice and extended-access cocaine intake in rhesus monkeys

PubMed Central

Hutsell, Blake A; Cheng, K; Rice, Kenner C; Negus, S Stevens; Banks, Matthew L

2015-01-01

The dynorphin/kappa opioid receptor system (KOR) has been implicated as one potential neurobiological modulator of the abuse-related effects of cocaine and as a potential target for medications development. This study determined effects of the KOR antagonist nor-binaltorphimine (nor-BNI) on cocaine self-administration under a novel procedure that featured two daily components: (1) a 2 h “choice” component (9-11 am) when monkeys could choose between food pellets and cocaine injections (0-0.1 mg/kg/inj, IV), and (2) a 20 h “extended-access” component (noon-8 am) when cocaine (0.1 mg/kg/inj) was available under a fixed-ratio schedule to promote high daily cocaine intakes. Rhesus monkeys (n=4) were given 14 days of exposure to the choice + extended-access procedure, then treated with nor-BNI (3.2 or 10.0 mg/kg, IM), and cocaine choice and extended-access cocaine intake were evaluated for an additional 14 days. Consistent with previous studies, cocaine maintained both a dose-dependent increase in cocaine choice during choice components and a high level of cocaine intake during extended-access components. Neither 3.2 nor 10 mg/kg nor-BNI significantly altered cocaine choice or extended-access cocaine intake. In two additional monkeys, nor-BNI also had no effect on cocaine choice or extended-access cocaine intake when it was administered at the beginning of exposure to the extended-access components. Overall, these results do not support a major role for the dynorphin/KOR system in modulating cocaine self-administration under these conditions in nonhuman primates, nor do they support the clinical utility of KOR antagonists as a pharmacotherapeutic strategy for cocaine addiction. PMID:25581305

(-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine self-administration in rats.

PubMed

Manuszak, M; Harding, W; Gadhiya, S; Ranaldi, R

2018-05-31

Dopamine receptors are implicated in cocaine reward and seeking. We hypothesize that (-)-stepholidine, a dopamine D1/D2/D3 multi-receptor agent, would be effective in reducing cocaine reward and seeking in an animal model. We investigated the effects of (-)-stepholidine in cue-induced reinstatement of cocaine seeking and cocaine self-administration (reward). Cue-induced reinstatement experiment: Rats were trained to press a lever reinforced by cocaine (1 mg/kg/injection) for 15 consecutive daily sessions, after which the response was extinguished by withholding cocaine and cocaine-paired cues (light and pump activation). This was followed by a cue-induced reinstatement test where subjects were exposed to two cocaine cue presentations and presses on the active lever produced cues. Subjects were treated with one of four (-)-stepholidine doses prior to the reinstatement test. Cocaine self-administration (reward) experiment: Rats were trained to self-administer cocaine under a progressive ratio schedule of reinforcement. After stable breakpoints were established, rats were injected with four doses of (-)-stepholidine prior to testing; each dose was injected prior to a separate test session with no-treatment sessions intervening to re-establish break points. (-)-Stepholidine significantly reduced cue-induced reinstatement of cocaine seeking in a dose-related manner. Additionally, (-)-stepholidine significantly reduced break points for cocaine reward. (-)-Stepholidine did not significantly affect locomotor activity. (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine reward, suggesting that it may be useful in treating relapse in cocaine addiction. Copyright © 2018 Elsevier B.V. All rights reserved.

Testing human hair for drugs of abuse. IV. Environmental cocaine contamination and washing effects.

PubMed

Wang, W L; Cone, E J

1995-01-05

Active cocaine use results in sequestration of parent drug in hair. In addition, hair has unique physicochemical properties that permit absorption of cocaine from the environment. When hair is tested for evidence of cocaine, it is important to consider whether the positive test resulted from active drug use or environmental contamination. In a series of laboratory experiments, it was found that exposure of 'cut' hair to cocaine vapor ('crack' smoke) and to aqueous solutions of cocaine hydrochloride resulted in significant contamination of hair samples. Similar results were obtained with two subjects who were exposed to cocaine vapor in an unventilated room. The amount of contamination adsorbed by hair depended upon both time and extent of exposure. Washing the hair samples with methanol removed > 70% of the cocaine contaminant after cocaine vapor exposure, but was less effective (< 50%) following contamination with aqueous cocaine. Shampoo treatment cycles (overnight soaking) progressively removed increasing amounts of cocaine from the contaminated hair, but residual cocaine remained after 10 cycles. Studies were also performed to determine the usefulness of benzoylecgonine as a marker of active cocaine administration. Small amounts of benzoylecgonine (ca. 1 ng/mg) were formed in hair as a result of environmental contamination with cocaine. Also, it was found that benzoylecgonine could be adsorbed from illicit cocaine contaminated with benzoylecgonine. It was concluded that positive hair test results should be interpreted cautiously due to the possibility of environmental contamination from cocaine and related constituents.

No evidence that environmental enrichment during rearing protects against cocaine behavioral effects but as an intervention reduces an already established cocaine conditioned place preference.

PubMed

Galaj, E; Shukur, A; Manuszak, M; Newman, K; Ranaldi, R

2017-05-01

Environmental enrichment (EE) produces differential effects on psychostimulant-related behaviors. Therefore, we investigated whether the timing of EE exposure - during rearing and before cocaine exposure versus in adulthood and after cocaine exposure might be a determining factor. In Experiment 1, rats reared with EE or not (non-EE) were conditioned with cocaine (5, 10 or 20mg/kg) in one compartment of a CPP apparatus and saline in the other, and later tested for cocaine CPP. In Experiment 2, locomotor activity in response to repeated injections of saline or cocaine was measured in rats raised with EE or non-EE. In Experiment 3 we measured the effects of EE or non-EE during rearing on food-based conditioned approach learning. In Experiment 4, rats were exposed to cocaine CPP conditioning then underwent 60days of EE or non-EE treatment after which they were tested for cocaine CPP. Our results show that rearing in EE did not reduce cocaine CPP or cocaine-induced locomotor activity (Experiments 1 and 2) but significantly facilitated conditioned approach learning (Experiment 3). On the other hand, EE treatment introduced after cocaine conditioning significantly reduced the expression of cocaine CPP (Experiment 4). These findings suggest that EE does not protect against cocaine's rewarding and stimulant effects but can reduce already established cocaine effects, suggesting that EE might be an effective treatment for cocaine addiction-related behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

PubMed Central

Uys, Joachim D; Knackstedt, Lori; Hurt, Phelipe; Tew, Kenneth D; Manevich, Yefim; Hutchens, Steven; Townsend, Danyelle M; Kalivas, Peter W

2011-01-01

Impaired glutamate homeostasis in the nucleus accumbens has been linked to cocaine relapse in animal models, and results in part from cocaine-induced downregulation of the cystine–glutamate exchanger. In addition to regulating extracellular glutamate, the uptake of cystine by the exchanger is a rate-limiting step in the synthesis of glutathione (GSH). GSH is critical for balancing cellular redox in response to oxidative stress. Cocaine administration induces oxidative stress, and we first determined if downregulated cystine–glutamate exchange alters redox homeostasis in rats withdrawn from daily cocaine injections and then challenged with acute cocaine. Among the daily cocaine-induced changes in redox homeostasis were an increase in protein S-glutathionylation and a decrease in expression of GSH-S-transferase pi (GSTpi). To mimic reduced GSTpi, a genetic mouse model of GSTpi deletion or pharmacological inhibition of GSTpi by administering ketoprofen during daily cocaine administration was used. The capacity of cocaine to induce conditioned place preference or locomotor sensitization was augmented, indicating that reducing GSTpi may contribute to cocaine-induced behavioral neuroplasticity. Conversely, an acute cocaine challenge after withdrawal from daily cocaine elicited a marked increase in accumbens GSTpi, and the expression of behavioral sensitization to a cocaine challenge injection was inhibited by ketoprofen pretreatment; supporting a protective effect by the acute cocaine-induced rise in GSTpi. Together, these data indicate that cocaine-induced oxidative stress induces changes in GSTpi that contribute to cocaine-induced behavioral plasticity. PMID:21796101

Discriminative and Reinforcing Stimulus Effects of Nicotine, Cocaine, and Cocaine + Nicotine Combinations in Rhesus Monkeys

PubMed Central

Mello, Nancy K.; Newman, Jennifer L.

2011-01-01

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was two-fold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine’s discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. PMID:21480727

The compulsion zone: a pharmacological theory of acquired cocaine self-administration.

PubMed

Norman, Andrew B; Tsibulsky, Vladimir L

2006-10-20

In rats trained to reliably self-administer cocaine, the cumulative drug level was calculated during sessions in which cocaine was administered either contingently or non-contingently. During both types of sessions a high rate of responding was observed only when cocaine levels were above the priming threshold but below the satiety threshold. When the levels of non-contingently administered cocaine were maintained between the priming and satiety thresholds for at least 5 h rats continuously maintained high rates of responding. Although it is generally assumed that rats are responding for cocaine during self-administration sessions, the persistence of responding during non-contingent administration is consistent with responding being induced by cocaine. Therefore, in contrast to the basic assumptions underlying the operant theory of self-administration behavior, choice, contingency and reinforcement are not necessary to explain acquired cocaine self-administration. The presented data demonstrate that there is no ascending limb of the dose-response curve and that the cocaine priming and satiety thresholds delineate the lower and upper limits, respectively, of a cocaine "compulsion zone". It is concluded that the self-administration paradigm is the sum of cocaine induced responding and cocaine induced satiety and which of these cocaine-induced effects occur at any time is dependent on the cocaine level. This novel pharmacokinetic/pharmacodynamic theory provides a basis for a comprehensive understanding of the cocaine self-administration paradigm.

Priming with BTCP, a dopamine reuptake blocker, reinstates cocaine-seeking and enhances cocaine cue-induced reinstatement.

PubMed

Martin-Fardon, Rémi; Lorentz, Christina U; Stuempfig, Nathan D; Weiss, Friedbert

2005-09-01

N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP), a potent dopamine reuptake inhibitor, substitutes for the reinforcing effects of cocaine and meets other criteria for possible agonist pharmacotherapeutic potential. The purpose of this study was to determine (1) whether BTCP modifies reinstatement of cocaine-seeking elicited by cocaine-related environmental stimuli and (2) whether this compound produces priming effects. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with cocaine availability (0.25 mg/infusion) versus non-reward and then were subjected to repeated extinction sessions during which the reinforcer and S(D) were withheld. Subsequent presentation of the cocaine S(D) produced recovery of cocaine-seeking. BTCP (2.5-30 mg/kg; i.p.) did not attenuate the conditioned reinstatement induced by the cocaine S(D) but, rather, potentiated this effect at 10 mg/kg. To test whether BTCP, by itself, exerts priming effects, different groups of rats were trained to self-administer cocaine (0.25 mg/infusion) for 2 weeks. After a 2-week extinction period, BTCP (5, 10 and 20 mg/kg, i.p.) reinstated cocaine-seeking, showing that BTCP not only increases cocaine-seeking induced by cocaine-related stimuli but also produces priming effects following abstinence. The results suggest that, in cocaine abstinent rats, BTCP produces cocaine-like effects.

The compulsion zone: A pharmacological theory of acquired cocaine self-administration

PubMed Central

Norman, Andrew B.; Tsibulsky, Vladimir L.

2010-01-01

In rats trained to reliably self-administer cocaine, the cumulative drug level was calculated during sessions in which cocaine was administered either contingently or non-contingently. During both types of sessions a high rate of responding was observed only when cocaine levels were above the priming threshold but below the satiety threshold. When the levels of non-contingently administered cocaine were maintained between the priming and satiety thresholds for at least 5 h rats continuously maintained high rates of responding. Although it is generally assumed that rats are responding for cocaine during self-administration sessions, the persistence of responding during non-contingent administration is consistent with responding being induced by cocaine. Therefore, in contrast to the basic assumptions underlying the operant theory of self-administration behavior, choice, contingency and reinforcement are not necessary to explain acquired cocaine self-administration. The presented data demonstrate that there is no ascending limb of the dose-response curve and that the cocaine priming and satiety thresholds delineate the lower and upper limits, respectively, of a cocaine “compulsion zone”. It is concluded that the self-administration paradigm is the sum of cocaine induced responding and cocaine induced satiety and which of these cocaine-induced effects occur at any time is dependent on the cocaine level. This novel pharmacokinetic/pharmacodynamic theory provides a basis for a comprehensive understanding of the cocaine self-administration paradigm. PMID:16942754

Ventral tegmental area neurons are either excited or inhibited by cocaine’s actions in the peripheral nervous system

PubMed Central

Mejías-Aponte, Carlos A.; Kiyatkin, Eugene A.

2012-01-01

Cocaine’s multiple pharmacological substrates are ubiquitously present in the peripheral and central nervous system. Thus, upon its administration, cocaine acts in the periphery before directly acting in the brain. We determined whether cocaine alters ventral tegmental area (VTA) neuronal activity via peripheral actions, and whether this precedes its central actions. In urethane-anesthetized rats, we recorded VTA neurons responses to intravenous injections of two cocaine analogs: cocaine-hydrochloride (HCl, 0.25 mg/kg) that readily cross the blood-brain barrier (BBB) and cocaine-methiodide (MI, 0.33 mg/kg) that does not cross the BBB. Both cocaine analogs produced sustained changes in discharge rates that began 5s after the initiation of a 10s drug infusion. Within the first 90s post-injection the magnitudes of neuronal responsive of both cocaine analogs were comparable, but later in time the effects of cocaine-HCl were stronger and persisted longer than those of cocaine-MI. The proportion of neurons responsive to cocaine-HCl was twice to that of cocaine-MI (74% and 35% respectively). Both analogs also differed in the response onsets. Cocaine-MI rarely evoked responses after 1 min whereas cocaine-HCl continued to evoke responses within 3 min post-injection. VTA neurons were either excited or inhibited by both cocaine analogs. Most units responsive to cocaine-MI, regardless of excitation or inhibition, had electrophysiological characteristics of putative DA neurons. Units inhibited by cocaine-HCl also had characteristic of DA neurons whereas excited neurons had widely varying action potential durations and discharge rates. Cocaine-MI and cocaine-HCl each produced changes in VTA neuron activity under full DA receptor blockade. However, the duration of inhibition was shortened, the number of excitations increased, and they occurred with an earlier onset during DA receptor blockade. These findings indicate that cocaine acts peripherally with a short latency and alters the activity of VTA neurons prior to its well-known direct actions in the brain. PMID:22300980

Modafinil decreases cocaine choice in human cocaine smokers only when the response requirement and the alternative reinforcer magnitude are large.

PubMed

Foltin, Richard W; Haney, Margaret; Bedi, Gillinder; Evans, Suzette M

This study examined how response effort (pressing a keyboard button) for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance for money) combined with 'free' cocaine (with no response effort) affected cocaine choice when participants were maintained on modafinil or placebo. Nontreatment-seeking current cocaine smokers were enrolled in a placebo-controlled, double-blind, within-subject study comprising both inpatient and outpatient phases. Participants were maintained on placebo capsules (0mg/day) during one inpatient phase and modafinil (300mg/day) capsules during another inpatient phase in counter-balanced order. A minimum of 8 medication-free days separated the two 15-day inpatient phases to allow for medication clearance. Under each medication condition participants had the opportunity to self-administer smoked cocaine (25mg) when the response effort for cocaine was low (500responses/dose) and had a low value alternative (2 game plays for money) or when the response effort for cocaine was large (2500responses/dose) and had a more valuable alternative (4 game plays for money). Under both conditions, participants received one free dose of cocaine (0, 12, 25 or 50mg) prior to making their first choice of the session. Fifteen individuals began the study and 7 completed it. Participants chose fewer cocaine doses when the response effort for cocaine and the alternative value was high (4.4±0.19) compared to when the response effort for cocaine and the alternative value was low (5.3±0.14). Providing individuals a free "priming" dose of cocaine prior to making their cocaine choice did not alter cocaine taking. Modafinil decreased cocaine choice only when the response effort for cocaine and the alternative value was high. These results suggest that modafinil may be most effective when combined with therapy emphasizing the large personal costs of using cocaine. Copyright © 2016 Elsevier Inc. All rights reserved.

Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats

PubMed Central

Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M.; See, Ronald E.; Reichel, Carmela M.

2015-01-01

Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin’s impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin’s attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin’s effect on cocaine seeking may be mediated by different mechanisms in male and females. PMID:26523890

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

PubMed Central

Ali, Solav; Hashim, Audrey; Sheikh, Imran S.; Theddu, Naresh; Gaddiraju, Narendra V.; Mehrotra, Suneet; Schmitt, Kyle C.; Murray, Thomas F.; Sershen, Henry; Unterwald, Ellen M.; Davis, Franklin A.

2012-01-01

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(−)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like “atypical” DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential. PMID:22895898

Efficacy of an Adenovirus-based Anti-cocaine Vaccine to Reduce Cocaine Self-administration and Reacqusition using a Choice Procedure in Rhesus Macaques

PubMed Central

Evans, Suzette M.; Foltin, Richard W.; Hicks, Martin J.; Rosenberg, Jonathan B.; De, Bishnu P.; Janda, Kim D.; Kaminsky, Stephen M.; Crystal, Ronald G.

2016-01-01

Immunopharmacotherapy offers an approach for treating cocaine abuse by specifically targeting the cocaine molecule and preventing its access to the CNS. dAd5GNE is a novel cocaine vaccine that attenuates the stimulant and the reinforcing effects of cocaine in rats. The goal of this study was to extend and validate dAd5GNE vaccine efficacy in non-human primates. Six experimentally naïve adult female rhesus monkeys (Macaca mulatta) were trained to self-administer 0.1 mg/kg/injection intravenous (i.v.) cocaine or receive candy; then 4 monkeys were administered the vaccine and 2 monkeys were administered vehicle intramuscularly, with additional vaccine boosts throughout the study. The reinforcing effects of cocaine were measured during self-administration, extinction, and reacquisition (relapse) phases. Serum antibody titers in the vaccinated monkeys remained high throughout the study. There was no change in the preference for cocaine over candy over a 20-week period in 5 of the 6 monkeys; only one of the 4 (25%) vaccinated monkeys showed a decrease in cocaine choice. All 6 monkeys extinguished responding for cocaine during saline extinction testing; vaccinated monkeys tended to take longer to extinguish responding than control monkeys (17.5 vs. 7.0 sessions). Vaccination substantially retarded reacquisition of cocaine self-administration; control monkeys resumed cocaine self-administration within 6–41 sessions and 1 vaccinated monkey resumed cocaine self-administration in 19 sessions. The other 3 vaccinated monkeys required between 57–94 sessions to resume cocaine self-administration even in the context of employing several manipulations to encourage cocaine reacquisition. These data suggest that the dAdGNE vaccine may have therapeutic potential for humans who achieve cocaine abstinence as part of a relapse prevention strategy. PMID:27697554

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

PubMed Central

Wee, Sunmee; Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B; Moreno, Amira Y; Kaminsky, Stephen M; Janda, Kim D; Crystal, Ronald G; Koob, George F

2012-01-01

Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>105) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited ‘extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction. PMID:21918504

A potential vaccine for cocaine abuse prophylaxis.

PubMed

Bagasra, O; Forman, L J; Howeedy, A; Whittle, P

1992-01-01

Presently, there are estimated to be 1.5 to 2.0 million individuals infected with HIV-1 in the U.S. and about 12 million worldwide. In the U.S. over 90% of reported cases of AIDS occurred among two subgroups, homosexual males and intravenous substance abusers (IVSAs). Currently, there is no anti-cocaine addiction medication available. In order to explore vaccination as an alternative means for protection against cocaine addition, we immunized inbred male Fisher rats with either cocaine emulsification in complete Freund adjuvant (CFA) or with cocaine conjugated with keyhole limpet hemocyanin (KLH), as carrier plus CFA. Animals were initially immunized with 0.1 mg/animal of cocaine or cocaine-KLH. Animals were given a booster with the corresponding agents after 4 weeks. Ten animals/group were used. Controls received normal saline at the time of immunizations. These animals were injected, intraperitoneally, with 25 mg/kg of cocaine, and were examined for the analgesic effect of cocaine by the hot plate method. The average analgesic effect of cocaine was significantly reduced (p greater than 0.03) in animals immunized with cocaine-KLH (13.77 s) as compared to saline controls (21.6 s). Fifty percent of the animals (5/10) in the cocaine-KLH group and 33% of the animals (3/9) in the cocaine immunized group appeared completely resistant to the effect of cocaine on the central nervous system (CNS). We also have determined the levels of cocaine-specific antibodies produced by each animal by an ELISA method. Degree of protection from cocaine seems to correlate well with the amount of anti-cocaine antibodies produced by each animal (-0.61).(ABSTRACT TRUNCATED AT 250 WORDS)

Combined Cocaine Hydrolase Gene Transfer and Anti-Cocaine Vaccine Synergistically Block Cocaine-Induced Locomotion

PubMed Central

Carroll, Marilyn E.; Zlebnik, Natalie E.; Anker, Justin J.; Kosten, Thomas R.; Orson, Frank M.; Shen, Xiaoyun; Kinsey, Berma; Parks, Robin J.; Gao, Yang; Brimijoin, Stephen

2012-01-01

Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a “training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final “challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence. PMID:22912888

Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects.

PubMed

Wee, Sunmee; Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B; Moreno, Amira Y; Kaminsky, Stephen M; Janda, Kim D; Crystal, Ronald G; Koob, George F

2012-04-01

Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with (3)H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>10(5)) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

Topiramate's effects on cocaine-induced subjective mood, craving and preference for money over drug taking.

PubMed

Johnson, Bankole A; Roache, John D; Ait-Daoud, Nassima; Gunderson, Erik W; Haughey, Heather M; Wang, Xin-Qun; Liu, Lei

2013-05-01

Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine's abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving and preference for cocaine over money induced by low and high doses (0.325 and 0.65 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university in-patient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square cross-over design in which three experimental challenge doses of low-dose cocaine, high-dose cocaine and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pre-treatments separated by a 1-week washout period (2006-2009). After placebo pre-treatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine and monetary value of cocaine in a behavioral preference test of cocaine versus money choice. Topiramate pre-treatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine's abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate's prominent sedative effects. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

AAVrh.10-Mediated Expression of an Anti-Cocaine Antibody Mediates Persistent Passive Immunization That Suppresses Cocaine-Induced Behavior

PubMed Central

Rosenberg, Jonathan B.; Hicks, Martin J.; De, Bishnu P.; Pagovich, Odelya; Frenk, Esther; Janda, Kim D.; Wee, Sunmee; Koob, George F.; Hackett, Neil R.; Kaminsky, Stephen M.; Worgall, Stefan; Tignor, Nicole; Mezey, Jason G.

2012-01-01

Abstract Cocaine addiction is a major problem affecting all societal and economic classes for which there is no effective therapy. We hypothesized an effective anti-cocaine vaccine could be developed by using an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain. To accomplish this, we constructed AAVrh.10antiCoc.Mab, an AAVrh.10 gene transfer vector expressing the heavy and light chains of the high affinity anti-cocaine monoclonal antibody GNC92H2. Intravenous administration of AAVrh.10antiCoc.Mab to mice mediated high, persistent serum levels of high-affinity, cocaine-specific antibodies that sequestered intravenously administered cocaine in the blood. With repeated intravenous cocaine challenge, naive mice exhibited hyperactivity, while the AAVrh.10antiCoc.Mab-vaccinated mice were completely resistant to the cocaine. These observations demonstrate a novel strategy for cocaine addiction by requiring only a single administration of an AAV vector mediating persistent, systemic anti-cocaine passive immunity. PMID:22486244

The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-administration, but does not occasion cocaine-like levels of generalization.

PubMed

Batman, Angela M; Dutta, Aloke K; Reith, Maarten E A; Beardsley, Patrick M

2010-12-01

A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED(50) value of 3.13 (1.54-6.34) mg/kg, and reduced response rates with an ED(50) value of 20.39 (7.24-57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine-lever responding, while reducing response rates with lower potency than cocaine (ED(50)=30.94 (12.34-77.60) mg/kg). Pretreatment with D-84 (9.6-30.4 mg/kg) significantly (P<0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self-administration tests with D-84 (0.1-1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pretreatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine-abusing patients. Copyright © 2010 Elsevier B.V. All rights reserved.

Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens.

PubMed

Tzeng, Wen-Yu; Cherng, Chian-Fang G; Wang, Shyi-Wu; Yu, Lung

2016-06-01

This study aimed to assess the impact of companions on the rewarding effects of cocaine. Three cage mates, serving as companions, were housed with each experimental mouse throughout cocaine-place conditioning in a cocaine-induced conditioned place preference (CPP) paradigm using conditioning doses of 10 and 20mg/kg. The presence of companions decreased the magnitude of the CPP. At 20mg/kg, cocaine stimulated dopamine (DA) release in the nucleus accumbens as evidenced by a significant decrease in total (spontaneous and electrical stimulation-provoked) DA release in accumbal superfusate samples. The presence of companions prevented this cocaine-stimulated DA release; such a reduction in cocaine-induced DA release may account for the reduction in the magnitude of the CPP in the presence of the companions. Furthermore, cocaine pretreatment (2.5mg/kg) was found to prevent the companion-produced decreases in cocaine (10mg/kg/conditioning)-induced CPP as well as the cocaine (10mg/kg)-stimulated DA release. Moreover, the presence of methamphetamine (MA) (1mg/kg)-treated companions decreased cocaine (20mg/kg/conditioning)-induced CPP and prevented the cocaine (20mg/kg)-stimulated DA release. Finally, the presence of companions decreased the magnitude of the CPP could not seem to be accounted for by cocaine-stimulated corticosterone (CORT) release. Taken together, these results indicate that familiar companions, regardless of their pharmacological status, may exert dampening effects on CPP induced by moderate to high conditioning doses of cocaine, at least in part, by preventing cocaine-stimulated DA release in the nucleus accumbens. Copyright © 2016 Elsevier B.V. All rights reserved.

Estradiol increases choice of cocaine over food in male rats.

PubMed

Bagley, Jared R; Adams, Julia; Bozadjian, Rachel V; Bubalo, Lana; Ploense, Kyle L; Kippin, Tod E

2017-10-19

Estradiol modulates the rewarding and reinforcing properties of cocaine in females, including an increase in selection of cocaine over alternative reinforcers. However, the effects of estradiol on male cocaine self-administration behavior are less studied despite equivalent levels of estradiol in the brains of adult males and females, estradiol effects on motivated behaviors in males that share underlying neural substrates with cocaine reinforcement as well as expression of estrogen receptors in the male brain. Therefore, we sought to characterize the effects of estradiol in males on choice between concurrently-available cocaine and food reinforcement as well as responding for cocaine or food in isolation. Male castrated rats (n=46) were treated daily with estradiol benzoate (EB) (5μg/0.1, S.C.) or vehicle (peanut oil) throughout operant acquisition of cocaine (1mg/kg, IV; FI20 sec) and food (3×45mg; FI20 sec) responding, choice during concurrent access and cocaine and food reinforcement under progressive ratio (PR) schedules. EB increased cocaine choice, both in terms of percent of trials on which cocaine was selected and the proportion of rats exhibiting a cocaine preference as well as increased cocaine, but not food, intake under PR. Additionally, within the EB treated group, cocaine-preferring rats exhibited enhanced acquisition of cocaine, but not food, reinforcement whereas no acquisition differences were observed across preferences in the vehicle treated group. These findings demonstrate that estradiol increases cocaine choice in males similarly to what is observed in females. Copyright © 2017 Elsevier Inc. All rights reserved.

Cocaine self-administration and reinstatement in female rats selectively bred for high and low voluntary running.

PubMed

Smethells, J R; Zlebnik, N E; Miller, D K; Will, M J; Booth, F; Carroll, M E

2016-10-01

Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues. A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats. Published by Elsevier Ireland Ltd.

Increased serum brain-derived neurotrophic factor (BDNF) is predictive of cocaine relapse outcomes: A prospective study

PubMed Central

D’Sa, Carrol; Fox, Helen C.; Hong, Adam K.; Dileone, Ralph J.; Sinha, Rajita

2011-01-01

Background Cocaine dependence is associated with high relapse rates but few biological markers associated with relapse outcomes have been identified. Extending preclinical research showing a role for central Brain Derived Neurotrophic Factor (BDNF) in cocaine seeking, we examined whether serum BDNF is altered in abstinent, early recovering, cocaine-dependent individuals and if it is predictive of subsequent relapse risk. Methods Serum samples were collected across three consecutive mornings from 35 treatment-engaged, 3 week abstinent cocaine-dependent inpatients (17M/18F) and 34 demographically matched hospitalized healthy control participants (17M/17F). Cocaine dependent individuals were prospectively followed on days 14, 30 and 90 post-treatment discharge to assess cocaine relapse outcomes. Time to cocaine relapse, number of days of cocaine use (frequency), and amount of cocaine use (quantity) were the main outcome measures. Results High correlations in serum BDNF across days indicated reliable and stable serum BDNF measurements. Significantly higher mean serum BDNF levels were observed for the cocaine-dependent patients compared to healthy control participants (p<.001). Higher serum BDNF levels predicted shorter subsequent time to cocaine relapse (hazard ratio: HR: 1.09, p<.05), greater number of days (p<.05) and higher total amounts of cocaine used (p = .05). Conclusions High serum BDNF levels in recovering cocaine-dependent individuals are predictive of future cocaine relapse outcomes and may represent a clinically relevant marker of relapse risk. These data suggest that serum BDNF levels may provide an indication of relapse risk during early recovery from cocaine dependence. PMID:21741029

Cocaine

MedlinePlus

... confidencial Press Room » Multi-Media Library » Image Gallery » Cocaine COCAINE To Save Images: First click on the thumbnail ... your Save in directory and then click Save. Cocaine Crack Cocaine RESOURCE CENTER Controlled Substances Act DEA ...

Cocaine (Coke, Crack) Facts

MedlinePlus

... That People Abuse » Cocaine (Coke, Crack) Facts Cocaine (Coke, Crack) Facts Listen Cocaine is a white ... 69 KB) "My life was built around getting cocaine and getting high." ©istock.com/ Marjot Stacey is ...

Myocardial uptake of cocaine and effects of cocaine on myocardial substrate utilization and perfusion in hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Som, P.; Wang, G.J.; Oster, Z.H.

Cocaine abuse is a problem causing world-wide concern and the number of deaths following cocaine use is increasing. Cardiovascular complications following cocaine include severe tachyarrythmias, pulmonary edema, myocardial infarction, and acute renal failure, which are major problems confronting emergency facilities. While the studies of cocaine effects on the brain have been given the most attention, it is clear that the effects of cocaine on the cardiovascular system are of great importance, given the increasing number of reports on sudden death and myocardial infarctions in young adults related to cocaine use. The precise mechanisms of cardiotoxic actions of cocaine are unclear.more » We investigated the whole-body distribution of C-14-labeled cocaine to determine the cocaine-binding sites, including blocking experiments to determine the nature of regional binding sites, and differential response of the normal vs. diseased heart (hypertensive cardiomyopathy) in an animal model to mimic a potentially high risk population. We investigated the acute effects of cocaine on myocardial metabolism using two myocardial energy substrate analogs, fatty acid and glucose with comparison with regional perfusion.« less

Reciprocal Inhibitory Interactions Between the Reward-Related Effects of Leptin and Cocaine.

PubMed

You, Zhi-Bing; Wang, Bin; Liu, Qing-Rong; Wu, Yan; Otvos, Laszlo; Wise, Roy A

2016-03-01

Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food- and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats. First, we report that cocaine and the expectancy of cocaine each depresses plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates the ability of cocaine to elevate dopamine levels in the nucleus accumbens, the ability of cocaine to establish a conditioned place preference, and the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus, whereas leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine.

The 5-HT(2C) receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.

PubMed

Harvey-Lewis, Colin; Li, Zhaoxia; Higgins, Guy A; Fletcher, Paul J

2016-02-01

Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Substance use -- cocaine

MedlinePlus

... Charlie, coca, coke, flake, rock, snow, speedball, toot. Cocaine's Effects on Your Brain Cocaine is a strong stimulant. ... injecting, and last 15 to 30 minutes. Harmful Effects of Cocaine Cocaine can harm the body in many ways ...

Crystal structure of a cocaine-binding antibody.

PubMed

Larsen, N A; Zhou, B; Heine, A; Wirsching, P; Janda, K D; Wilson, I A

2001-08-03

Murine monoclonal antibody GNC92H2 was elicited by active immunization with a cocaine immunoconjugate and binds free cocaine with excellent specificity and moderate affinity. Improvement of affinity, as well as humanization of GNC92H2, would be advantageous in immunopharmacotherapy for cocaine addiction, and for emergency cases of drug overdose. Toward this end, the crystal structure of an engineered murine-human chimeric Fab of GNC92H2 complexed with cocaine was determined at 2.3 A resolution. Structural analysis reveals a binding pocket with high shape and charge complementarity to the cocaine framework, which explains the specificity for cocaine, as opposed to the pharmacologically inactive cocaine metabolites. Importantly, the structure provides a foundation for mutagenesis to enhance the binding affinity for cocaine and potent cocaine derivatives, such as cocaethylene, and for additional humanization of the antibody. Copyright 2001 Academic Press.

The Ability of Bacterial Cocaine Esterase to Hydrolyze Cocaine Metabolites and Their Simultaneous Quantification Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry

PubMed Central

Brim, Remy L.; Noon, Kathleen R.; Collins, Gregory T.; Nichols, Joseph; Narasimhan, Diwahar; Sunahara, Roger K.

2011-01-01

Cocaine toxicity is a widespread problem in the United States, responsible for more than 500,000 emergency department visits a year. There is currently no U.S. Food and Drug Administration-approved pharmacotherapy to directly treat cocaine toxicity. To this end, we have developed a mutant bacterial cocaine esterase (DM-CocE), which has been previously shown to rapidly hydrolyze cocaine into inert metabolites, preventing and reversing toxicity with limited immunogenic potential. Herein we describe the ability of DM-CocE to hydrolyze the active cocaine metabolites norcocaine and cocaethylene and its inability to hydrolyze benzoylecgonine. DM-CocE hydrolyzes norcocaine and cocaethylene with 58 and 45% of its catalytic efficiency for cocaine in vitro as measured by a spectrophotometric assay. We have developed a mass spectrometry method to simultaneously detect cocaine, benzoylecgonine, norcocaine, and ecgonine methyl ester to quantify the effect of DM-CocE on normal cocaine metabolism in vivo. DM-CocE administered to rats 10 min after a convulsant dose of cocaine alters the normal metabolism of cocaine, rapidly decreasing circulating levels of cocaine and norcocaine while increasing ecgonine methyl ester formation. Benzoylecgonine was not hydrolyzed in vivo, but circulating concentrations were reduced, suggesting that DM-CocE may bind and sequester this metabolite. These findings suggest that DM-CocE may reduce cocaine toxicity by eliminating active and toxic metabolites along with the parent cocaine molecule. PMID:21885621

Demand curves for hypothetical cocaine in cocaine-dependent individuals.

PubMed

Bruner, Natalie R; Johnson, Matthew W

2014-03-01

Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks, drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and O max (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, P max, were significantly correlated with real-world cocaine use. Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use.

Effects of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) on cocaine versus food choice and extended-access cocaine intake in rhesus monkeys.

PubMed

Hutsell, Blake A; Cheng, Kejun; Rice, Kenner C; Negus, Sidney Stevens; Banks, Matthew L

2016-03-01

The dynorphin/kappa opioid receptor (KOR) system has been implicated as one potential neurobiological modulator of the abuse-related effects of cocaine and as a potential target for medications development. This study determined effects of the KOR antagonist nor-binaltorphimine (nor-BNI) on cocaine self-administration under a novel procedure that featured two daily components: (1) a 2-hour 'choice' component (9:00-11:00 am) when monkeys could choose between food pellets and cocaine injections (0-0.1 mg/kg per injection, intravenous) and (2) a 20-hour 'extended-access' component (noon to 8:00 am) when cocaine (0.1 mg/kg per injection) was available under a fixed-ratio schedule to promote high daily cocaine intakes. Rhesus monkeys (n = 4) were given 14 days of exposure to the choice + extended-access procedure then treated with nor-BNI (3.2 or 10.0 mg/kg, intramuscular), and cocaine choice and extended-access cocaine intake were evaluated for an additional 14 days. Consistent with previous studies, cocaine maintained both a dose-dependent increase in cocaine choice during choice components and a high level of cocaine intake during extended-access components. Neither 3.2 nor 10 mg/kg nor-BNI significantly altered cocaine choice or extended-access cocaine intake. In two additional monkeys, nor-BNI also had no effect on cocaine choice or extended-access cocaine intake when it was administered at the beginning of exposure to the extended-access components. Overall, these results do not support a major role for the dynorphin/KOR system in modulating cocaine self-administration under these conditions in non-human primates nor do they support the clinical utility of KOR antagonists as a pharmacotherapeutic strategy for cocaine addiction. © 2015 Society for the Study of Addiction.

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

PubMed Central

Hutsell, Blake A.; Blough, Bruce E.; Poklis, Justin L.; Negus, S. Stevens

2015-01-01

Background: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown. Methods: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. Conclusions: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction. PMID:25618405

Covalent modification of proteins by cocaine

NASA Astrophysics Data System (ADS)

Deng, Shi-Xian; Bharat, Narine; Fischman, Marian C.; Landry, Donald W.

2002-03-01

Cocaine covalently modifies proteins through a reaction in which the methyl ester of cocaine acylates the -amino group of lysine residues. This reaction is highly specific in vitro, because no other amino acid reacts with cocaine, and only cocaine's methyl ester reacts with the lysine side chain. Covalently modified proteins were present in the plasma of rats and human subjects chronically exposed to cocaine. Modified endogenous proteins are immunogenic, and specific antibodies were elicited in mouse and detected in the plasma of human subjects. Covalent modification of proteins could explain cocaine's autoimmune effects and provide a new biochemical approach to cocaine's long-term actions.

College students' use of cocaine.

PubMed

Williams, Jenny; Pacula, Rosalie Liccardo; Chaloupka, Frank J; Wechsler, Henry

2006-01-01

After experiencing a period of rapid decline between 1986 and 1994, cocaine use is once again on the rise in the United States. The increased prevalence of use among college students is particularly troubling because of its potential impact on human capital acquisition and long-term labor market success. Merging information on the price of cocaine and marijuana from the U.S. Drug Enforcement Agency with data on cocaine use from the College Alcohol Study, we investigate the demand for cocaine in the college population. We find evidence that participation in cocaine use by college students is responsive to changes in the price of cocaine and marijuana and that cocaine and marijuana are economic complements for this population. Further investigation revealed significant differences in the demand for cocaine by those less than age 21 and those at least age 21, years, with the younger age group being more responsive to changes in the price of cocaine. No difference is found, however, in the demand for cocaine across gender.

Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

PubMed Central

Calipari, Erin S.; Ferris, Mark J.; Siciliano, Cody A.; Zimmer, Benjamin A.

2014-01-01

Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well. PMID:24566123

Cocaine self-administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine.

PubMed

Siciliano, Cody A; Ferris, Mark J; Jones, Sara R

2015-08-01

Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine-induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self-administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self-administration (fixed-ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self-administration, there was a marked reduction in ventral tegmental area-stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug-taking and drug-seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Aripiprazole maintenance increases smoked cocaine self-administration in humans

PubMed Central

Rubin, Eric; Foltin, Richard W.

2011-01-01

Rationale Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence. Objective This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D2 receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers. Methods In order to achieve steady-state concentrations, participants (n=8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose–response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a “sample” trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00. Results Cocaine’s reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo. Conclusions These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence. PMID:21373790

Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle

PubMed Central

Feltenstein, Matthew W.; See, Ronald E.

2007-01-01

Previous studies have reported sex and estrous cycle dependent differences in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues. However, the relationship between estradiol or progesterone levels and cocaine-seeking in a reinstatement model of relapse has not been explored. Thus, we examined changes in plasma hormone levels during cocaine-taking and cocaine-seeking behaviors in gonadally intact female rats. Rats self-administered cocaine (0.5 mg/kg/infusion) during daily 2-h sessions, followed by extinction. For reinstatement, cocaine (0, 5, or 10 mg/kg, i.p.) was administered 30 min prior to testing. Vaginal smears and blood samples were collected prior to and during chronic cocaine self-administration, extinction, and reinstatement testing. Relative to nonestrous females, females in estrus showed greater responding during self-administration, extinction, and during cocaine-primed reinstatement. The highest progesterone levels were noted at the time of lowest cocaine-seeking (proestrus) and the lowest levels of progesterone occurred at the time of highest cocaine-seeking (estrus). In contrast, plasma estradiol levels did not show any clear pattern with cocaine-seeking. These data from an animal model of relapse supports recent clinical evidence that progesterone reduces subjective craving in cocaine-dependent women. Overall, these results suggest that progesterone administration may be a useful intervention for reducing the incidence of relapse. PMID:17240083

Accelerating cocaine metabolism as an approach to the treatment of cocaine abuse and toxicity

PubMed Central

Schindler, Charles W; Goldberg, Steven R

2012-01-01

One pharmacokinetic approach to the treatment of cocaine abuse and toxicity involves the development of compounds that can be safely administered to humans and that accelerate the metabolism of cocaine to inactive components. Catalytic antibodies have been developed and shown to accelerate cocaine metabolism, but their catalytic efficiency for cocaine is relatively low. Mutations of human butyrylcholinesterase and a bacterial cocaine esterase found in the soil of coca plants have also been developed. These compounds accelerate cocaine metabolism and antagonize the behavioral and toxic effects of cocaine in animal models. Of these two approaches, the human butyrylcholinesterase mutants show the most immediate promise as they would not be expected to evoke an immune response in humans. PMID:22300096

β1-Adrenoceptor in the Central Amygdala Is Required for Unconditioned Stimulus-Induced Drug Memory Reconsolidation

PubMed Central

Zhu, Huiwen; Zhou, Yiming; Liu, Zhiyuan; Chen, Xi; Li, Yanqing; Liu, Xing; Ma, Lan

2018-01-01

Abstract Background Drug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus) or drugs (unconditioned stimulus). Whether conditioned stimulus and unconditioned stimulus retrieval trigger different memory reconsolidation processes is not clear. Methods Protein synthesis inhibitor or β-adrenergic receptor (β-AR) antagonist was systemically administrated or intra-central amygdala infused immediately after cocaine reexposure in cocaine-conditioned place preference or self-administration mice models. β-ARs were selectively knocked out in the central amygdala to further confirm the role of β-adrenergic receptor in cocaine reexposure-induced memory reconsolidation of cocaine-conditioned place preference. Results Cocaine reexposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-conditioned place preference. Cocaine-priming-induced reinstatement was also impaired with post cocaine retrieval manipulation, in contrast to the relapse behavior with post context retrieval manipulation. Cocaine retrieval, but not context retrieval, induced central amygdala activation. Protein synthesis inhibitor or β1-adrenergic receptor antagonist infused in the central amygdala after cocaine retrieval, but not context retrieval, inhibited memory reconsolidation and reinstatement. β1-adrenergic receptor knockout in the central amygdala suppressed cocaine retrieval-triggered memory reconsolidation and reinstatement of cocaine conditioned place preference. β1-adrenergic receptor antagonism after cocaine retrieval also impaired reconsolidation and reinstatement of cocaine self-administration. Conclusions Cocaine reward memory triggered by unconditioned stimulus retrieval is distinct from conditioned stimulus retrieval. Unconditioned stimulus retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. Post unconditioned stimulus retrieval manipulation can prevent drug memory reconsolidation and relapse to cocaine, thus providing a potential strategy for the prevention of substance addiction. Significance Statement It is well known that drug memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS and US retrieval trigger different memory reconsolidation processes is unknown. In this study, we found that US retrieval, but not CS retrieval, triggered memory reconsolidation of cocaine-conditioned place preference dependent on β1-AR and de novo protein synthesis in the central amygdala. Furthermore, cocaine priming-induced reinstatement was impaired with post US retrieval manipulation in contrast to the relapse behavior with post CS retrieval manipulation. In cocaine self-administration, β1-AR antagonism after US retrieval also impaired reconsolidation and reinstatement. Our study indicates that reconsolidation of cocaine reward memory triggered by US retrieval is distinct from CS retrieval. US retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. PMID:29216351

Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys

PubMed Central

Schindler, Charles W.; Justinova, Zuzana; Lafleur, David; Woods, Doug; Roschke, Viktor; Hallak, Hussein; Sklair-Tavron, Liora; Redhi, Godfrey H.; Yasar, Sevil; Bergman, Jack; Goldberg, Steven R.

2011-01-01

Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 μg/kg/injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted. PMID:22264200

Attenuation of behavioral effects of cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine.

PubMed

Lee, Buyean; Platt, Donna M; Rowlett, James K; Adewale, Adepero S; Spealman, Roger D

2005-03-01

Growing evidence suggests a role for metabotropic glutamate receptors (mGluRs) in the behavioral effects of cocaine related to its abuse. The mGluR5 subtype, in particular, has come under scrutiny due to its distribution in brain regions associated with drug addiction. This study investigated interactions between the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and cocaine in squirrel monkeys whose lever-pressing behavior was 1) maintained under a second-order schedule of cocaine self-administration, 2) extinguished and then reinstated by cocaine priming, and 3) controlled by the discriminative stimulus (DS) effects of cocaine. Additional studies determined the effects of MPEP on unconditioned behaviors, coordination, and muscle resistance. In each experiment, the effects of MPEP were compared with those of the N-methyl-d-aspartate antagonist dizocilpine. MPEP attenuated cocaine self-administration, cocaine-induced reinstatement of drug seeking, and the DS effects of cocaine at doses that did not markedly impair motor function or operant behavior in the context of drug discrimination. Dizocilpine also attenuated cocaine self-administration, but it did not significantly alter cocaine-induced reinstatement of drug seeking, and it enhanced rather than attenuated the DS effects of cocaine. The findings point to a significant contribution of mGluR5 mechanisms in the behavioral effects of cocaine related to its abuse and suggest that MPEP has properties of a functional cocaine antagonist, which are not secondary to antagonism at NMDA receptors. The contrasting interactions of MPEP and dizocilpine with cocaine imply that glutamate acting through different metabotropic and ionotropic receptors may modulate the behavioral effects of cocaine in qualitatively different ways.

Increased intra-individual reaction time variability in cocaine-dependent subjects: role of cocaine-related cues.

PubMed

Liu, Shijing; Lane, Scott D; Schmitz, Joy M; Green, Charles E; Cunningham, Kathryn A; Moeller, F Gerard

2012-02-01

Neuroimaging data suggest that impaired performance on response inhibition and information processing tests in cocaine-dependent subjects is related to prefrontal and frontal cortical dysfunction and that dysfunction in these brain areas may underlie some aspects of cocaine addiction. In subjects with attention-deficit hyperactivity disorder and other psychiatric disorders, the Intra-Individual Reaction Time Variability (IIRTV) has been associated with frontal cortical dysfunction. In the present study, we evaluated IIRTV parameters in cocaine-dependent subjects vs. controls using a cocaine Stroop task. Fifty control and 123 cocaine-dependent subjects compiled from three studies completed a cocaine Stroop task. Standard deviation (SD) and coefficient of variation (CV) for reaction times (RT) were calculated for both trials with neutral and trials with cocaine-related words. The parameters mu, sigma, and tau were calculated using an ex-Gaussian analysis employed to characterize variability in RTs. The ex-Gaussian analysis divides the RTs into normal (mu, sigma) and exponential (tau) components. Using robust regression analysis, cocaine-dependent subjects showed greater SD, CV and Tau on trials with cocaine-related words compared to controls (p<0.05). However, in trials with neutral words, there was no evidence of group differences in any IIRTV parameters (p>0.05). The Wilcoxon matched-pairs signed-rank test showed that for cocaine-dependent subjects, both SD and tau were larger in trials with cocaine-related words than in trials with neutral words (p<0.05). The observation that only cocaine-related words increased IIRTV in cocaine-dependent subjects suggests that cocaine-related stimuli might disrupt information processing subserved by prefrontal and frontal cortical circuits. Copyright © 2011 Elsevier Ltd. All rights reserved.

Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys.

PubMed

Johnson, Amy R; Banks, Matthew L; Blough, Bruce E; Lile, Joshua A; Nicholson, Katherine L; Negus, S Stevens

2016-08-01

Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial "sample" trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine "choice" trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. Preference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32-3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. These results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Repeated Administration of a Mutant Cocaine Esterase: Effects on Plasma Cocaine Levels, Cocaine-Induced Cardiovascular Activity, and Immune Responses in Rhesus Monkeys

PubMed Central

Collins, Gregory T.; Brim, Remy L.; Noon, Kathleen R.; Narasimhan, Diwahar; Lukacs, Nicholas W.; Sunahara, Roger K.; Woods, James H.

2012-01-01

Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans. PMID:22518021

Inactivation of the central nucleus of the amygdala reduces the effect of punishment on cocaine self-administration in rats.

PubMed

Xue, YueQiang; Steketee, Jeffery D; Sun, WenLin

2012-03-01

Continued cocaine use despite the negative consequences is a hallmark of cocaine addiction. One such consequence is punishment, which is often used by society to curb cocaine use. Unfortunately, we know little about the mechanism involved in regulation by punishment of cocaine use. The fact that cocaine addicts continue to use cocaine despite potentially severe punishment suggests that the mechanism may be impaired. Such impairment is expected to critically contribute to compulsive cocaine use. This study was aimed at testing the hypothesis that the central nucleus of the amygdala (CeN) plays a critical role in such regulation. To this end, rats were trained to press a lever to self-administer cocaine under a chained schedule: a response on one lever (cocaine-seeking lever) led to access to the other lever (cocaine-taking lever), on which a response was reinforced by cocaine and cues. Thereafter, responses on the seeking lever were punished by footshock with a probability of 0.5. Cocaine self-administration (SA) was significantly suppressed by punishment in an intensity-dependent manner. Interestingly, rats trained with daily 6-h (extended access) but not 2-h (limited access) sessions showed resistance to the lower intensity of punishment. Inactivation of the CeN induced a robust anti-punishment effect in both groups. These data provided evidence that the CeN is a critical neural substrate involved in regulation by punishment of cocaine SA. Rats with a history of extended cocaine SA appeared to be less sensitive to punishment. The decreased sensitivity could result from the neuroplastic changes induced by extended cocaine SA in the CeN. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Inactivation of the central nucleus of the amygdala reduces the effect of punishment on cocaine self-administration in rats

PubMed Central

Xue, YueQiang; Steketee, Jeffery D.; Sun, WenLin

2012-01-01

Continued cocaine use despite the negative consequences is a hallmark of cocaine addiction. One such consequence is punishment that is often used by society to curb cocaine use. Unfortunately, we know little about the mechanism involved in regulation by punishment of cocaine use. The fact that cocaine addicts continue cocaine use despite potential severe punishment suggests that the mechanism may be impaired. Such impairment is expected to critically contribute to compulsive cocaine use. This study aimed to test the hypothesis that the central nucleus of amygdala (CeN) plays a critical role in such regulation. To this end, rats were trained to press a lever to self-administer cocaine under a chained schedule: a response on one lever (cocaine-seeking lever) led to access to the other lever (cocaine-taking lever) on which a response was reinforced by cocaine and cues. Thereafter, responses on the seeking lever were punished by footshock with a probability of 0.5. Cocaine self-administration (SA) was significantly suppressed by punishment in an intensity-dependent manner. Interestingly, rats trained with daily 6-h (extended access) but not 2-h (limited access) sessions showed resistance to the lower intensity of punishment. Inactivation of the CeN induced a robust anti-punishment effect in both groups. These data provided evidence that the CeN is a critical neural substrate involved in regulation by punishment of cocaine SA. Rats with a history of extended cocaine SA appeared to be less sensitive to punishment. The decreased sensitivity could result from the neuroplastic changes induced by extended cocaine SA in the CeN. PMID:22304754

Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations.

PubMed

Zhang, Yuxin; Huang, Xiaoqin; Han, Keli; Zheng, Fang; Zhan, Chang-Guo

2016-11-25

The combined molecular dynamics (MD) and potential of mean force (PMF) simulations have been performed to determine the free energy profile of the CocE)-(+)-cocaine binding process in comparison with that of the corresponding CocE-(-)-cocaine binding process. According to the MD simulations, the equilibrium CocE-(+)-cocaine binding mode is similar to the CocE-(-)-cocaine binding mode. However, based on the simulated free energy profiles, a significant free energy barrier (∼5 kcal/mol) exists in the CocE-(+)-cocaine binding process whereas no obvious free energy barrier exists in the CocE-(-)-cocaine binding process, although the free energy barrier of ∼5 kcal/mol is not high enough to really slow down the CocE-(+)-cocaine binding process. In addition, the obtained free energy profiles also demonstrate that (+)-cocaine and (-)-cocaine have very close binding free energies with CocE, with a negligible difference (∼0.2 kcal/mol), which is qualitatively consistent with the nearly same experimental K M values of the CocE enzyme for (+)-cocaine and (-)-cocaine. The consistency between the computational results and available experimental data suggests that the mechanistic insights obtained from this study are reasonable. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Brain imaging studies of the cocaine addict: Implications for reinforcement and addiction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Fowler, J.S.

1995-07-01

These studies document dopaminergic abnormalities in cocaine abusers. They also suggest a regulatory role of Dopamine (DA) in frontal metabolism. The correlation of striatal D{sub 2} receptor availability with metabolism was strongest for orbital frontal cortex (OFC) cingulate and prefrontal cortices. In cocaine abusers tested during early withdrawal (<1 week) the OFC was found to be hypermetabolic and metabolism in OFC and prefrontal cortices were found to be significantly associated with cocaine craving . Thus, we postulate that repeated and intermittent DA stimulation, as seen during a cocaine binge, activates the prefrontal and OFC cortices increasing the drive to compulsivelymore » self-administer cocaine. During cocaine discontinuation and protracted withdrawal and with decreased DA stimulation, these frontal cortical regions become hyponietabolic. Dopaminergic stimulation by a DA-enhancing drug and/or environmental conditioning will reactivate these frontal regions resetting the compulsion to self-administer cocaine and the inability to terminate this behavior. The pharmacokionetic studies with [11C]cocaine are consistent with behavioral and pharmacological studies in animals as well as in vitro studies which have revealed that while the mechanisms for cocaine`s reinforcing properties are complex, they partly involve the brain`s dopamine system and also highlight the importance of cocaine`s pharmacokinetic on its unique reinforcing properties.« less

Reinstatement in a Cocaine vs. Food Choice Situation: Reversal of Preference between Drug and Non-Drug Rewards

PubMed Central

Tunstall, Brendan J.; Kearns, David N.

2013-01-01

Recent studies (for review see Ahmed, 2010; 2012) show that when given a mutually exclusive choice between cocaine and food, rats almost exclusively choose food. The present experiment investigated potential shifts in preference between levers associated with either food or cocaine which might occur during extinction (food and cocaine no longer available) and during footshock-induced, cocaine-primed, and food-primed reinstatement. During self-administration sessions where food and cocaine were simultaneously available, rats demonstrated a stable food preference, choosing food over cocaine on 83% of trials. During extinction when neither reinforcer was available, no preference between levers was evident and responding decreased until rats responded on the previously food- and cocaine-associated levers at equally low rates. Footshock resulted in a non-specific reinstatement of responding upon both levers, while cocaine priming resulted in a significant preference for cocaine seeking over food seeking. This suggests that the mechanism underlying footshock-induced reinstatement is distinct from that of cocaine-primed reinstatement. Food priming engendered a mild, non-specific increase in responding on both levers. Although rats generally prefer food over cocaine when presented with a choice between these primary reinforcers, the present results suggest that in certain situations cocaine-seeking behavior prevails over food-seeking behavior. PMID:23551949

Hippocampal Regulation of Contextual Cue-Induced Reinstatement of Cocaine-Seeking Behavior

PubMed Central

Atkins, Alison L.; Mashhoon, Yasmin; Kantak, Kathleen M.

2008-01-01

Associations between cocaine and cues facilitate development and maintenance of addiction. We hypothesized that the ventral hippocampus is important for acquisition of these associations. Rats were trained to self-administer cocaine, with or without pre-exposure to distinct sets of cocaine- and saline-paired contextual cues. Next, rats were conditioned for 3 days with the distinct sets of contextual cues paired with cocaine and saline along with distinct discrete cues. Vehicle or lidocaine was infused into the ventral hippocampus prior to conditioning sessions. Following extinction, reinstatement of cocaine-seeking behavior was examined following exposure to contextual cues, discrete cues, or their combination. Inactivation of the ventral hippocampus during conditioning blocked acquisition of the association between cocaine and cocaine-paired contextual cues in that only lidocaine-treated rats with short-term cue exposure failed to reinstate responding in the presence of cocaine-paired contextual cues. Lidocaine also prevented rats in both cue exposure groups from discriminating between cocaine-and saline-paired contextual cues during reinstatement tests. Reinstatement induced by cocaine-paired discrete cues or by contextual and discrete cues together was not impaired for either cue exposure condition. The hippocampus is important for acquisition of the association between cocaine and context and in maintaining discrimination between cocaine-relevant and -irrelevant contextual cues. PMID:18499239

Bradycardia as a Marker of Chronic Cocaine Use: A Novel Cardiovascular Finding.

PubMed

Sharma, Jyoti; Rathnayaka, Nuvan; Green, Charles; Moeller, F Gerard; Schmitz, Joy M; Shoham, Daniel; Dougherty, Anne Hamilton

2016-01-01

Few studies have examined the effects of chronic cocaine use on the resting surface electrocardiogram (ECG) between exposures to cocaine. Researchers compared 12-lead ECGs from 97 treatment-seeking cocaine-dependent patients, with ECG parameters from 8,513 non-cocaine-using control patients from the Atherosclerosis Risk in Communities study. After matching and adjusting for relevant covariates, cocaine use demonstrated large and statistically reliable effects on early repolarization, bradycardia, severe bradycardia, and heart rate. Current cocaine dependence corresponds to an increased odds of demonstrating early repolarization by a factor of 4.92 and increased odds of bradycardia and severe bradycardia by factors 3.02 and 5.11, respectively. This study demonstrates the novel finding that long-lasting effects of cocaine use on both the cardiac conduction and the autonomic nervous system pose a risk of adverse cardiovascular events between episodes of cocaine use, and that bradycardia is a marker of chronic cocaine use.

Cocaine, Appetitive Memory and Neural Connectivity

PubMed Central

Ray, Suchismita

2013-01-01

This review examines existing cognitive experimental and brain imaging research related to cocaine addiction. In section 1, previous studies that have examined cognitive processes, such as implicit and explicit memory processes in cocaine users are reported. Next, in section 2, brain imaging studies are reported that have used chronic users of cocaine as study participants. In section 3, several conclusions are drawn. They are: (a) in cognitive experimental literature, no study has examined both implicit and explicit memory processes involving cocaine related visual information in the same cocaine user, (b) neural mechanisms underlying implicit and explicit memory processes for cocaine-related visual cues have not been directly investigated in cocaine users in the imaging literature, and (c) none of the previous imaging studies has examined connectivity between the memory system and craving system in the brain of chronic users of cocaine. Finally, future directions in the field of cocaine addiction are suggested. PMID:25009766

Demand Curves for Hypothetical Cocaine in Cocaine-Dependent Individuals

PubMed Central

Bruner, Natalie R.; Johnson, Matthew W.

2013-01-01

Rationale Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. Objectives This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Methods Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Results Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and Omax (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, Pmax, were significantly correlated with real-world cocaine use. Conclusions Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use. PMID:24217899

TOPIRAMATE’S EFFECTS ON COCAINE-INDUCED SUBJECTIVE MOOD, CRAVING, AND PREFERENCE FOR MONEY OVER DRUG TAKING

PubMed Central

Johnson, Bankole A.; Roache, John D.; Ait-Daoud, Nassima; Gunderson, Erik W.; Haughey, Heather M.; Wang, Xin-Qun; Liu, Lei

2012-01-01

Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine’s abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving, and preference for cocaine over money induced by low and high doses (0.325 and 0.650 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university inpatient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square crossover design in which 3 experimental challenge doses of low-dose cocaine, high-dose cocaine, and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pretreatments separated by a 1-week washout period (2006–2009). After placebo pretreatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine, and monetary value of cocaine in a behavioral preference test of cocaine vs. money choice. Topiramate pretreatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria, and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine’s abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate’s prominent sedative effects. PMID:23039088

Response to novelty as a predictor of cocaine sensitization and conditioning in rats: a correlational analysis.

PubMed

Carey, Robert J; DePalma, Gail; Damianopoulos, Ernest

2003-07-01

An animal's response to novelty has been suggested to be a predictor of its response to drugs of abuse. The possible relationship between an individual's behavioral response to novelty and its subsequent behavioral response to cocaine has not been subjected to a detailed correlational analysis. To use a repeated cocaine treatment protocol to induce cocaine sensitization and conditioned cocaine locomotor stimulant effects and to assess the relationship of these effects to pre-cocaine locomotor behavior in a novel environment. In two separate experiments, rats were given a 20-min test in a novel open-field environment. Subsequently, the rats were given a series of additional tests in conjunction with either saline or cocaine (10 mg/kg) treatments to induce cocaine sensitization and conditioned effects. The repeated cocaine treatments induced cocaine behavioral sensitization and conditioned effects. Correlational analyses showed that the initial 20-min novel environment test proved to be a strong predictor of an animal's subsequent saline activity level but did not predict the rats' behavioral acute and sensitized response to cocaine. When change in activity was used as the dependent variable, initial activity level was reliably negatively correlated with activity changes on cocaine tests as well as cocaine conditioning tests. The negative correlation between initial activity in a novel environment and the change in activity induced by cocaine indicates that low responders to environmental novelty tend to have the strongest response to cocaine. These results appear consistent with the classic initial value and response rate dependent analyses of stimulant drug effects.

Cocaine adulteration.

PubMed

Kudlacek, Oliver; Hofmaier, Tina; Luf, Anton; Mayer, Felix P; Stockner, Thomas; Nagy, Constanze; Holy, Marion; Freissmuth, Michael; Schmid, Rainer; Sitte, Harald H

2017-10-01

Cocaine is a naturally occurring and illicitly used psychostimulant drug. Cocaine acts at monoaminergic neurotransmitter transporters to block uptake of the monoamines, dopamine, serotonin and norepinephrine. The resulting increase of monoamines in the extracellular space underlies the positively reinforcing effects that cocaine users seek. In turn, this increase in monoamines underlies the development of addiction, and can also result in a number of severe side effects. Currently, cocaine is one of the most common illicit drugs available on the European market. However, cocaine is increasingly sold in impure forms. This trend is driven by cocaine dealers seeking to increase their profit margin by mixing ("cutting") cocaine with numerous other compounds ("adulterants"). Importantly, these undeclared compounds put cocaine consumers at risk, because consumers are not aware of the additional potential threats to their health. This review describes adulterants that have been identified in cocaine sold on the street market. Their typical pharmacological profile and possible reasons why these compounds can be used as cutting agents will be discussed. Since a subset of these adulterants has been found to exert effects similar to cocaine itself, we will discuss levamisole, the most frequently used cocaine cutting agent today, and its metabolite aminorex. Copyright © 2017. Published by Elsevier B.V.

Experience-Dependent Effects of Cocaine Self-Administration/Conditioning on Prefrontal and Accumbens Dopamine Responses

PubMed Central

Ikegami, Aiko; Olsen, Christopher M.; D’Souza, Manoranjan S.; Duvauchelle, Christine L.

2008-01-01

Experiments were performed to examine the effects of cocaine self-administration and conditioning experience on operant behavior, locomotor activity, and nucleus accumbens (NAcc) and prefrontal cortex (PFC) dopamine (DA) responses. Sensory cues were paired with alternating cocaine and nonreinforcement during 12 (limited training) or 40 (long-term training) daily operant sessions. After limited training, NAcc DA responses to cocaine were significantly enhanced in the presence of cocaine-associated cues compared with nonreward cues and significantly depressed after cocaine-paired cues accompanied a nonreinforced lever response. PFC DA levels were generally nonresponsive to cues after the same training duration. However, after long-term training, cocaine-associated cues increased the magnitude of cocaine-stimulated PFC DA levels significantly over levels observed with nonreinforcement cues. Conversely, conditioned cues no longer influenced NAcc DA levels after long-term training. In addition, cocaine-stimulated locomotor activity was enhanced by cocaine-paired cues after long-term, but not after limited, training. Findings demonstrate that cue-induced cocaine expectation exerts a significant impact on dopaminergic and behavioral systems, progressing from mesolimbic to mesocortical regions and from latent to patent behaviors as cocaine and associative experiences escalate. PMID:17469929

Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones.

PubMed

Mendelson, J H; Mello, N K; Teoh, S K; Ellingboe, J; Cochin, J

1989-12-01

Pulse frequency analysis of LH, PRL, testosterone, and cortisol was carried out with the Cluster Analysis Program in eight male cocaine abusers and eight aged-matched normal men. Four of the eight cocaine abusers had hyperprolactinemia (range, 22.08-44.65 micrograms/L). Cocaine users as a group had significantly higher mean peak height (P less than 0.02) than control subjects. Cocaine users with hyperprolactinemia had higher mean peak height than control subjects or cocaine users with normal PRL levels (P less than 0.01). Cocaine users with hyperprolactinemia also had higher mean amplitude increments than control subjects (P less than 0.02). Cocaine users with hyperprolactinemia had a higher mean valley than controls (P less than 0.01) and cocaine users with normal PRL levels (P less than 0.03). However, there were no significant differences in PRL peak frequency, peak duration, or interpulse intervals between cocaine users with or without hyperprolactinemia and control subjects. There were minimal differences between cocaine users and control subjects in pulse frequency analysis of LH parameters; the small differences in mean LH levels and average interpulse interval were not in the abnormal range and were probably not biologically significant. No differences between cocaine users and controls were detected for pulse frequency analysis of testosterone or cortisol. Cocaine-induced hyperprolactinemia may contribute to disorders of sexual and reproductive function in men who abuse the drug, and recent reports that PRL modulates immune function suggest that cocaine-induced derangements of PRL secretion may also contribute to cocaine-related comorbidity in infectious disease. Since cocaine users with hyperprolactinemia had a higher mean valley as well as a higher peak pulse PRL height than control subjects, but did not have greater PRL pulse frequencies, we conclude that hyperprolactinemia in these men may be due to a cocaine-induced derangement of dopaminergic inhibition of basal PRL secretion.

Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence

PubMed Central

Dürsteler, Kenneth M; Berger, Eva-Maria; Strasser, Johannes; Caflisch, Carlo; Mutschler, Jochen; Herdener, Marcus; Vogel, Marc

2015-01-01

Background Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. Aim To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. Methods We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. Results MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder. Conclusion Clinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research. PMID:26124696

Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

PubMed Central

Maloney, Thomas; Parvaz, Muhammad A.; Alia-Klein, Nelly; Woicik, Patricia A.; Telang, Frank; Wang, Gene-Jack; Volkow, Nora D.; Goldstein, Rita Z.

2010-01-01

Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects’ self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes. PMID:20395264

The Extracellular Matrix Protein Brevican Limits Time-Dependent Enhancement of Cocaine Conditioned Place Preference.

PubMed

Lubbers, Bart R; Matos, Mariana R; Horn, Annemarie; Visser, Esther; Van der Loo, Rolinka C; Gouwenberg, Yvonne; Meerhoff, Gideon F; Frischknecht, Renato; Seidenbecher, Constanze I; Smit, August B; Spijker, Sabine; van den Oever, Michel C

2016-06-01

Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting memories of cocaine reward. During periods of abstinence, responding to cocaine cues can time-dependently intensify a phenomenon referred to as 'incubation of cocaine craving'. Here, we investigated the role of the extracellular matrix protein brevican in recent (1 day after training) and remote (3 weeks after training) expression of cocaine conditioned place preference (CPP). Wild-type and Brevican heterozygous knock-out mice, which express brevican at ~50% of wild-type levels, received three cocaine-context pairings using a relatively low dose of cocaine (5 mg/kg). In a drug-free CPP test, heterozygous mice showed enhanced preference for the cocaine-associated context at the remote time point compared with the recent time point. This progressive increase was not observed in wild-type mice and it did not generalize to contextual-fear memory. Virally mediated overexpression of brevican levels in the hippocampus, but not medial prefrontal cortex, of heterozygous mice prevented the progressive increase in cocaine CPP, but only when overexpression was induced before conditioning. Post-conditioning overexpression of brevican did not affect remote cocaine CPP, suggesting that brevican limited the increase in remote CPP by altering neuro-adaptive mechanisms during cocaine conditioning. We provide causal evidence that hippocampal brevican levels control time-dependent enhancement of cocaine CPP during abstinence, pointing to a novel substrate that regulates incubation of responding to cocaine-associated cues.

Self-reported cue-induced physical symptoms of craving as an indicator of cocaine dependence.

PubMed

Vorspan, Florence; Fortias, Maeva; Zerdazi, El-Hadi; Karsinti, Emily; Bloch, Vanessa; Lépine, Jean-Pierre; Bellivier, Frank; Brousse, Georges; van den Brink, Wim; Derks, Eske M

2015-12-01

The presence of cocaine dependence is under-recognized by cocaine users and requires a careful standardized interview to be ascertained by clinicians. To test if past experiences of cue-induced physical symptoms of craving (nausea, vomiting, sweating, shaking, nervousness) before cocaine use could be a useful way to boost the diagnosis of cocaine dependence. A cross-sectional study of 221 cocaine users from several outpatient addiction treatment services in France, addressing the most severe period of cocaine use. DSM-IV cocaine dependence was determined with the MINI International Neuropsychiatric Interview (MINI). Physical symptoms before using cocaine were retrospectively assessed with a single item rated on a 0-5 scale. The prevalence of DSM-IV cocaine dependence was 84.6%. The mean score on the physical symptoms item was 1.3 (SD 1.3). A cut-off score of ≥ 1 on this item alone resulted in a sensitivity of 62%, a specificity of 88.2%, a positive predictive value of 96.6% and a negative predictive value of 29.7% to detect DSM IV cocaine dependence in this sample. Adding this item to a model with the frequency of cocaine use significantly increased the predictive power: Nagelkerke's R(2) increased from .149 to .326 (p < .001). Recalling past experiences of cue-induced physical signs of cocaine craving is associated with a clinical diagnosis of lifetime cocaine dependence and could be a simple way to improve its detection in clinical settings. © American Academy of Addiction Psychiatry.

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference*

PubMed Central

Mannangatti, Padmanabhan; NarasimhaNaidu, Kamalakkannan; Damaj, Mohamad Imad; Ramamoorthy, Sammanda; Jayanthi, Lankupalle Damodara

2015-01-01

The noradrenergic and p38 mitogen-activated protein kinase (p38 MAPK) systems are implicated in cocaine-elicited behaviors. Previously, we demonstrated a role for p38 MAPK-mediated norepinephrine transporter (NET) Thr30 phosphorylation in cocaine-induced NET up-regulation (Mannangatti, P., Arapulisamy, O., Shippenberg, T. S., Ramamoorthy, S., and Jayanthi, L. D. (2011) J. Biol. Chem. 286, 20239–20250). The present study explored the functional interaction between p38 MAPK-mediated NET regulation and cocaine-induced behaviors. In vitro cocaine treatment of mouse prefrontal cortex synaptosomes resulted in enhanced NET function, surface expression, and phosphorylation. Pretreatment with PD169316, a p38 MAPK inhibitor, completely blocked cocaine-mediated NET up-regulation and phosphorylation. In mice, in vivo administration of p38 MAPK inhibitor SB203580 completely blocked cocaine-induced NET up-regulation and p38 MAPK activation in the prefrontal cortex and nucleus accumbens. When tested for cocaine-induced locomotor sensitization and conditioned place preference (CPP), mice receiving SB203580 on cocaine challenge day or on postconditioning test day exhibited significantly reduced cocaine sensitization and CPP. A transactivator of transcription (TAT) peptide strategy was utilized to test the involvement of the NET-Thr30 motif. In vitro treatment of synaptosomes with TAT-NET-Thr30 (wild-type peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In vivo administration of TAT-NET-Thr30 peptide but not TAT-NET-T30A (mutant peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In the cocaine CPP paradigm, mice receiving TAT-NET-Thr30 but not TAT-NET-T30A on postconditioning test day exhibited significantly reduced cocaine CPP. Following extinction, TAT-NET-Thr30 when given prior to cocaine challenge significantly reduced reinstatement of cocaine CPP. These results demonstrate that the direct inhibition of p38 MAPK or the manipulation of NET-Thr30 motif/phosphorylation via a TAT peptide strategy prevents cocaine-induced NET up-regulation, locomotor sensitization, and CPP, suggesting a role for Thr30-linked NET regulation in cocaine-elicited behaviors. PMID:25724654

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.J.; Fowler, J.S.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability the authors compared the levels of DAT occupancies that they had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography usingmore » [{sup 11}C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [{sup 11}C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd+1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockage of DAT with an estimated ED{sub 50} for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine.« less

Effects of levodopa-carbidopa-entacapone and smoked cocaine on facial affect recognition in cocaine smokers.

PubMed

Bedi, Gillinder; Shiffrin, Laura; Vadhan, Nehal P; Nunes, Edward V; Foltin, Richard W; Bisaga, Adam

2016-04-01

In addition to difficulties in daily social functioning, regular cocaine users have decrements in social processing (the cognitive and affective processes underlying social behavior) relative to non-users. Little is known, however, about the effects of clinically-relevant pharmacological agents, such as cocaine and potential treatment medications, on social processing in cocaine users. Such drug effects could potentially alleviate or compound baseline social processing decrements in cocaine abusers. Here, we assessed the individual and combined effects of smoked cocaine and a potential treatment medication, levodopa-carbidopa-entacapone (LCE), on facial emotion recognition in cocaine smokers. Healthy non-treatment-seeking cocaine smokers (N = 14; two female) completed this 11-day inpatient within-subjects study. Participants received LCE (titrated to 400mg/100mg/200mg b.i.d.) for five days with the remaining time on placebo. The order of medication administration was counterbalanced. Facial emotion recognition was measured twice during target LCE dosing and twice on placebo: once without cocaine and once after repeated cocaine doses. LCE increased the response threshold for identification of facial fear, biasing responses away from fear identification. Cocaine had no effect on facial emotion recognition. Results highlight the possibility for candidate pharmacotherapies to have unintended impacts on social processing in cocaine users, potentially exacerbating already existing difficulties in this population. © The Author(s) 2016.

Effects of cocaine on honey bee dance behaviour

PubMed Central

Barron, Andrew B.; Maleszka, Ryszard; Helliwell, Paul G.; Robinson, Gene E.

2009-01-01

Summary The role of cocaine as an addictive drug of abuse in human society is hard to reconcile with its ecological role as a natural insecticide and plant-protective compound, preventing herbivory of coca plants (Erythroxylum spp.). This paradox is often explained by proposing a fundamental difference in mammalian and invertebrate responses to cocaine, but here we show effects of cocaine on honey bees (Apis mellifera L.) that parallel human responses. Forager honey bees perform symbolic dances to advertise the location and value of floral resources to their nest mates. Treatment with a low dose of cocaine increased the likelihood and rate of bees dancing after foraging but did not otherwise increase locomotor activity. This is consistent with cocaine causing forager bees to overestimate the value of the floral resources they collected. Further, cessation of chronic cocaine treatment caused a withdrawal-like response. These similarities likely occur because in both insects and mammals the biogenic amine neuromodulator systems disrupted by cocaine perform similar roles as modulators of reward and motor systems. Given these analogous responses to cocaine in insects and mammals, we propose an alternative solution to the paradox of cocaine reinforcement. Ecologically, cocaine is an effective plant defence compound via disruption of herbivore motor control but, because the neurochemical systems targeted by cocaine also modulate reward processing, the reinforcing properties of cocaine occur as a `side effect'. PMID:19112134

Effects of cocaine on honey bee dance behaviour.

PubMed

Barron, Andrew B; Maleszka, Ryszard; Helliwell, Paul G; Robinson, Gene E

2009-01-01

The role of cocaine as an addictive drug of abuse in human society is hard to reconcile with its ecological role as a natural insecticide and plant-protective compound, preventing herbivory of coca plants (Erythroxylum spp.). This paradox is often explained by proposing a fundamental difference in mammalian and invertebrate responses to cocaine, but here we show effects of cocaine on honey bees (Apis mellifera L.) that parallel human responses. Forager honey bees perform symbolic dances to advertise the location and value of floral resources to their nest mates. Treatment with a low dose of cocaine increased the likelihood and rate of bees dancing after foraging but did not otherwise increase locomotor activity. This is consistent with cocaine causing forager bees to overestimate the value of the floral resources they collected. Further, cessation of chronic cocaine treatment caused a withdrawal-like response. These similarities likely occur because in both insects and mammals the biogenic amine neuromodulator systems disrupted by cocaine perform similar roles as modulators of reward and motor systems. Given these analogous responses to cocaine in insects and mammals, we propose an alternative solution to the paradox of cocaine reinforcement. Ecologically, cocaine is an effective plant defence compound via disruption of herbivore motor control but, because the neurochemical systems targeted by cocaine also modulate reward processing, the reinforcing properties of cocaine occur as a ;side effect'.

Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle.

PubMed

Feltenstein, Matthew W; See, Ronald E

2007-07-10

Previous studies have reported sex and estrous cycle-dependent differences in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues. However, the relationship between estradiol or progesterone levels and cocaine-seeking in a reinstatement model of relapse has not been explored. Thus, we examined changes in plasma hormone levels during cocaine-taking and -seeking behaviors in gonadally intact female rats. Rats self-administered cocaine (0.5mg/kg infusion) during daily 2-h sessions, followed by extinction. For reinstatement, cocaine (0, 5, or 10mg/kg, i.p.) was administered 30 min prior to testing. Vaginal smears and blood samples were collected prior to and during chronic cocaine self-administration, extinction, and reinstatement testing. Relative to non-estrous females, females in estrus showed greater responding during self-administration, extinction, and during cocaine-primed reinstatement. The highest progesterone levels were noted at the time of lowest cocaine-seeking (proestrus) and the lowest levels of progesterone occurred at the time of highest cocaine-seeking (estrus). In contrast, plasma estradiol levels did not show any clear pattern with cocaine-seeking. These data from an animal model of relapse supports recent clinical evidence that progesterone reduces subjective craving in cocaine-dependent women. Overall, these results suggest that progesterone administration may be a useful intervention for reducing the incidence of relapse.

Performance on a strategy set shifting task in rats following adult or adolescent cocaine exposure

PubMed Central

Kantak, Kathleen M.; Barlow, Nicole; Tassin, David H.; Brisotti, Madeline F.; Jordan, Chloe J

2014-01-01

Rationale Neuropsychological testing is widespread in adult cocaine abusers, but lacking in teens. Animal models may provide insight into age-related neuropsychological consequences of cocaine exposure. Objectives Determine whether developmental plasticity protects or hinders behavioral flexibility after cocaine exposure in adolescent vs. adult rats. Methods Using a yoked-triad design, one rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling cocaine delivery (1.0 mg/kg) self-administered for 18 sessions (starting P37 or P77), followed by 18 drug-free days. Rats next were tested in a strategy set shifting task, lasting 11–13 sessions. Results Cocaine self-administration did not differ between age groups. During initial set formation, adolescent-onset groups required more trials to reach criterion and made more errors than adult-onset groups. During the set shift phase, rats with adult-onset cocaine self-administration experience had higher proportions of correct trials and fewer perseverative + regressive errors than age-matched yoked-controls or rats with adolescent-onset cocaine self-administration experience. During reversal learning, rats with adult-onset cocaine experience (self-administered or passive) required fewer trials to reach criterion and the self-administering rats made fewer perseverative + regressive errors than yoked-saline rats. Rats receiving adolescent-onset yoked-cocaine had more trial omissions and longer lever press reaction times than age-matched rats self-administering cocaine or receiving yoked-saline. Conclusions Prior cocaine self-administration may impair memory to reduce proactive interference during set shifting and reversal learning in adult-onset but not adolescent-onset rats (developmental plasticity protective). Passive cocaine may disrupt aspects of executive function in adolescent-onset but not adult-onset rats (developmental plasticity hinders). PMID:24800898

Cocaine- and amphetamine-regulated transcript peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient over-expression of α-Ca2+ /calmodulin-dependent protein kinase II.

PubMed

Xiong, Lixia; Meng, Qing; Sun, Xi; Lu, Xiangtong; Fu, Qiang; Peng, Qinghua; Yang, Jianhua; Oh, Ki-Wan; Hu, Zhenzhen

2018-01-04

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca 2+ /calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. This study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca 2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-over-expressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca 2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-over-expressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-over-expressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. © 2018 International Society for Neurochemistry.

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats.

PubMed

Galaj, E; Ananthan, S; Saliba, M; Ranaldi, Robert

2014-02-01

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments. We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats. In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively. SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity. SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine's rewarding, incentive motivational and stimulant effects.

Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine.

PubMed

Simmler, Linda D; Anacker, Allison M J; Levin, Michael H; Vaswani, Nina M; Gresch, Paul J; Nackenoff, Alex G; Anastasio, Noelle C; Stutz, Sonja J; Cunningham, Kathryn A; Wang, Jing; Zhang, Bing; Henry, L Keith; Stewart, Adele; Veenstra-VanderWeele, Jeremy; Blakely, Randy D

2017-08-01

The psychostimulant cocaine induces complex molecular, cellular and behavioural responses as a consequence of inhibiting presynaptic dopamine, noradrenaline and 5-HT transporters. To elucidate 5-HT transporter (SERT)-specific contributions to cocaine action, we evaluated cocaine effects in the SERT Met172 knock-in mouse, which expresses a SERT coding substitution that eliminates high-affinity cocaine recognition. We measured the effects of SERT Met172 on cocaine antagonism of 5-HT re-uptake using ex vivo synaptosome preparations and in vivo microdialysis. We assessed SERT dependence of cocaine actions behaviourally through acute and chronic locomotor activation, sensitization, conditioned place preference (CPP) and oral cocaine consumption. We used c-Fos, quantitative RT-PCR and RNA sequencing methods for insights into cellular and molecular networks supporting SERT-dependent cocaine actions. SERT Met172 mice demonstrated functional insensitivity for cocaine at SERT. Although they displayed wild-type levels of acute cocaine-induced hyperactivity or chronic sensitization, the pattern of acute motor activation was different, with a bias toward thigmotaxis. CPP was increased, and a time-dependent elevation in oral cocaine consumption was observed. SERT Met172 mice displayed relatively higher levels of neuronal activation in the hippocampus, piriform cortex and prelimbic cortex (PrL), accompanied by region-dependent changes in immediate early gene expression. Distinct SERT-dependent gene expression networks triggered by acute and chronic cocaine administration were identified, including PrL Akt and nucleus accumbens ERK1/2 signalling. Our studies reveal distinct SERT contributions to cocaine action, reinforcing the possibility of targeting specific aspects of cocaine addiction by modulation of 5-HT signalling. © 2017 The British Pharmacological Society.

Discriminative Stimulus Effects of Binary Drug Mixtures: Studies with Cocaine, MDPV, and Caffeine.

PubMed

Collins, Gregory T; Abbott, Megan; Galindo, Kayla; Rush, Elise L; Rice, Kenner C; France, Charles P

2016-10-01

Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4-methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra-additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1:1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3:1 and 1:3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine. U.S. Government work not protected by U.S. copyright.

Sex differences in selecting between food and cocaine reinforcement are mediated by estrogen.

PubMed

Kerstetter, Kerry A; Ballis, Maya A; Duffin-Lutgen, Stevie; Carr, Amanda E; Behrens, Alexandra M; Kippin, Tod E

2012-11-01

Cocaine-dependent women, relative to their male counterparts, report shorter cocaine-free periods and report transiting faster from first use to entering treatment for addiction. Similarly, preclinical studies indicate that female rats, particularly those in the estrus phase of their reproductive cycle, show increased operant responding for cocaine under a wide variety of schedules. Making maladaptive choices is a component of drug dependence, and concurrent reinforcement schedules that examine cocaine choice offers an animal model of the conditions of human drug use; therefore, the examination of sex differences in decision-making may be critical to understanding why women display a more severe profile of cocaine addiction than men. Accordingly, we assessed sex and estrous cycle differences in choice between food (45 mg grain pellets) and intravenous cocaine (0.4 or 1.0 mg/kg per infusion) reinforcement in male, female (freely cycling), and ovariectomized (OVX) females treated with either estrogen benzoate (EB; 5 μg per day) or vehicle. At both cocaine doses, intact female rats choose cocaine over food significantly more than male rats. However, the estrous cycle did not impact the level of cocaine choice in intact females. Nevertheless, OVX females treated with vehicle exhibited a substantially lower cocaine choice compared with those receiving daily EB or to intact females. These results demonstrate that intact females have a greater preference for cocaine over food compared with males. Furthermore, this higher preference is estrogen-dependent, but does not vary across the female reproductive cycle, suggesting that ovarian hormones regulate cocaine choice. The present findings indicate that there is a biological predisposition for females to forgo food reinforcement to obtain cocaine reinforcement, which may substantially contribute to women experiencing a more severe profile of cocaine addiction than men.

The cocaine cutting agent levamisole is frequently detected in cocaine users.

PubMed

Pope, Jeffrey D; Drummer, Olaf H; Schneider, Hans G

2018-06-21

Cocaine use in Australia is increasing, with approximately 2.5% of the surveyed population having used cocaine. In the USA, levamisole, a widely used anti-helminthic veterinary drug has been increasingly detected as a cutting agent in cocaine seizures. Levamisole is known to cause agranulocytosis in humans. We ascertained the prevalence of levamisole-adulterated cocaine, detectable in the urine from patients that had undergone a pathology request for a urine drug screen. We assayed routinely requested urines that were positive for cocaine on immunoassay with liquid chromatography high resolution quadrupole time of flight mass spectrometry (LC-QToF). We investigated available urine samples from a period of 2 years that had a positive result for cocaine. In addition, we examined samples that were below the cut-off for cocaine on immunoassay. Specimens were analysed for the presence of levamisole and other 'unknown' drugs. In the period under investigation the laboratory examined 3665 urine samples for cocaine: 1.4% (n = 51) of the samples were positive for cocaine by immunoassay and half of these (n = 26, 51%) were further examined by LC-QToF. In addition, we examined 10 samples that were negative by immunoassay (as defined by AS/NZS 4308:2008). Levamisole was detected in the urine of cocaine users in approximately 75% of cases. Other illicit drugs were also frequently found in this cohort. The most common illicit drugs detected were methamphetamine, ecstasy and cannabis. Australian cocaine is widely adulterated with levamisole. Cocaine users are at risk of levamisole related health problems in addition to the problems related to cocaine. Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anticocaine Vaccine

PubMed Central

Hicks, Martin J.; Kaminsky, Stephen M.; De, Bishnu P.; Rosenberg, Jonathan B.; Evans, Suzette M.; Foltin, Richard W.; Andrenyak, David M.; Moody, David E.; Koob, George F.; Janda, Kim D.; Ricart Arbona, Rodolfo J.; Lepherd, Michelle L.

2014-01-01

Abstract Cocaine use disorders are mediated by the cocaine blockade of the dopamine transporter in the central nervous system (CNS). On the basis of the concept that these effects could be obviated if cocaine were prevented from reaching its cognate receptors in the CNS, we have developed an anticocaine vaccine, dAd5GNE, based on a cocaine analog covalently linked to capsid proteins of an E1−E3− serotype 5 adenovirus. While the vaccine effectively blocks systemically administered cocaine from reaching the brain by mediating sequestration of the cocaine in the blood, the fact that cocaine also has significant peripheral effects raises concerns that vaccination-mediated redistribution could lead to adverse effects in the visceral organs. The distribution of systemically administered cocaine at a weight-adjusted typical human dose was evaluated along with cocaine metabolites in both dAd5GNE-vaccinated and control nonhuman primates. dAd5GNE sequestration of cocaine to the blood not only prevented cocaine access to the CNS, but also limited access of both the drug and its metabolites to other cocaine-sensitive organs. The levels of cocaine in the blood of vaccinated animals rapidly decreased, suggesting that while the antibody limits access of the drug and its active metabolites to the brain and sensitive organs of the periphery, it does not prolong drug levels in the blood compartment. Gross and histopathology of major organs found no vaccine-mediated untoward effects. These results build on our earlier measures of efficacy and demonstrate that the dAd5GNE vaccine-mediated redistribution of administered cocaine is not likely to impact the vaccine safety profile. PMID:24649839

Cocaine sensitization does not alter SP effects on locomotion or excitatory synaptic transmission in the NAc of rats.

PubMed

Kombian, Samuel B; Ananthalakshmi, Kethireddy V V; Zidichouski, Jeffrey A; Saleh, Tarek M

2012-02-01

Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of naïve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 ± 85.9% (n = 5) which further increased by 733.1 ± 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 ± 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP(5-11) (10-100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from naïve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in naïve rats, cocaine's effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine's effects are mimicked by SP. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Spontaneous Development of IgM Anti-Cocaine Antibodies in Habitual Cocaine Users: Effect on IgG Antibody Responses to a Cocaine Cholera Toxin B Conjugate Vaccine

PubMed Central

Orson, Frank M.; Rossen, Roger D.; Shen, Xiaoyun; Lopez, Angel Y.; Wu, Yan; Kosten, Thomas R.

2014-01-01

Background and Objectives In cocaine vaccine studies, only a minority of subjects made strong antibody responses. To investigate this issue, IgG and IgM antibody responses to cocaine and to cholera toxin B (CTB—the carrier protein used to enhance immune responses to cocaine) were measured in sera from the 55 actively vaccinated subjects in a Phase IIb randomized double-blind placebo-controlled trial (TA-CD 109). Methods Isotype specific ELISAs were used to measure IgG and IgM anti-cocaine and anti-CTB antibody in serial samples collected prior to and at intervals after immunization. We assessed IgG anti-cocaine responses of patients with pre-vaccination IgM anti-cocaine antibodies. Competitive inhibition ELISA was used to evaluate antibody specificity. Results and Conclusions Before immunization, 36/55 subjects had detectable IgM antibodies to cocaine, and 9 had IgM levels above the 95% confidence limit of 11 µg/ml. These nine had significantly reduced peak IgG anti-cocaine responses at 16 weeks, and all were below the concentration (40 µg/ml) considered necessary to discourage recreational cocaine use. The IgG anti-CTB responses of these same subjects were also reduced. Scientific Significance Subjects who develop an IgM antibody response to cocaine in the course of repeated recreational exposure to this drug are significantly less likely to produce high levels of IgG antibodies from the cocaine conjugate vaccine. The failure may be due to recreational cocaine exposure induction of a type 2 T-cell independent immune response. Such individuals will require improved vaccines and are poor candidates for the currently available vaccine. PMID:23414504

Glycogen synthase kinase 3β in the basolateral amygdala is critical for the reconsolidation of cocaine reward memory.

PubMed

Wu, Ping; Xue, Yan-Xue; Ding, Zeng-Bo; Xue, Li-Fen; Xu, Chun-Mei; Lu, Lin

2011-07-01

Exposure to cocaine-associated conditioned stimuli elicits craving and increases the probability of cocaine relapse in cocaine users even after extended periods of abstinence. Recent evidence indicates that cocaine seeking can be inhibited by disrupting the reconsolidation of the cocaine cue memories and that basolateral amygdala (BLA) neuronal activity plays a role in this effect. Previous studies demonstrated that glycogen synthase kinase 3β (GSK-3β) plays a role in the reconsolidation of fear memory. Here, we used a conditioned place preference procedure to examine the role of GSK-3β in the BLA in the reconsolidation of cocaine cue memories. GSK-3β activity in the BLA, but not central amygdala (CeA), in rats that acquired cocaine (10 mg/kg)-induced conditioned place preference increased after re-exposure to a previously cocaine-paired chamber (i.e., a memory reactivation procedure). Systemic injections of the GSK-3β inhibitor lithium chloride after memory reactivation impaired the reconsolidation of cocaine cue memories and inhibited subsequent cue-induced GSK-3β activity in the BLA. Basolateral amygdala, but not central amygdala, injections of SB216763, a selective inhibitor of GSK-3β, immediately after the reactivation of cocaine cue memories also disrupted cocaine cue memory reconsolidation and prevented cue-induced increases in GSK-3β activity in the BLA. The effect of SB216763 on the reconsolidation of cocaine cue memories lasted at least 2 weeks and was not recovered by a cocaine priming injection. These results indicate that GSK-3β activity in the BLA mediates the reconsolidation of cocaine cue memories. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Context-dependent efficacy of a counter-conditioning strategy with atypical neuroleptic drugs in mice previously sensitized to cocaine.

PubMed

Oliveira-Lima, A J; Marinho, Eav; Santos-Baldaia, R; Hollais, A W; Baldaia, M A; Talhati, F; Ribeiro, L T; Wuo-Silva, R; Berro, L F; Frussa-Filho, R

2017-02-06

We have previously demonstrated that treatment with ziprasidone and aripiprazole selectively inhibit the development of behavioral sensitization to cocaine in mice. We now investigate their effects on a counter-conditioning strategy in mice and the importance of the treatment environment for this phenomenon. Evaluate the context-specificity of ziprasidone and aripiprazole on conditioned locomotion to cocaine and cocaine-induced hyperlocomotion and behavioral sensitization in a counter-conditioning strategy in mice. Animals were sensitized with saline or cocaine injections in the open-field apparatus in a 15-day intermittent treatment and subsequently treated with vehicle, 5mg/kg ziprasidone or 0.1mg/kg aripiprazole paired to the open-field or the home-cage for 4 alternate days. Mice were then challenged with saline and cocaine in the open-field apparatus on subsequent days. While treatment with ziprasidone decreased spontaneous locomotion and conditioned locomotion alike, treatment with aripiprazole specifically attenuated the expression of conditioned hyperlocomotion to cocaine. Ziprasidone and aripiprazole had no effects on cocaine-induced conditioned hyperlocomotion observed during saline challenge after drug withdrawal. Treatment with either ziprasidone or aripiprazole when previously given in the cocaine-paired environment attenuated the subsequent expression of behavioral sensitization to cocaine. Animals treated with aripiprazole in the open-field, but not in the home-cage, showed a blunted response to cocaine when receiving a cocaine challenge for the first time. Both neuroleptic drugs showed a context-dependent effectiveness in attenuating long-term expression of cocaine-induced behavioral sensitization when administered in the cocaine-associated environment, with aripiprazole also showing effectiveness in blocking the expression of acute cocaine effects. Copyright © 2016. Published by Elsevier Inc.

Sex Differences in Selecting Between Food and Cocaine Reinforcement are Mediated by Estrogen

PubMed Central

Kerstetter, Kerry A; Ballis, Maya A; Duffin-Lutgen, Stevie; Carr, Amanda E; Behrens, Alexandra M; Kippin, Tod E

2012-01-01

Cocaine-dependent women, relative to their male counterparts, report shorter cocaine-free periods and report transiting faster from first use to entering treatment for addiction. Similarly, preclinical studies indicate that female rats, particularly those in the estrus phase of their reproductive cycle, show increased operant responding for cocaine under a wide variety of schedules. Making maladaptive choices is a component of drug dependence, and concurrent reinforcement schedules that examine cocaine choice offers an animal model of the conditions of human drug use; therefore, the examination of sex differences in decision-making may be critical to understanding why women display a more severe profile of cocaine addiction than men. Accordingly, we assessed sex and estrous cycle differences in choice between food (45 mg grain pellets) and intravenous cocaine (0.4 or 1.0 mg/kg per infusion) reinforcement in male, female (freely cycling), and ovariectomized (OVX) females treated with either estrogen benzoate (EB; 5 μg per day) or vehicle. At both cocaine doses, intact female rats choose cocaine over food significantly more than male rats. However, the estrous cycle did not impact the level of cocaine choice in intact females. Nevertheless, OVX females treated with vehicle exhibited a substantially lower cocaine choice compared with those receiving daily EB or to intact females. These results demonstrate that intact females have a greater preference for cocaine over food compared with males. Furthermore, this higher preference is estrogen-dependent, but does not vary across the female reproductive cycle, suggesting that ovarian hormones regulate cocaine choice. The present findings indicate that there is a biological predisposition for females to forgo food reinforcement to obtain cocaine reinforcement, which may substantially contribute to women experiencing a more severe profile of cocaine addiction than men. PMID:22871910

Discriminative Stimulus Effects of Binary Drug Mixtures: Studies with Cocaine, MDPV, and Caffeine

PubMed Central

Abbott, Megan; Galindo, Kayla; Rush, Elise L.; Rice, Kenner C.; France, Charles P.

2016-01-01

Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4-methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra-additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1:1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3:1 and 1:3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine. PMID:27493274

Monitoring cocaine use and abstinence among cocaine users for contingency management interventions.

PubMed

Holtyn, August F; Knealing, Todd W; Jarvis, Brantley P; Subramaniam, Shrinidhi; Silverman, Kenneth

2017-06-01

During contingency management interventions, reinforcement of cocaine abstinence is arranged by delivering an incentive when a urine sample tests cocaine-negative. The use of qualitative versus quantitative urinalysis testing may have important implications for effects on cocaine abstinence. Qualitative testing (i.e., testing that solely identifies whether a particular substance is present or absent) may not detect short-term cocaine abstinence because a single instance of cocaine use can result in cocaine-positive urine over many days. Quantitative testing (i.e., testing that identifies how much of a substance is present) may be more sensitive to short-term cocaine abstinence; however, the selection of a criterion for distinguishing new use versus carryover from previous use is an important consideration. The present study examined benzoylecgonine concentrations, the primary metabolite of cocaine, in urine samples collected three times per week for 30 weeks from 28 cocaine users who were exposed to a cocaine abstinence contingency. Of the positive urine samples (benzoylecgonine concentration >300 ng/ml), 29%, 21%, 14%, and 5% of the samples decreased in benzoylecgonine concentration by more than 20%, 40%, 60%, and 80% per day, respectively. As the size of the decrease increased, the likelihood of that sample occurring during a period leading to a cocaine-negative urine sample (benzoylecgonine concentration ≤300 ng/ml) also increased. The number of days required to produce a cocaine-negative sample following a positive sample ranged from 1 to 10 days and was significantly correlated with the starting benzoylecgonine level ( r = 0.43, p < 0.001). The present analyses may aid in the development of procedures that allow for the precise reinforcement of recent cocaine abstinence during contingency management interventions.

The effect of olanzapine pretreatment on acute cocaine toxicity in mice.

PubMed

Heard, Kennon J; Cleveland, Nathan R; Krier, Shay

2009-07-01

Acute cocaine poisoning causes neuroexcitation and can be fatal. The toxic effects of cocaine can be attenuated by antagonists of serotonin, muscarinic cholinergic, and dopamine receptors. Olanzapine, an atypical antipsychotic medication, is an antagonist of these receptors. The objective of this study is to evaluate the efficacy of olanzapine pretreatment for attenuation of acute cocaine toxicity using a mouse model. Eighty male CF-1 mice were randomly assigned to olanzapine (1 mg/kg) or placebo pretreatment. Fifteen minutes later, all animals received 103 mg/kg intraperitoneal cocaine. Overall mortality was 11% for olanzapine-treated animals and 45% for placebo. Olanzapine also appeared to alter the characteristics of seizures due to cocaine. In this model of acute cocaine toxicity, olanzapine pretreatment attenuated acute cocaine toxicity. Olanzapine should be evaluated further as a potential treatment for acute cocaine poisoning.

Bradycardia as a Marker of Chronic Cocaine Use: A Novel Cardiovascular Finding

PubMed Central

Sharma, Jyoti; Rathnayaka, Nuvan; Green, Charles; Moeller, F. Gerard; Schmitz, Joy M.; Shoham, Daniel; Dougherty, Anne Hamilton

2014-01-01

Background Few studies have examined the effects of chronic cocaine use on the resting surface electrocardiogram (ECG) between exposures to cocaine. Methods 12-lead ECGs from 97 treatment-seeking cocaine-dependent subjects were compared to ECG parameters from 8513 non-cocaine-using control subjects from the Atherosclerosis Risk in Communities study. Results After matching and adjusting for relevant covariates, cocaine use demonstrated large and statistically reliable effects on early repolarization, bradycardia, severe bradycardia, and heart rate. Current cocaine dependence corresponds to an increased odds of demonstrating early repolarization by a factor of 4.92 and increased odds of bradycardia and severe bradycardia by factors 3.02 and 5.11, respectively. Conclusion This study demonstrates the novel finding that long-lasting effects of cocaine use on both the cardiac conduction and the autonomic nervous system pose a risk of adverse cardiovascular events between episodes of cocaine use, and that bradycardia is a marker of chronic cocaine use. PMID:24621090

Probing active cocaine vaccination performance through catalytic and noncatalytic hapten design.

PubMed

Cai, Xiaoqing; Whitfield, Timothy; Hixon, Mark S; Grant, Yanabel; Koob, George F; Janda, Kim D

2013-05-09

Presently, there are no FDA-approved medications to treat cocaine addiction. Active vaccination has emerged as one approach to intervene through the rapid sequestering of the circulating drug, thus terminating both psychoactive effects and drug toxicity. Herein, we report our efforts examining two complementary, but mechanistically distinct active vaccines, i.e., noncatalytic and catalytic, for cocaine treatment. A cocaine-like hapten GNE and a cocaine transition-state analogue GNT were used to generate the active vaccines, respectively. GNE-KLH (keyhole limpet hemocyannin) was found to elicit persistent high-titer, cocaine-specific antibodies and blunt cocaine-induced locomotor behaviors. Catalytic antibodies induced by GNT-KLH were also shown to produce potent titers and suppress locomotor response in mice; however, upon repeated cocaine challenges, the vaccine's protecting effects waned. In depth kinetic analysis suggested that loss of catalytic activity was due to antibody modification by cocaine. The work provides new insights for the development of active vaccines for the treatment of cocaine abuse.

Probing Active Cocaine Vaccination Performance through Catalytic and Noncatalytic Hapten Design

PubMed Central

Cai, Xiaoqing; Whitfield, Timothy; Hixon, Mark S.; Grant, Yanabel; Koob, George F.; Janda, Kim D.

2013-01-01

Presently, there are no FDA-approved medications to treat cocaine addiction. Active vaccination has emerged as one approach to intervene through the rapid sequestering of the circulating drug, thus terminating both psychoactive effects and drug toxicity. Herein, we report our efforts examining two complimentary, but mechanistically distinct active vaccines, i.e., noncatalytic and catalytic, for cocaine treatment. A cocaine-like hapten GNE and a cocaine transition-state analogue GNT were used to generate the active vaccines, respectively. GNE-KLH was found to elicit persistent high-titer, cocaine-specific antibodies, and blunt cocaine induced locomotor behaviors. Catalytic antibodies induced by GNT-KLH were also shown to produce potent titers and suppress locomotor response in mice; however, upon repeated cocaine challenges the vaccine’s protecting effects waned. In depth kinetic analysis suggested that loss of catalytic activity was due to antibody modification by cocaine. The work provides new insights for the development of active vaccines for the treatment of cocaine abuse. PMID:23627877

Lack of behavioral sensitization to repeated cocaine administration from postnatal days 1 to 10.

PubMed

Meyer, J S; Yacht, A C

1993-09-01

This research determined whether sensitization (or tolerance) to the behavioral effects of cocaine in rat pups would occur following repeated cocaine administration. Rats were injected daily with 20 mg/kg of cocaine HCl s.c. from postnatal day 1 to day 10, injected with saline vehicle only, or left untreated during this period. On day 11, animals from each group were challenged with either 0, .625, 1.25, or 2.50 mg/kg of cocaine and their behavioral responses were recorded. Prior cocaine treatment did not influence the acute effects of cocaine on ultrasonic vocalizations or on any observed motor responses. In contrast, the cocaine- and saline-treated pups differed in a similar manner from the untreated control group on several behavioral measures. These results indicate that the sensitizing effects of repeated cocaine administration are not manifested during the neonatal period. However, the stimulation (stress) of handling and injection may alter the subsequent responsivity of infant rats to a cocaine challenge.

Personality risk factors for cocaine abuse.

PubMed

Yates, W R; Fulton, A I; Gabel, J M; Brass, C T

1989-07-01

To evaluate the role of personality in cocaine abuse, 59 adults meeting DSM-III criteria for cocaine abuse were compared to similar-aged non-cocaine alcohol abusers and community controls on a DSM-III measure of personality. Cocaine abusers were more likely than non-cocaine alcohol abusers to display narcissistic personality traits (Odds ratio 6.86, 95% CI = 4.52, 15.60). (Am J Public Health 1989; 79:891-892.

Maternal Cocaine Use and Mother-Toddler Aggression

PubMed Central

Eiden, Rina D.; Schuetze, Pamela; Colder, Craig; Veira, Yvette

2011-01-01

This study examined the direct and indirect associations between maternal cocaine use during pregnancy and mother-toddler aggression in an interactive context at 2 years of child age. We hypothesized that in addition to direct effects of cocaine exposure on maternal and child aggression, the association between maternal cocaine use and mother-toddler aggression may be indirect via higher maternal psychiatric symptoms, negative affect, or poor infant autonomic regulation at 13 months. Participants consisted of 220 (119 cocaine exposed, 101 non-cocaine exposed) mother-toddler dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that mothers who used cocaine during pregnancy displayed higher levels of aggression toward their toddlers compared to mothers in the control group. Results from model testing indicated significant indirect associations between maternal cocaine use and maternal aggression via higher maternal negative affect as well as lower infant autonomic regulation at 13 months. Although there were no direct associations between cocaine exposure and toddler aggression, there was a significant indirect effect via lower infant autonomic regulation at 13 months. Results highlight the importance of including maternal aggression in predictive models of prenatal cocaine exposure examining child aggression. Results also emphasize the important role of infant regulation as a mechanism partially explaining associations between cocaine exposure and mother-toddler aggression. PMID:21396441

Chronic cocaine disrupts neurovascular networks and cerebral function: optical imaging studies in rodents

NASA Astrophysics Data System (ADS)

Zhang, Qiujia; You, Jiang; Volkow, Nora D.; Choi, Jeonghun; Yin, Wei; Wang, Wei; Pan, Yingtian; Du, Congwu

2016-02-01

Cocaine abuse can lead to cerebral strokes and hemorrhages secondary to cocaine's cerebrovascular effects, which are poorly understood. We assessed cocaine's effects on cerebrovascular anatomy and function in the somatosensory cortex of the rat's brain. Optical coherence tomography was used for in vivo imaging of three-dimensional cerebral blood flow (CBF) networks and to quantify CBF velocities (CBFv), and multiwavelength laser-speckle-imaging was used to simultaneously measure changes in CBFv, oxygenated (Δ[HbO2]) and deoxygenated hemoglobin (Δ[HbR]) concentrations prior to and after an acute cocaine challenge in chronically cocaine exposed rats. Immunofluorescence techniques on brain slices were used to quantify microvasculature density and levels of vascular endothelial growth factor (VEGF). After chronic cocaine (2 and 4 weeks), CBFv in small vessels decreased, whereas vasculature density and VEGF levels increased. Acute cocaine further reduced CBFv and decreased Δ[HbO2] and this decline was larger and longer lasting in 4 weeks than 2 weeks cocaine-exposed rats, which indicates that risk for ischemia is heightened during intoxication and that it increases with chronic exposures. These results provide evidence of cocaine-induced angiogenesis in cortex. The CBF reduction after chronic cocaine exposure, despite the increases in vessel density, indicate that angiogenesis was insufficient to compensate for cocaine-induced disruption of cerebrovascular function.

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans.

PubMed

Newton, Thomas F; Haile, Colin N; Mahoney, James J; Shah, Ravi; Verrico, Christopher D; De La Garza, Richard; Kosten, Thomas R

2015-11-30

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. Published by Elsevier Ireland Ltd.

Post-Retrieval Extinction Attenuates Cocaine Memories

PubMed Central

Sartor, Gregory C; Aston-Jones, Gary

2014-01-01

Recent studies have shown that post-retrieval extinction training attenuates fear and reward-related memories in both humans and rodents. This noninvasive, behavioral approach has the potential to be used in clinical settings to treat maladaptive memories that underlie several psychiatric disorders, including drug addiction. However, few studies to date have used a post-retrieval extinction approach to attenuate addiction-related memories. In the current study, we attempted to disrupt cocaine-related memories by using the post-retrieval extinction paradigm in male Sprague Dawley rats. Results revealed that starting extinction training 1 h after cocaine contextual memory was retrieved significantly attenuated cocaine-primed reinstatement of conditioned place preference (CPP) and relapse of cocaine CPP (drug-free and cocaine-primed) following 30 days of abstinence. However, animals that did not retrieve the contextual cocaine memory before extinction training, or animals that began extinction training 24 h after retrieval (outside of the reconsolidation window), demonstrated normal cocaine CPP. Conversely, animals that received additional CPP conditioning, rather than extinction training, 1 h after reactivation of cocaine memory showed enhanced cocaine CPP compared with animals that did not reactivate the cocaine memory before conditioning. These results reveal that a behavioral manipulation that takes advantage of reconsolidation and extinction of drug memories may be useful in decreasing preference for, and abuse of, cocaine. PMID:24257156

Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo.

PubMed

Tallarida, Christopher S; Egan, Erin; Alejo, Gissel D; Raffa, Robert; Tallarida, Ronald J; Rawls, Scott M

2014-04-01

Levamisole is estimated by the Drug Enforcement Agency (DEA) to be present in about 80% of cocaine seized in the United States and linked to debilitating, and sometimes fatal, immunologic effects in cocaine abusers. One explanation for the addition of levamisole to cocaine is that it increases the amount of product and enhances profits. An alternative possibility, and one investigated here, is that levamisole alters cocaine's action in vivo. We specifically investigated effects of levamisole on cocaine's stereotypical and place-conditioning effects in an established invertebrate (planarian) assay. Acute exposure to levamisole or cocaine produced concentration-dependent increases in stereotyped movements. For combined administration of the two agents, isobolographic analysis revealed that the observed stereotypical response was enhanced relative to the predicted effect, indicating synergism for the interaction. In conditioned place preference (CPP) experiments, cocaine produced a significant preference shift; in contrast, levamisole was ineffective at all concentrations tested. For combination experiments, a submaximal concentration of cocaine produced CPP that was enhanced by inactive concentrations of levamisole, indicating synergism. The present results provide the first experimental evidence that levamisole enhances cocaine's action in vivo. Most important is the identification of synergism for the levamisole/cocaine interaction, which now requires further study in mammals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study.

PubMed

Kablinger, Anita S; Lindner, Marie A; Casso, Stephanie; Hefti, Franz; DeMuth, George; Fox, Barbara S; McNair, Lindsay A; McCarthy, Bruce G; Goeders, Nicholas E

2012-07-01

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.

Rearing environment differentially modulates cocaine self-administration after opioid pretreatment: A behavioral economic analysis.

PubMed

Hofford, Rebecca S; Beckmann, Joshua S; Bardo, Michael T

2016-10-01

Research has shown that previous experiences during development, especially if stressful, can alter an organism's response to opioids later in life. Given the previous literature on opioid modulation of cocaine self-administration, the current study raised rats in either an enriched condition (EC) or isolated condition (IC) and employed behavioral economics to study the effects of naltrexone and morphine on cocaine self-administration. EC and IC rats were trained to lever press for cocaine using a within-session demand procedure. This procedure measured cocaine consumption under changing cocaine price by decreasing the dose of cocaine earned throughout a session. Rats were able to self-administer cocaine on a FR1; every 10min the cocaine dose was systematically decreased (0.75-0.003mg/kg/infusion cocaine). After reaching stability on this procedure, rats were randomly pretreated with 0, 0.3, 1, or 3mg/kg naltrexone once every 3days, followed by random pretreatments of 0, 0.3, 1, or 3mg/kg morphine once every 3days. Economic demand functions were fit to each rat's cocaine consumption from each pretreatment, and appropriate mathematical parameters were extracted and analyzed. Naltrexone decreased the essential value of cocaine in IC rats only. However, morphine decreased the essential value of cocaine and the consumption of cocaine at zero price in both EC and IC rats. These results indicate that environmental experiences during development should be considered when determining the efficacy of opioid drugs, especially for the treatment of substance abuse. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The effects of social contact on cocaine intake in female rats.

PubMed

Robinson, Andrea M; Fronk, Gaylen E; Zhang, Huailin; Tonidandel, Scott; Smith, Mark A

2017-08-01

Studies conducted in male rats report that social contact can either facilitate or inhibit drug intake depending on the behavior of social partners. The purpose of the present study was to: (1) examine the effects of social contact on cocaine intake in female rats, (2) examine the behavioral mechanisms by which social contact influences cocaine intake, and (3) examine whether the estrous cycle moderates the effects of social contact on cocaine intake. Female rats were assigned to either isolated or pair-housed conditions in which a social partner either had access to cocaine (cocaine partner) or did not have access to cocaine (abstinent partner). Pair-housed rats were tested in custom-built operant conditioning chambers that allowed both rats to be tested simultaneously in the same chamber. Rats housed with a cocaine partner self-administered more cocaine than isolated rats and rats housed with an abstinent partner. A behavioral economic analysis indicated that these differences were driven by a greater intensity of cocaine demand (i.e., greater intake at lower unit prices) in rats housed with a cocaine partner. Multivariate modeling revealed that the estrous cycle did not moderate the effects of social contact on cocaine intake. These findings indicate that: (1) social contact influences cocaine self-administration in females in a manner similar to that reported in males, (2) these effects are due to differences in the effects of social contact on the intensity of cocaine demand, and (3) these effects are consistent across all phases of the estrous cycle. Copyright © 2017. Published by Elsevier B.V.

Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moeller, S.J.; Moeller, S.J.; Maloney, T.

Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessedmore » objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes.« less

Enhanced Choice for Viewing Cocaine Pictures in Cocaine Addiction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moeller, S.J.; Goldstein, R.; Moeller, S.J.

Individuals with cocaine use disorder (CUD) chose cocaine over nondrug rewards. In two newly designed laboratory tasks with pictures, we document this modified choice outside of a cocaine administration paradigm. Choice for viewing cocaine, pleasant, unpleasant, or neutral pictures-under explicit contingencies (choice made between two fully visible side-by-side images) and under more implicit contingencies (selections made between pictures hidden under flipped-over cards)-was examined in 20 CUD and 20 matched healthy control subjects. Subjects also provided self-reported ratings of each picture's pleasantness and arousal. Under both contingencies, CUD subjects chose to view more cocaine pictures than control subjects, group differences thatmore » were not fully explained by the self-reported picture ratings. Furthermore, whereas CUD subjects choice for viewing cocaine pictures exceeded choice for viewing unpleasant pictures (but did not exceed choice for viewing pleasant pictures, in contrast to their self-reported ratings), healthy control subjects avoided viewing cocaine pictures as frequently as, or even more than, unpleasant pictures. Finally, CUD subjects with the most cocaine viewing selections, even when directly compared with selections of the pleasant pictures, also reported the most frequent recent cocaine use. Enhanced drug-related choice in cocaine addiction can be demonstrated even for nonpharmacologic (pictorial) stimuli. This choice, which is modulated by alternative stimuli, partly transcends self-reports (possibly indicative of a disconnect in cocaine addiction between self-reports and objective behavior) to provide an objective marker of addiction severity. Neuroimaging studies are needed to establish the neural underpinnings of such enhanced cocaine-related choice.« less

Cocaine-specific Antibodies Blunt the Subjective Effects of Smoked Cocaine in Humans

PubMed Central

Haney, Margaret; Gunderson, Erik W.; Jiang, Huiping; Collins, Eric D.; Foltin, Richard W.

2012-01-01

Background Rates of relapse among cocaine-dependent patients are high, and new treatment approaches are needed. Clinical data demonstrate that a cocaine vaccine (TA-CD: Celtic Pharmaceutical) produces selective anti-cocaine antibodies, yet the impact of these antibodies on cocaine’s direct effects is unknown. The objective of this human laboratory study was to measure the relationship between antibody titers and the effects of smoked cocaine on ratings of intoxication, craving and cardiovascular effects. Methods Ten cocaine-dependent men not seeking drug treatment spent 2 nights per week for 13 weeks inpatient where the effects of cocaine (0, 25, 50 mg) were determined prior to vaccination and at weekly intervals thereafter. Two doses of TA-CD (82 µg, n=4; 360 µg, n=6) were administered at weeks 1, 3, 5 and 9. Results Peak plasma antibody levels, which were highly variable, significantly predicted cocaine’s effects. Those individuals in the upper half of antibody production had an immediate (within 4 minutes of cocaine smoking) and robust (55–81%) reduction in ratings of Good Drug Effect and Cocaine Quality, while those in the lower half showed only a nonsignificant attenuation (6–26%). Self-reported cocaine use while participants were outpatient tended to decrease as a function of antibody titer (p < 0.12). By contrast, higher antibody levels predicted significantly greater cocaine-induced tachycardia. Conclusions The TA-CD vaccine substantially decreased smoked cocaine’s intoxicating effects in those generating sufficient antibody. These data support further testing of cocaine immunotherapy as a treatment for cocaine dependence. PMID:19846066

Levamisole: a Common Adulterant in Cocaine Street Samples Hindering Electrochemical Detection of Cocaine.

PubMed

de Jong, Mats; Florea, Anca; Vries, Anne-Mare de; van Nuijs, Alexander L N; Covaci, Adrian; Van Durme, Filip; Martins, José C; Samyn, Nele; De Wael, Karolien

2018-04-17

The present work investigates the electrochemical determination of cocaine in the presence of levamisole, one of the most common adulterants found in cocaine street samples. Levamisole misleads cocaine color tests, giving a blue color (positive test) even in the absence of cocaine. Moreover, the electrochemical detection of cocaine is also affected by the presence of levamisole, with a suppression of the oxidation signal of cocaine. When levamisole is present in the sample in ratios higher than 1:1, the cocaine signal is no longer detected, thus leading to false negative results. Mass spectrometry and nuclear magnetic resonance were used to investigate if the signal suppression is due to the formation of a complex between cocaine and levamisole in bulk solution. Strategies to eliminate this suppressing effect are further suggested in this manuscript. In a first approach, the increase of the pH of the sample solution from pH 7 to pH 12 allowed the voltammetric determination of cocaine in the presence of levamisole in a concentration range from 10 to 5000 μM at nonmodified graphite disposable electrodes with a detection limit of 5 μM. In a second approach, the graphite electrode was cathodically pretreated, resulting in the presence of oxidation peaks of both cocaine and levamisole, with a detection limit for cocaine of 3 μM over the linear range of concentrations from 10 to 2500 μM. Both these strategies have been successfully applied for the simultaneous detection of cocaine and levamisole in three street samples on unmodified graphite disposable electrodes.

Extended cocaine-seeking produces a shift from goal-directed to habitual responding in rats.

PubMed

Leong, Kah-Chung; Berini, Carole R; Ghee, Shannon M; Reichel, Carmela M

2016-10-01

Cocaine addiction is often characterized by a rigid pattern of behavior in which cocaine users continue seeking and taking drug despite negative consequences associated with its use. As such, full acquisition and relapse of drug-seeking behavior may be attributed to a shift away from goal-directed responding and a shift towards the maladaptive formation of rigid and habit-like responses. This rigid nature of habitual responding can be developed with extended training and is typically characterized by insensitivity to changes in outcome value. The present study determined whether cocaine (primary reinforcer) and cocaine associated cues (secondary reinforcer) could be devalued in rats with different histories of cocaine self-administration. Specifically, rats were trained on two schedules of cocaine self-administration (long-access vs. short-access). Following training the cocaine reinforcer was devalued through three separate pairings of lithium chloride with cocaine infusions. Cocaine history did not have an impact on devaluation of cocaine-associated cues. However, the reinforcing properties of cocaine were devalued only in rats on a short-access cocaine schedule but not those trained on a long-access schedule. Taken together this pattern of findings suggests that, in short access rats, devaluation is specific to the primary reinforcer and not associative stimuli such as cues. Importantly, rats that received extended training during self-administration displayed insensitivity to outcome devaluation of the primary reinforcer as well as all associative stimuli, thus displaying rigid behavioral responding similar to behavioral patterns found in addiction. Alternatively, long access cocaine exposure may have altered the devaluation threshold. Copyright © 2016 Elsevier Inc. All rights reserved.

Ontogeny of cocaine-induced behaviors and cocaine pharmacokinetics in male and female neonatal, preweanling, and adult rats.

PubMed

McDougall, Sanders A; Apodaca, Matthew G; Mohd-Yusof, Alena; Mendez, Adrian D; Katz, Caitlin G; Teran, Angie; Garcia-Carachure, Israel; Quiroz, Anthony T; Crawford, Cynthia A

2018-04-18

Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to the maturation of dopaminergic elements (e.g., dopamine transporters, D2 High receptors, receptor coupling, etc.). The purpose of this study was to determine whether ontogenetic changes in cocaine pharmacokinetics might contribute to age-dependent differences in behavioral responsiveness. Male and female neonatal (PD 5), preweanling (PD 10 and PD 20), and adult (PD 70) rats were injected (IP) with cocaine or saline and various behaviors (e.g., locomotor activity, forelimb paddle, vertical activity, head-down sniffing, etc.) were measured for 90 min. In a separate experiment, the dorsal striata of young and adult rats were removed at 10 time points (0-210 min) after IP cocaine administration. Peak cocaine values, cocaine half-life, and dopamine levels were determined using HPLC. When converted to percent of saline controls, PD 5 and PD 10 rats were generally more sensitive to cocaine than older rats, but this effect varied according to the behavior being assessed. Peak cocaine values did not differ according to age or sex, but cocaine half-life in brain was approximately 2 times longer in PD 5 and PD 10 rats than adults. Cocaine pharmacokinetics did not differ between PD 20 and PD 70 rats. Differences in the cocaine-induced behavioral responsiveness of very young rats (PD 5 and PD 10) and adults may be attributable, at least in part, to pharmacokinetic factors; whereas, age-dependent behavioral differences between the late preweanling period and adulthood cannot readily be ascribed to cocaine pharmacokinetics.

Effects of self-administered cocaine in adolescent and adult male rats on orbitofrontal cortex-related neurocognitive functioning

PubMed Central

Harvey, Roxann C.; Dembro, Kimberly A.; Rajagopalan, Kiran; Mutebi, Michael M.; Kantak, Kathleen M.

2010-01-01

Rationale Deficits in amygdala-related stimulus-reward learning are produced following 18 drug-free days of cocaine self-administration or its passive delivery in rats exposed during adulthood. No deficits in stimulus-reward learning are produced by cocaine exposure initiated during adolescence. Objectives To determine if age of initiating cocaine exposure differentially affects behavioral functioning of an additional memory system linked to cocaine addiction, the orbitofrontal cortex. Materials and methods A yoked-triad design (n=8) was used. One rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling drug delivery (1.0 mg/kg) self-administered cocaine from either P37–P59 or P77–P99, and then underwent 18 drug-free days (P60–P77 vs. P100–P117). Rats next were tested for acquisition of odor-delayed win-shift behavior conducted over 15 sessions (P78–P96 vs. P118–P136). Results Cocaine self-administration did not differ between adults and adolescents. During the test phase of the odor-delayed win-shift task (relatively difficult task demands), rats from both drug-onset ages showed learning deficits. Rats with cocaine self-administration experience committed more errors and had longer session latencies compared to rats passively receiving saline or cocaine. Rats with adolescent-onset cocaine self-administration experience showed an additional learning deficit by requiring more sessions to reach criterion levels for task acquisition compared to same-aged passive saline controls or rats with adult-onset cocaine self-administration experience. Rats passively receiving cocaine did not differ from the passive saline control from either age group. Conclusions Rats with adolescent-onset cocaine self-administration experience were more impaired in an orbitofrontal cortex-related learning task than rats with adult-onset cocaine self-administration experience. PMID:19513699

Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory.

PubMed

Liu, Jian-Feng; Thorn, David A; Zhang, Yanan; Li, Jun-Xu

2016-07-01

As a modulator of dopaminergic system, trace amine-associated receptor 1 has been shown to play a critical role in regulating the rewarding properties of additive drugs. It has been demonstrated that activation of trace amine-associated receptor 1 decreased the abuse-related behaviors of cocaine in rats. However, the role of trace amine-associated receptor 1 in specific stages of cocaine reward memory is still unclear. Here, using a cocaine-induced conditioned place preference model, we tested the effects of a selective trace amine-associated receptor 1 agonist RO5166017 on the expression, reconsolidation, and extinction of cocaine reward memory. We found that RO5166017 inhibited the expression but not retention of cocaine-induced conditioned place preference. RO5166017 had no effect on the reconsolidation of cocaine reward memory. Pretreatment with RO5166017 before extinction hindered the formation of extinction long-term memory. RO5166017 did not affect the movement during the conditioned place preference test, indicating the inhibitory effect of RO5166017 on the expression of cocaine-induced conditioned place preference was not caused by locomotion inhibition. Using a cocaine i.v. self-administration model, we found that the combined trace amine-associated receptor 1 partial agonist RO5263397 with extinction had no effect on the following cue- and drug-induced reinstatement of cocaine-seeking behavior. Repeated administration of the trace amine-associated receptor 1 agonist during extinction showed a continually inhibitory effect on the expression of cocaine reward memory both in cocaine-induced conditioned place preference and cocaine self-administration models. Taken together, these results indicate that activation of trace amine-associated receptor 1 specifically inhibited the expression of cocaine reward memory. The inhibitory effect of trace amine-associated receptor 1 agonists on cocaine reward memory suggests that trace amine-associated receptor 1 agonists could be a promising agent to prevent cocaine relapse. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Anhydroecgonine methyl ester, a cocaine pyrolysis product, may contribute to cocaine behavioral sensitization.

PubMed

Garcia, Raphael Caio Tamborelli; Torres, Larissa Helena; Balestrin, Natália Trigo; Andrioli, Tatiana Costa; Flório, Jorge Camilo; de Oliveira, Carolina Dizioli Rodrigues; da Costa, José Luiz; Yonamine, Mauricio; Sandoval, Maria Regina Lopes; Camarini, Rosana; Marcourakis, Tania

2017-02-01

Crack cocaine has a high potential to induce cocaine addiction and its smoke contains cocaine's pyrolysis product anhydroecgonine methyl ester (AEME), a partial agonist at M 1 - and M 3 -muscarinic acetylcholine receptor and an antagonist at the remaining subtypes. No reports have assessed AEME's role in addiction. Adult male Wistar rats were intraperitoneally administered with saline, 3mg/kg AEME, 15mg/kg cocaine, or a cocaine-AEME combination on every other day during a period of 9 days. After a 7-days withdrawal period, a challenge injection of the respective drugs was performed on the 17th day. The locomotor activity was evaluated on days 1, 3, 5, 7, 9 and 17, as well as dopamine levels (9th day) and dopaminergic receptors proteins (D 1 R and D 2 R on the 17th day) in the caudate-putamen (CPu) and nucleus accumbens (NAc). AEME was not able to induce the expression of behavioral sensitization, but it substantially potentiates cocaine-effects, with cocaine-AEME combination presenting higher expression than cocaine alone. An increase in the dopamine levels in the CPu in all non-saline groups was observed, with the highest levels in the cocaine-AEME group. There was a decrease in D 1 R protein level in this brain region only for cocaine and cocaine-AEME groups. In the NAc, an increase in the dopamine levels was only observed for cocaine and cocaine-AEME groups, with no changes in both D 1 R and D 2 R protein levels. These behavioral and neurochemical data indicate that AEME alone does not elicit behavioral sensitization but it significantly potentiates cocaine effects when co-administered, resulting in dopamine increase in CPu and NAc, brain regions where dopamine release is mediated by cholinergic activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys.

PubMed

Schindler, Charles W; Justinova, Zuzana; Lafleur, David; Woods, Doug; Roschke, Viktor; Hallak, Hussein; Sklair-Tavron, Liora; Redhi, Godfrey H; Yasar, Sevil; Bergman, Jack; Goldberg, Steven R

2013-01-01

Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 µg/kg/injection) for over 24 hours. Pre-treatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative-stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Effects of chronic varenicline treatment on nicotine, cocaine, and concurrent nicotine+cocaine self-administration.

PubMed

Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J; Carroll, F Ivy

2014-04-01

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004-0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7-10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.

Effects of Chronic Varenicline Treatment on Nicotine, Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

PubMed Central

Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J; Carroll, F Ivy

2014-01-01

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004–0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7–10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine. PMID:24304823

Cocaine Abuse: The Evolution from Coca Leaves to Freebase.

ERIC Educational Resources Information Center

Forno, Joseph J.; And Others

1981-01-01

Describes historical and sociological patterns of cocaine use. Discusses cocaine as an example of a new drug abuse trend as users search for new ways of using old drugs in ways that produce enhanced euphoria. Describes the use of cocaine freebase and emergency treatment of cocaine toxicity. (Author)

Cocaine smuggling in the gastrointestinal tract resulting in mechanical pylorostenosis.

PubMed

Sein Anand, Jacek; Chodorowski, Zygmunt; Masal, Andrzej; Nowak-Banasik, Livia

2005-01-01

A 45-year-old male, body packer, who confessed to have swallowed 44 packages of cocaine in a total dose of approx. 360 g, was admitted to hospital because of clinical signs of acute intoxication with cocaine followed by ileus. The emergency surgical gastrotomy was initiated, and the conglomerate of Scotch tape and packages with cocaine were removed. Small rupture of one package of cocaine in a body packer stomach caused acute poisoning with cocaine, confirmed additionally by the presence of its metabolites in the urine. Mechanical pylorostenosis provoked by cocaine packages required emergency surgical operation.

Cocaine use and the breastfeeding mother.

PubMed

Jones, Wendy

2015-01-01

Cocaine is the second most commonly used illicit drug. Use in pregnancy and breastfeeding may have severe consequences for the baby due to its pharmacokinetic properties. Midwives need to be aware of the prolonged action of cocaine and be alert to the possibility of cocaine toxicity if a baby is excessively irritable and tachycardic. Euphoric highs are brief but breast milk and urine remain positive for long periods. Infant urine following exposure to cocaine via breast milk may remain positive for up to 60 hours. Mothers who snort cocaine should pump and dump breast milk for 24-48 hours. Passive inhalation of crack cocaine smoke may also result in infants with positive toxicology screens. Cocaine powder should never be applied to the nipples of breastfeeding mothers.

Malignant hypertension-associated thrombotic microangiopathy following cocaine use.

PubMed

Lamia, Rais; El Ati, Zohra; Ben Fatma, Lilia; Zouaghi, Karim; Smaoui, Wided; Rania, Khedher; Krid, Madiha; Ben Hmida, Fathi; Béji, Soumaya; Ben Moussa, Fatma

2016-01-01

Cocaine is one of the most commonly used illicit drugs with distribution and consumption throughout the world. Acute renal failure associated with rhabdomyolysis, direct vasoconstriction and hemodynamic alteration is well described in patients with cocaine intoxication. Cocaine use is associated with high blood pressure and may rarely induce malignant hypertension associated with thrombotic microangiopathy. We report the case of a patient who developed malignant hypertension associated with thrombotic microangiopathy after chronic consumption of cocaine. A kidney biopsy revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. He required dialysis sessions. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop malignant hypertension associated with thrombotic microangiopathy. Clinicians need to be aware of this rare feature of cocaine intoxication.

[Current pharmacotherapies and immunotherapy in cocaine addiction].

PubMed

Karila, Laurent; Weinstein, Aviv; Benyamina, Amine; Coscas, Sarah; Leroy, Claire; Noble, Florence; Lowenstein, William; Aubin, Henri-Jean; Lépine, Jean-Pierre; Reynaud, Michel

2008-04-01

Cocaine is more and more used and abused in France. Cocaine dependence is quite serious and is associated with numerous adverse health consequences. No effective pharmacotherapy for cocaine dependence is yet available. Recent advances in neurobiology, brain imaging and some clinical trials suggest that certain medications that modulate GABAergic, dopaminergic, and glutamatergic systems, as well as immunotherapy, show promise in the treatment of cocaine addiction. Recent controlled clinical studies have tested some of these drugs, which act on the various neurobiological circuits modified by cocaine exposure and clinically improve patients' symptoms. Pharmacological agents such as modafinil, GABAergic agents (baclofen, topiramate, tiagabin, and vigabatrin), disulfiram, aripiprazole, N-acetylcysteine and cocaine vaccine seem very promising in the treatment of cocaine dependence. However, this must be confirmed in larger patient populations.

Predicting the clinical efficacy and potential adverse effects of a humanized anticocaine monoclonal antibody

PubMed Central

Norman, Andrew B; Ball, William J

2012-01-01

The effects of a humanized monoclonal antibody (mAb) having high affinity and specificity for cocaine in animal models are reviewed. The mAb reduced the concentration of cocaine in the brain of mice after intravenous injection of cocaine. In addition, the mAb increased the concentration of cocaine required to reinstate cocaine self-administration. These effects may predict clinical efficacy of a passive immunotherapy for reducing the probability of cocaine-induced relapse. However, in the presence of the mAb, once cocaine self-administration was reinstated, the consumption rate of cocaine was increased. This effect is hypothesized to result from a pharmacokinetic/pharmacodynamic interaction. A humanized mAb should minimize adverse events related to the immunogenicity of the mAb protein, and the specificity for cocaine should avoid adverse events related to interactions with physiologically relevant endogenous proteins. PMID:22401638

DAT isn’t all that: cocaine reward and reinforcement requires Toll Like Receptor 4 signaling

PubMed Central

Northcutt, A.L.; Hutchinson, M.R.; Wang, X.; Baratta, M.V.; Hiranita, T.; Cochran, T.A.; Pomrenze, M.B.; Galer, E.L.; Kopajtic, T.A.; Li, C.M.; Amat, J.; Larson, G.; Cooper, D.C.; Huang, Y.; O’Neill, C.E.; Yin, H.; Zahniser, N.R.; Katz, J.L.; Rice, K.C.; Maier, S.F.; Bachtell, R.K.; Watkins, L.R.

2014-01-01

The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine’s ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-Like Receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment. PMID:25644383

Cocaine Versus Food Choice Procedure in Rats: Environmental Manipulations and Effects of Amphetamine

PubMed Central

Thomsen, Morgane; Barrett, Andrew C.; Negus, S. Stevens; Caine, S. Barak

2014-01-01

We have adapted a nonhuman primate model of cocaine versus food choice to the rat species. To evaluate the procedure, we tested cocaine versus food choice under a variety of environmental manipulations as well as pharmacological pretreatments. Complete cocaine-choice dose-effect curves (0–1.0 mg/kg/infusion) were obtained for each condition under concurrent fixed ratio schedules of reinforcement. Percentage of responding emitted on the cocaine-reinforced lever was not affected significantly by removal of cocaine-associated visual or auditory cues, but it was decreased after removal of response-contingent or response-independent cocaine infusions. Cocaine choice was sensitive to the magnitude and fixed ratio requirement of both the cocaine and food reinforcers. We also tested the effects of acute (0.32, 0.56, 1.0, 1.8 mg/kg) and chronic (0.1, 0.32 mg/kg/hr) d-amphetamine treatment on cocaine choice. Acute and chronic d-amphetamine had opposite effects, with acute increasing and chronic decreasing cocaine choice, similar to observations in humans and in nonhuman primates. The results suggest feasibility and utility of the choice procedure in rats and support its comparability to similar procedures used in humans and monkeys. PMID:23319458

Cocaine Shifts the Estrus Cycle Out of Phase and Caffeine Restores It

PubMed Central

Malave, Lauren B.

2014-01-01

Background: Sex differences in cocaine abuse are well established. Females have a higher sensitivity and thus higher vulnerability to cocaine abuse compared to males. There are many studies showing that sensitivity to cocaine reward varies during the estrus cycle. Methods: Vaginal smears were examined through a DIFF staining kit and viewed through a microscope to determine the estrus cycle stage. Smears were taken immediately before and after cocaine and/or caffeine injections. Furthermore, we suggest a new tool to analyze the estrus cycle by using electrical resistance of the vaginal mucosa. Results: In the present study, we discovered that cocaine directly induced changes in the estrus cycle. Interestingly, caffeine did not affect the estrus cycle and nor did the combination of cocaine and caffeine. We observed that caffeine blocked the cocaine-induced estrus cycle changes using conventional exfoliate cytology. Therefore, caffeine may have neuroprotective properties on the changes induced by cocaine. Conclusion: These phase changes in the estrus cycle may be the underlying cause of sex differences in cocaine addiction that can be blocked by caffeine. Thus, we propose a valuable insight into sex differences in cocaine abuse and reveal a possible treatment with antagonizing the adenosine system. PMID:25538863

Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

PubMed Central

Yamamoto, Dorothy J.; Nelson, Anna M.; Mandt, Bruce H.; Larson, Gaynor A.; Rorabaugh, Jacki M.; Ng, Christopher M.C.; Barcomb, Kelsey M.; Richards, Toni L.; Allen, Richard M.; Zahniser, Nancy R.

2013-01-01

Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors. PMID:23850581

Increased Depression and Anxiety Symptoms are Associated with More Breakdowns in Cognitive Control to Cocaine Cues in Veterans with Cocaine Use Disorder.

PubMed

DiGirolamo, Gregory J; Gonzalez, Gerardo; Smelson, David; Guevremont, Nathan; Andre, Michael I; Patnaik, Pooja O; Zaniewski, Zachary R

2017-01-01

Cue-elicited craving is a clinically important aspect of cocaine addiction directly linked to cognitive control breakdowns and relapse to cocaine-taking behavior. However, whether craving drives breakdowns in cognitive control toward cocaine cues in veterans, who experience significantly more co-occurring mood disorders, is unknown. The present study tests whether veterans have breakdowns in cognitive control because of cue-elicited craving or current anxiety or depression symptoms. Twenty-four veterans with cocaine use disorder were cue-exposed, then tested on an antisaccade task in which participants were asked to control their eye movements toward cocaine or neutral cues by looking away from the cue. The relationship among cognitive control breakdowns (as measured by eye errors), cue-induced craving (changes in self-reported craving following cocaine cue exposure), and mood measures (depression and anxiety) was investigated. Veterans made significantly more errors toward cocaine cues than neutral cues. Depression and anxiety scores, but not cue-elicited craving, were significantly associated with increased subsequent errors toward cocaine cues for veterans. Increased depression and anxiety are specifically related to more cognitive control breakdowns toward cocaine cues in veterans. Depression and anxiety must be considered further in the etiology and treatment of cocaine use disorder in veterans. Furthermore, treating depression and anxiety as well, rather than solely alleviating craving levels, may prove a more effective combined treatment option in veterans with cocaine use disorder.

Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats

PubMed Central

Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

2011-01-01

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaine-seeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior. PMID:22005750

Cognitive Impairment in Cocaine Users is Drug-Induced but Partially Reversible: Evidence from a Longitudinal Study

PubMed Central

Vonmoos, Matthias; Hulka, Lea M; Preller, Katrin H; Minder, Franziska; Baumgartner, Markus R; Quednow, Boris B

2014-01-01

Cocaine users consistently display cognitive impairments. However, it is still unknown whether these impairments are cocaine-induced and if they are reversible. Therefore, we examined the relation between changing intensity of cocaine use and the development of cognitive functioning within 1 year. The present data were collected as part of the longitudinal Zurich Cocaine Cognition Study (ZuCo2St). Forty-eight psychostimulant-naive controls and 57 cocaine users (19 with increased, 19 with decreased, and 19 with unchanged cocaine use) were eligible for analysis. At baseline and after a 1-year follow-up, cognitive performance was measured by a global cognitive index and four neuropsychological domains (attention, working memory, declarative memory, and executive functions), calculated from 13 parameters of a broad neuropsychological test battery. Intensity of cocaine use was objectively determined by quantitative 6-month hair toxicology at both test sessions. Substantially increased cocaine use within 1 year (mean +297%) was associated with reduced cognitive performance primarily in working memory. By contrast, decreased cocaine use (−72%) was linked to small cognitive improvements in all four domains. Importantly, users who ceased taking cocaine seemed to recover completely, attaining a cognitive performance level similar to that of the control group. However, recovery of working memory was correlated with age of onset of cocaine use—early-onset users showed hampered recovery. These longitudinal data suggest that cognitive impairment might be partially cocaine-induced but also reversible within 1 year, at least after moderate exposure. The reversibility indicates that neuroplastic adaptations underlie cognitive changes in cocaine users, which are potentially modifiable in psychotherapeutical or pharmacological interventions. PMID:24651468

Involvement of the Lateral Orbitofrontal Cortex in Drug Context-induced Reinstatement of Cocaine-seeking Behavior in Rats

PubMed Central

Lasseter, Heather C.; Ramirez, Donna R.; Xie, Xiaohu; Fuchs, Rita A.

2009-01-01

Orbitofrontal cortex (OFC) damage produces impaired decision-making, impulsivity, and perseveration and potentially contributes to compulsive drug seeking in cocaine users. To further explore this phenomenon, we assessed the role of the lateral OFC (lOFC) in drug context-induced cocaine-seeking behavior in the reinstatement model of drug relapse. Rats were trained to lever press for intravenous cocaine infusions in a distinct environmental context (cocaine-paired context) followed by extinction training in a different context (extinction-paired context). Reinstatement of cocaine seeking (non-reinforced lever presses) was assessed in the cocaine context in the absence of response-contingent stimuli. In experiment 1, we evaluated whether acute inhibition of lOFC output alters context-induced cocaine-seeking behavior by infusing the GABAB+A agonists, baclofen+muscimol, or vehicle into the lOFC immediately before exposure to the cocaine-paired context. In experiments 2–3, we assessed how prolonged loss of lOFC output affects drug context-induced cocaine seeking by administering bilateral NMDA or sham lesions of the lOFC either before or after self-administration and extinction training. Remarkably, OFC functional inactivation attenuated, post-training lesions failed to alter, and pre-training lesions potentiated drug context-induced cocaine seeking without altering responding in the extinction context. These results suggest that neural activity in the lOFC promotes context-induced cocaine-seeking behavior. However, prolonged loss of lOFC output enhances the motivational salience of cocaine-paired contextual stimuli likely by eliciting compensatory neuroadaptations, with the effects of post-training lOFC lesions reflecting an intermediate state of compensatory neuroplasticity. Overall, these findings support the idea that OFC dysfunction may promote cue reactivity and enhance relapse propensity in cocaine users. PMID:19769591

Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

PubMed

Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

2017-12-01

Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of L-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys.

PubMed

Kohut, Stephen J; Bergman, Jack; Blough, Bruce E

2016-03-01

Monoamine releasers with prominent dopaminergic actions, e.g., D-methamphetamine (D-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, D-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder. The L-isomer of methamphetamine (L-MA), unlike D-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether L-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration. Separate groups (N = 4-5) of rhesus monkeys were studied to determine whether L-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement. L-MA, like D-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10-day treatments with continuously infused L-MA (0.032-0.32 mg/kg/h, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding. These results indicate that L-MA both shares discriminative stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. L-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans

PubMed Central

Lile, Joshua A.; Stoops, William W.; Rush, Craig R.; Negus, S. Stevens; Glaser, Paul E. A.; Hatton, Kevin W.; Hays, Lon R.

2016-01-01

Background A medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination. Therefore, we designed homologous cocaine self-administration studies in rhesus monkeys (see companion article) and human subjects in an attempt to develop linked, functionally equivalent procedures for research on candidate medications for cocaine use disorder. Methods Eight (N=8) subjects with cocaine use disorder completed 12 experimental sessions in which they responded to receive money ($0.01, $1.00 and $3.00) or intravenous cocaine (0, 3, 10 and 30 mg/70 kg) under independent, concurrent progressive-ratio schedules. Prior to the completion of 9 choice trials, subjects sampled the cocaine dose available during that session and were informed of the monetary alternative value. Results The allocation of behavior varied systematically as a function of cocaine dose and money value. Moreover, a similar pattern of cocaine choice was demonstrated in rhesus monkeys and humans across different cocaine doses and magnitudes of the species-specific alternative reinforcers. The subjective and cardiovascular responses to IV cocaine were an orderly function of dose, although heart rate and blood pressure remained within safe limits. Conclusions These coordinated studies successfully established drug vs. non-drug choice procedures in humans and rhesus monkeys that yielded similar cocaine choice behavior across species. This translational research platform will be used in future research to enhance the efficiency of developing interventions to reduce cocaine use. PMID:27269368

Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

PubMed

Grasing, Kenneth; Mathur, Deepan; DeSouza, Cherilyn; Newton, Thomas F; Moody, David E; Sturgill, Marc

2016-08-01

In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399). © 2016 American Academy of Addiction Psychiatry.

Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats

PubMed Central

Collins, Gregory T.; Zaks, Matthew E.; Cunningham, Alyssa R.; St. Clair, Carley; Nichols, Joseph; Narasimhan, Diwahar; Ko, Mei-Chuan; Sunahara, Roger K.; Woods, James H.

2011-01-01

Background A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine’s cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine’s cardiovascular, convulsant, and lethal effects in male and female rats. Methods Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats. Results Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4 hrs, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity. Conclusions Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity. PMID:21481548

Pharmacodynamic effects and relationships to plasma and oral fluid pharmacokinetics after intravenous cocaine administration.

PubMed

Ellefsen, Kayla N; Concheiro, Marta; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A

2016-06-01

No controlled cocaine administration data describe cocaine and metabolite disposition in oral fluid (OF) collected with commercially-available collection devices, OF-plasma ratios, and pharmacodynamic relationships with plasma and OF cocaine and metabolite concentrations. Eleven healthy, cocaine-using adults received 25mg intravenous cocaine. Physiological and subjective effects (visual analogue scales), and plasma were collected one hour prior, and up to 21h post-dose. OF was collected with the Quantisal™ device up to 69h post-dose. Cocaine, benzoylecgonine (BE) and ecgonine methyl ester were quantified in plasma by liquid chromatography-tandem mass spectrometry; cocaine and BE were quantified in OF by two dimensional-gas chromatography-mass spectrometry. Increases in heart rate, blood pressure and positive subjective effects occurred within the first 15min, persisting up to 1h ("Rush"), with clockwise hysteresis observed for plasma and OF concentrations and some subjective measures. Peak subjective effects ("Rush," "Good drug effect" and "Bad drug effect") occurred prior to peak OF cocaine concentration, whereas observed peak plasma concentrations and subjective measures occurred simultaneously, most likely due to significantly earlier plasma Tmax compared to OF Tmax.Tlast was generally longer in OF (12.5h cocaine; 33.0h BE) than plasma (9.5h cocaine; >21h BE, cutoffs 1μg/L); 8 and 10μg/L OF cocaine confirmatory cutoffs yielded detection times similar to cocaine's impairing effects, suggesting usefulness for DUID testing. OF offers advantages as an alternative matrix to blood and plasma for identifying cocaine intake, defining pharmacokinetic parameters at different confirmation cutoffs, and aiding different drug testing programs to best achieve their monitoring goals. Copyright © 2016. Published by Elsevier Ireland Ltd.

Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys.

PubMed

Kohut, Stephen J; Jacobs, David S; Rothman, Richard B; Partilla, John S; Bergman, Jack; Blough, Bruce E

2017-12-01

The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability. The present study examined the effects of several novel "norepinephrine (NE)-preferring" monoamine releasers relative to non-selective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329 < l-methamphetamine < PAL-169). Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine. Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the "NE-preferring" releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine's discriminative stimulus effects. These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other "NE-preferring" monoamine releasers should provide insight into their potential for the management of cocaine addiction.

Effect of GABA agonists and GABA-A receptor modulators on cocaine- and food-maintained responding and cocaine discrimination in rats.

PubMed

Barrett, Andrew C; Negus, S Stevens; Mello, Nancy K; Caine, S Barak

2005-11-01

Recent studies indicate that GABAergic ligands modulate abuse-related effects of cocaine. The goal of this study was to evaluate the effects of a mechanistically diverse group of GABAergic ligands on the discriminative stimulus and reinforcing effects of cocaine in rats. One group of rats was trained to discriminate 5.6 mg/kg cocaine from saline in a two-lever, food-reinforced, drug discrimination procedure. In two other groups, responding was maintained by cocaine (0-3.2 mg/kg/injection) or liquid food (0-100%) under a fixed ratio 5 schedule. Six GABA agonists were tested: the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), and three GABA-A receptor modulators (the barbiturate pentobarbital, the high-efficacy benzodiazepine midazolam, and the low-efficacy benzodiazepine enazenil). When tested alone, none of the compounds substituted fully for the discriminative stimulus effects of cocaine. As acute pretreatments, select doses of midazolam and pentobarbital produced 2.2- to 3.6-fold rightward shifts in the cocaine dose-effect function. In contrast, muscimol, baclofen, GVG, and enazenil failed to alter the discriminative stimulus effects of cocaine. In assays of cocaine- and food-maintained responding, midazolam and pentobarbital decreased cocaine self-administration at doses 9.6- and 3.3-fold lower, respectively, than those that decreased food-maintained responding. In contrast, muscimol, baclofen, and GVG decreased cocaine self-administration at doses that also decreased food-maintained responding. Enazenil failed to alter cocaine self-administration. Together with previous studies, these data suggest that among mechanistically diverse GABA agonists, high-efficacy GABA-A modulators may be the most effective for modifying the abuse-related effects of cocaine.

Effects of dopamine D2/D3 receptor ligands on food-cocaine choice in socially housed male cynomolgus monkeys.

PubMed

Czoty, Paul W; Nader, Michael A

2013-02-01

Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. The present experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of whether social status, known to alter D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(-)-norpropylapomorphine [(-)-NPA], low-efficacy agonist aripiprazole (ARI), and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (-)-NPA were characterized under conditions in which monkeys did (ARI) or did not [ARI and (-)-NPA] self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased the choice of low cocaine doses, and only (-)-NPA decreased the choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self administration occurred only on days 1 and 5 of treatment, ARI, but not (-)-NPA, decreased cocaine choice in dominant monkeys, whereas (-)-NPA, but not ARI, did so in subordinates. When dominant monkeys self-administered cocaine on all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine.

Oral Fluid Cocaine and Benzoylecgonine Concentrations Following Controlled Intravenous Cocaine Administration

PubMed Central

Ellefsen, Kayla N.; Concheiro, Marta; Pirard, Sandrine; Gorelick, David A.; Huestis, Marilyn A.

2016-01-01

Limited oral fluid (OF) pharmacokinetic data collected with commercially available collection devices after controlled cocaine administration hinder OF result interpretations. Ten cocaine-using adults provided OF, collected with Oral-Eze® (OE) and StatSure Saliva Sampler™ (SS) devices, an hour prior to and up to 69 h after 25 mg intravenous (IV) cocaine administration. Cocaine and benzoylecgonine (BE) were quantified by a validated 2D-GC-MS method. Large inter-subject variability was observed. Cocaine was detected in OF in the first 0.17 h sample after IV administration, with much more rapid elimination than BE. OE median observed Cmax (range) was 932 (394–1,574) μg/L for cocaine and 248 (96.9–953) μg/L for BE. SS median (range) observed cocaine and BE Cmax trended lower at 732 (83.3–1,892) μg/L and 360 (77.2–836) μg/L, respectively. OE and SS cocaine OF detection times were 12.5 and 6.5 h and for BE 30.5 and 28.0 h, respectively at 1 μg/L. There were no significant pharmacokinetic differences between OE and SS OF collection devices, except cocaine half-life was significantly shorter in SS OF specimens. This difference could be attributed to differences in stabilizing buffers present in OF collection devices, which may affect cocaine stability in OF specimens, or decreased recovery from collection pads. Both OE and SS OF collection devices were effective in monitoring cocaine and metabolite concentrations with similar detection windows. Furthermore, we demonstrated that different confirmatory OF cutoffs can be selected to produce shorter or longer cocaine and metabolite detection windows to address specific needs of clinical and forensic drug testing programs. PMID:26851651

Effects of Phendimetrazine Treatment on Cocaine vs Food Choice and Extended-Access Cocaine Consumption in Rhesus Monkeys

PubMed Central

Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R; Snyder, Rodney W; Negus, S Stevens

2013-01-01

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1–7: 0.32 mg/kg/h; days 8–21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM). PMID:23893022

Cocaine Cardiovascular Effects and Pharmacokinetics after Treatment with the Acetylcholinesterase Inhibitor Donepezil

PubMed Central

Grasing, Kenneth; Mathur, Deepan; DeSouza, Cherilyn; Newton, Thomas F.; Moody, David E.; Sturgill, Marc

2016-01-01

Background In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. Methods Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at 0.0, 0.18, 0.36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. Results Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (0.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (0.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo- treated participants. Conclusions and Scientific Significance We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. PMID:27392137

Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R; Snyder, Rodney W; Negus, S Stevens

2013-12-01

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).

Effects of l-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys

PubMed Central

Kohut, Stephen J.; Bergman, Jack; Blough, Bruce E.

2015-01-01

Rationale Monoamine releasers with prominent dopaminergic actions, e.g., d-methamphetamine (d-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, d-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder. Objectives The l-isomer of methamphetamine (l-MA), unlike d-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether l-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration. Methods Separate groups (N=4-5) of rhesus monkeys were studied to determine whether l-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and, (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement. Results l-MA, like d-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10 day treatments with continuously infused l-MA (0.032-0.32 mg/kg/hr, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding. Conclusions These results indicate that l-MA both shares discriminative-stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. l-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder. PMID:26713332

Maintained cocaine self-administration is determined by quantal responses: implications for the measurement of antagonist potency.

PubMed

Norman, Andrew B; Tabet, Michael R; Norman, Mantana K; Tsibulsky, Vladimir L

2014-02-01

The change in frequency of cocaine self-administration as a function of the unit dose is widely assumed to represent a graded pharmacodynamic response. Alternatively, a pharmacological theory states that during maintained self-administration, a quantal response occurs at a minimum maintained cocaine concentration (satiety threshold). Rats self-administered cocaine at unit doses spanning an 8-fold range from 0.75 to 6 µmol/kg. Despite an approximately 7-fold difference in the interinjection intervals, there were no differences in the plasma cocaine concentration at the time of lever press across this range of unit doses, consistent with the satiety threshold representing an equiactive cocaine concentration. Because self-administration always occurs when cocaine concentrations decline back to the satiety threshold, this behavior represents a process of automatic back titration of equiactive agonist concentrations. Therefore, the lower frequency of self-administration at higher unit doses is caused by an increase in the duration of the cocaine-induced satiety response, and the graded dose-frequency relationship is due to cocaine pharmacokinetics. After the interinjection intervals at a particular unit dose were stable, rats were injected with the competitive D₁-like dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390; 15 nmol/kg intravenously) and the session continued. At all cocaine unit doses, SCH23390 accelerated self-administration with a concomitant increase in the calculated satiety threshold, and these equiactive cocaine concentration ratios were independent of the cocaine unit dose. Therefore, the measurement of antagonist potency requires only a single unit dose of cocaine, selected on the basis of convenience, and using multiple cocaine unit doses is redundant.

Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys.

PubMed

Platt, Donna M; Rowlett, James K; Spealman, Roger D

2007-08-01

Norepinephrine (NE) uptake and NE receptor mechanisms play important modulating roles in the discriminative stimulus and stimulant effects of cocaine. The present study investigated the role of NE mechanisms in cocaine priming-induced reinstatement of extinguished drug seeking. Squirrel monkeys (Saimiri sciureus) were trained to stability under a second-order fixed interval, fixed ratio schedule of drug self-administration in which operant responding was maintained jointly by i.v. cocaine injections and presentations of a cocaine-paired stimulus. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In test sessions during which the cocaine-paired stimulus was reintroduced but only vehicle was available for self-administration, priming with cocaine, the dopamine transport inhibitor 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), and the NE transport inhibitors nisoxetine and talsupram induced dose-dependent reinstatement of drug seeking. The maximum effect of the NE transport inhibitors was less than half that of cocaine. Both nisoxetine and talsupram augmented the priming effects of a low but not a high dose of cocaine. The priming effects of nisoxetine were blocked by the alpha1-adrenoceptor antagonist prazosin, the alpha2-adrenoceptor agonist clonidine, and the beta-adrenoceptor antagonist propranolol, but not by the dopamine receptor antagonist flupenthixol. The priming effects of cocaine were antagonized by clonidine and flupenthixol. Neither nisoxetine nor cocaine increased physiological (salivary cortisol) or behavioral (self-directed behaviors) markers of stress. These findings suggest that NE transporter inhibition and alpha2-adrenoceptor mechanisms play a significant role in cocaine-induced reinstatement of drug seeking that is not secondary to activation of brain stress pathways.

Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments*

PubMed Central

Jordan, Chloe J.; Harvey, Roxann C.; Baskin, Britahny B.; Dwoskin, Linda P.; Kantak, Kathleen M.

2014-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown. Methods To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule. Results Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains. Conclusions The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD. PMID:24811203

The cocaine-abused heart.

PubMed

Keller, Kathryn Buchanan; Lemberg, Louis

2003-11-01

Recreational use of cocaine dates back to the Incas in South America 5000 years ago. Cocaine is derived from the leaves of Erythroxylon coca, a shrub native to South America. In the late 1800s, Sigmund Freud popularized the drug in Europe. He used cocaine to treat depression, asthma, cachexia, and for overcoming morphine addiction. Also in this period cocaine rapidly gained acceptance in surgical procedures as a local anesthetic and vasoconstrictor. Cocaine reached the United States in the early 1900s, and its popularity led President Taft to declare it public enemy number one in 1910. Cocaine became popular again in the 1980s. Currently cocaine use is responsible for more ED visits then any of the other illicit drugs. Because most cocaine users are young, they are at a lower risk for coronary artery atherosclerotic disease. An estimated 25 million people between the ages of 26 and 34 years have used cocaine at least once, 20% were women and 30% men. Habitual users of cocaine are estimated to number 1.5 million. Most cocaine-induced chest pains do not progress to MI, and in fact many originate in the chest wall. The chest pains due to cocaine, however, are induced by myocardial ischemia, a result of vasospasm and not a thrombotic occlusion of a coronary artery that has a ruptured atheromatous plaque. ECG findings can be misleading in the diagnosis because the early repolarization syndrome, a normal variant, is a frequent finding in young African American men. Measurement of cardiac troponin levels is the most reliable diagnostic test. Percutaneous coronary intervention and angioplasty, rather than thrombolysis, is the treatment of choice because intense coronary vasospasm is the primary pathophysiology in cocaine-induced MI.

Involvement of delta and mu opioid receptors in the acute and sensitized locomotor action of cocaine in mice.

PubMed

Kotlinska, J H; Gibula-Bruzda, E; Witkowska, E; Izdebski, J

2013-10-01

Analogs of deltorphins, such as cyclo(Nδ, Nδ-carbonyl-d-Orn2, Orn4)deltorphin (DEL-6) and deltorphin II N-(ureidoethyl)amide (DK-4) are functional agonists predominantly for the delta opioid receptors (DOR) in the guinea-pig ileum and mouse vas deferens bioassays. The purpose of this study was to examine an influence of these peptides (5, 10 or 20 nmol, i.c.v.) on the acute cocaine-induced (10mg/kg, i.p.) locomotor activity and the expression of sensitization to cocaine locomotor effect. Sensitization to locomotor effect of cocaine was developed by five injections of cocaine at the dose of 10mg/kg, i.p. every 3 days. Our results indicated that DK-4 and DEL-6 differently affected the acute and sensitized cocaine locomotion. Co-administration of DEL-6 with cocaine enhanced acute cocaine locomotion only at the dose of 10 nmol, with minimal effects at the doses 5 and 20 nmol, whereas co-administration of DK-4 with cocaine enhanced acute cocaine-induced locomotion in a dose-dependent manner. Similarly to the acute effects, DEL-6 only at the dose of 10 nmol but DK-4 dose-dependently enhanced the expression of cocaine sensitization. Pre-treatment with DOR antagonist - naltrindole (5 nmol, i.c.v.) and mu opioid receptor (MOR) antagonist, β-funaltrexamine abolished the ability of both peptides to potentiate the effects of cocaine. Our study suggests that MOR and DOR are involved in the interactions between cocaine and both deltorphins analogs. A distinct dose-response effects of these peptides on cocaine locomotion probably arise from differential functional activation (targeting) of the DOR and MOR by both deltorphins analogs. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity.

PubMed

Zlebnik, Natalie E; Carroll, Marilyn E

2015-03-01

Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive). Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO). HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects. These findings demonstrated greater attenuation of cue- versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans.

PubMed

Lile, Joshua A; Stoops, William W; Rush, Craig R; Negus, S Stevens; Glaser, Paul E A; Hatton, Kevin W; Hays, Lon R

2016-08-01

A medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination. Therefore, we designed homologous cocaine self-administration studies in rhesus monkeys (see companion article) and human subjects in an attempt to develop linked, functionally equivalent procedures for research on candidate medications for cocaine use disorder. Eight (N=8) subjects with cocaine use disorder completed 12 experimental sessions in which they responded to receive money ($0.01, $1.00 and $3.00) or intravenous cocaine (0, 3, 10 and 30mg/70kg) under independent, concurrent progressive-ratio schedules. Prior to the completion of 9 choice trials, subjects sampled the cocaine dose available during that session and were informed of the monetary alternative value. The allocation of behavior varied systematically as a function of cocaine dose and money value. Moreover, a similar pattern of cocaine choice was demonstrated in rhesus monkeys and humans across different cocaine doses and magnitudes of the species-specific alternative reinforcers. The subjective and cardiovascular responses to IV cocaine were an orderly function of dose, although heart rate and blood pressure remained within safe limits. These coordinated studies successfully established drug versus non-drug choice procedures in humans and rhesus monkeys that yielded similar cocaine choice behavior across species. This translational research platform will be used in future research to enhance the efficiency of developing interventions to reduce cocaine use. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Hygrine and cuscohygrine as possible markers to distinguish coca chewing from cocaine abuse in workplace drug testing.

PubMed

Rubio, C; Strano-Rossi, S; Tabernero, M J; Anzillotti, L; Chiarotti, M; Bermejo, A M

2013-04-10

Cocaine abuse is widespread all over the world, and is performed generally by sniffing, injecting or smoking cocaine or crack. The distinction between the recreational use of cocaine from the practice of the so called "coqueo" is still an issue in those countries where this habit is diffused and where it is not considered an addiction, by this reason is necessary to develop a method for to distinguish the coca chewers and cocaine abusers. The use of an unique marker to distinguish between cocaine abuse and chewing of coca leaves is of fundamental importance in those countries where this habit is diffused. Certain alkaloids of the leaves of Erythroxylum coca are lost during the process of extraction/purification of cocaine and it is not possible to find them neither in seizures of chlorhidrate of cocaine nor urine samples of cocaine abusers. These markers are the hygrine and cuscohygrine that are present in the leaves of E. coca. A fast GC/MS method involving a liquid:liquid extraction procedure with tertbutylmethylether (TBME) is proposed for the determination of some alkaloids in cocaine leaves, cocaine seizures and biological samples. All specimens were alkalinized to pH 9 with a carbonate/bicarbonate buffer and then extracted with TBME. The analysis was carry out by GC/MS with electron impact at 70 eV and in full scan mode. The results demonstrate that hygrine and cuscohygrine are not found neither in the urine of cocaine abusers nor in cocaine seizures. For this reason this compounds could be considered as markers of coca chewing. This developed method permits to distinguish coca chewing from cocaine abuse in workplace drug testing through the analysis of urine samples. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Attenuation of Cocaine-Induced Conditioned Place Preference and Motor Activity via Cannabinoid CB2 Receptor Agonism and CB1 Receptor Antagonism in Rats

PubMed Central

Delis, Foteini; Polissidis, Alexia; Poulia, Nafsika; Justinova, Zuzana; Nomikos, George G.; Goldberg, Steven R.

2017-01-01

Abstract Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine’s reinforcing and psychomotor effects. PMID:27994006

Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

PubMed

Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

2018-06-01

The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

Binge-pattern cocaine administration causes long-lasting behavioral hyperarousal but does not enhance vulnerability to single prolonged stress in rats.

PubMed

Lisieski, Michael J; Perrine, Shane A

2017-11-01

Cocaine use disorder and post-traumatic stress disorder (PTSD) commonly co-occur. This could be due to vulnerability to post-traumatic symptoms conferred by previous exposure to cocaine. Therefore, we combined chronic binge-pattern cocaine with a model of psychological trauma (single prolonged stress) to determine whether the behavioral effects of psychological trauma are enhanced in cocaine-sensitized individuals. Adult male Sprague Dawley rats received 14 days of cocaine (15mg/kg/injection) or saline in a binge pattern (3 injections per day, 1h apart). Seven days after the last injection animals were exposed to traumatic stress or a control procedure. Seven days after stress, activity and anxiety-like behaviors were measured. Binge-pattern cocaine increased locomotor activity in the open field and elevated plus maze, and both cocaine and SPS exposure increased the rapidity with which rats moved through grooming sequences. Neither binge-pattern cocaine nor SPS increased anxiety-like behaviors, and no interactions were found between binge-pattern cocaine exposure and SPS exposure. A behavioral phenotype categorization approach demonstrated that cocaine-exposed groups expressed a high incidence of hyperactivity-like symptoms. These results suggest that binge-pattern cocaine exposure causes a long-lasting hyper-exploratory phenotype but does not make individuals more vulnerable to a later traumatic stress exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Mephedrone interactions with cocaine: prior exposure to the 'bath salt' constituent enhances cocaine-induced locomotor activation in rats.

PubMed

Gregg, Ryan A; Tallarida, Christopher S; Reitz, Allen B; Rawls, Scott M

2013-12-01

Concurrent use of mephedrone (4-methylmethcathinone; MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity after pretreatment with cocaine or MEPH than after pretreatment with saline. METH challenge produced greater locomotor activity after METH pretreatment than after saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bidirectional and did not extend to METH, suggesting that the phenomenon is sensitive to specific psychostimulants.

Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

PubMed Central

Cunningham, Kathryn A.

2015-01-01

Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. PMID:25505168

The effects of N-acetylcysteine on cocaine reward and seeking behaviors in a rat model of depression.

PubMed

Frankowska, Małgorzata; Jastrzębska, Joanna; Nowak, Ewa; Białko, Magdalena; Przegaliński, Edmund; Filip, Małgorzata

2014-06-01

Depression and substance-abuse (e.g., cocaine) disorders are common concurrent diagnoses. In the present study, we combined bilateral olfactory bulbectomy (OBX) with a variety of procedures of intravenous cocaine self-administration and extinction/reinstatement in rats. We also investigated the effects of N-acetylcysteine (NAC) on rewarding and seeking behaviors for cocaine in OBX rats and compared the drug's effects in sham-operated control animals (SHAM). The occurrence of depressive symptoms before introduction to cocaine self-administration enhanced subsequent cocaine-seeking behaviors but did not significantly influence cocaine's rewarding properties or extinction training. NAC (25-100mg/kg) given acutely or repeatedly did not alter the co-occurrence of cocaine reward and depression but effectively reduced the cocaine-seeking behavior observed in both phenotypes. Our results indicate that depression behavior is linked to more pronounced drug craving and a higher propensity to relapse in rats. We also show the lack of efficacy of repeated NAC treatment on SHAM or OBX animals in terms of cocaine self-administration, while the drug was an effective blocker of cocaine-seeking behavior in both studied phenotypes, with a more pronounced drug effect observed in OBX animals. The last finding demonstrates the potential clinical utility of NAC to reduce cocaine seeking enhanced by co-existing depression. Copyright © 2014 Elsevier B.V. All rights reserved.

Novelty-induced locomotion is positively associated with cocaine ingestion in adolescent rats; anxiety is correlated in adults

PubMed Central

Walker, Q. David; Schramm-Sapyta, Nicole L.; Caster, Joseph M.; Waller, Samuel T.; Brooks, Matthew P.; Kuhn, Cynthia M.

2009-01-01

The present studies assessed the roles of sex, age, novelty-seeking and plus-maze behavior on cocaine drinking in rats. Cocaine/saccharin solution was available in three daily, 5-hour sessions then a saccharin-only solution was also available in following sessions. In the one-bottle drinking phase, early and late adolescent males, post-natal day 28 (PN28) and PN42, consumed more cocaine/saccharin solution than young adults (PN65), but females did not exhibit significant age differences. Adolescents of both sexes consumed more cocaine/saccharin than adults during choice drinking. Saccharin availability in the two-bottle trials decreased cocaine/saccharin consumption in PN28 and PN65 rats. After a drug-free period, cocaine-stimulated locomotion was lower in cocaine/saccharin drinking than saccharin-only males, indicating tolerance. We tested the hypothesis that individual differences in pre-screened behavioral traits would correlate with cocaine/saccharin consumption in PN28 and PN65 male rats. High locomotor responses to novelty were associated with greater cocaine/saccharin drinking in adults in one-bottle sessions. In the subsequent choice drinking phase, correlations were age-specific. Adolescents with high novelty-induced locomotion and adults that spent less time on open arms of the elevated plus-maze drank more cocaine/saccharin. Thus, behavioral phenotypes correlated with individual differences in cocaine/saccharin consumption in an age-related manner. PMID:18790706

Cocaine dependent individuals discount future rewards more than future losses for both cocaine and monetary outcomes.

PubMed

Johnson, Matthew W; Bruner, Natalie R; Johnson, Patrick S

2015-01-01

Cocaine dependence and other forms of drug dependence are associated with steeper devaluation of future outcomes (delay discounting). Although studies in this domain have typically assessed choices between monetary gains (e.g., receive less money now versus receive more money after a delay), delay discounting is also applicable to decisions involving losses (e.g., small loss now versus larger delayed loss), with gains typically discounted more than losses (the "sign effect"). It is also known that drugs are discounted more than equivalently valued money. In the context of drug dependence, however, relatively little is known about the discounting of delayed monetary and drug losses and the presence of the sign effect. In this within-subject, laboratory study, delay discounting for gains and losses was assessed for cocaine and money outcomes in cocaine-dependent individuals (n=89). Both cocaine and monetary gains were discounted at significantly greater rates than cocaine and monetary losses, respectively (i.e., the sign effect). Cocaine gains were discounted significantly more than monetary gains, but cocaine and monetary losses were discounted similarly. Results suggest that cocaine is discounted by cocaine-dependent individuals in a systematic manner similar to other rewards. Because the sign effect was shown for both cocaine and money, delayed aversive outcomes may generally have greater impact than delayed rewards in shaping present behavior in this population. Copyright © 2014. Published by Elsevier Ltd.

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females

PubMed Central

Hong, Kwangik A.; Paliwal, Prashni; Morgan, Peter T.; Sinha, Rajita

2009-01-01

Rationale There is growing evidence of alterations in brain stress and reward circuits associated with cocaine dependence. Sex differences are also documented and sex steroid hormones have been linked to cocaine reinforcement. Objectives The current study therefore assessed daily fluctuations in stress and sex hormones in cocaine-dependent females compared with healthy females. Method Daily salivary samples of cortisol, progesterone, and estradiol were collected at waking across 28 days from 12 cocaine-dependent females receiving inpatient treatment and 10 healthy females. Participants also completed mood-rating scales each week corresponding to four phases of the menstrual cycle and cocaine craving was monitored in cocaine patients at each phase. Results Cocaine-dependent females in their first month of abstinence demonstrated significantly higher levels of both cortisol and progesterone across the menstrual cycle and significantly lower estradiol/progesterone (E2/P) ratios compared to healthy controls. They also showed significantly increased negative mood compared with controls, but no variation in cocaine craving across the menstrual cycle. Conclusions Findings indicate altered stress and sex hormones suggestive of an overactive stress system during the first month of cocaine abstinence after chronic cocaine abuse. These increased levels of cortisol and progesterone could impact both abstinence-related symptoms such as negative mood and susceptibility to drug-seeking behavior in cocaine-dependent females. PMID:17891383

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

PubMed Central

Xi, Zheng-Xiong; Song, Rui; Li, Xia; Lu, Guan-Yi; Peng, Xiao-Qing; He, Yi; Bi, Guo-Hua; Sheng, Siyuan Peter; Yang, Hong-Ju; Zhang, Haiying; Li, Jin; Froimowitz, Mark; Gardner, Eliot L

2017-01-01

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaine-associated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 is a unique DAT inhibitor that not only could satisfy ‘drug hunger' through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual—thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction. PMID:27534265

Cocaine/Crack: The Big Lie.

ERIC Educational Resources Information Center

National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

This pamphlet focuses on cocaine and crack use and the addictive nature of cocaine/crack. It contains a set of 21 questions about crack and cocaine, each accompanied by a clear and complete response. Interspersed throughout the booklet are photographs and quotes from former cocaine or crack users/addicts. Questions and answers focus on what…

Cocaine.

ERIC Educational Resources Information Center

Piazza, Nick J.; Yeager, Rebecca D.

Cocaine was first used by Europeans in the nineteenth century when extract from the coca leaf was combined with various beverages. Cocaine comes as a white crystalline powder. However, a product called crack cocaine may come as an opaque crystal similar in size and shape to rock salt. A third form of cocaine is known as coca paste, which is an…

Cocaine inhibition of nicotinic acetylcholine receptors influences dopamine release

PubMed Central

Acevedo-Rodriguez, Alexandra; Zhang, Lifen; Zhou, Fuwen; Gong, Suzhen; Gu, Howard; De Biasi, Mariella; Zhou, Fu-Ming; Dani, John A.

2014-01-01

Nicotinic acetylcholine receptors (nAChRs) potently regulate dopamine (DA) release in the striatum and alter cocaine's ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit nAChR-mediated currents in midbrain DA neurons and consequently alter DA release in the dorsal and ventral striatum. At very high concentrations, cocaine also inhibits voltage-gated Na channels in DA neurons. Furthermore, our results show that partial inhibition of nAChRs by cocaine reduces evoked DA release. This diminution of DA release via nAChR inhibition more strongly influences release evoked at low or tonic stimulation frequencies than at higher (phasic) stimulation frequencies, particularly in the dorsolateral striatum. This cocaine-induced shift favoring phasic DA release may contribute to the enhanced saliency and motivational value of cocaine-associated memories and behaviors. PMID:25237305

Cocaine detection using piezoresistive microcantilevers

NASA Astrophysics Data System (ADS)

Srijanto, Bernadeta; Cheney, Christine P.; Hedden, David L.; Gehl, Anthony; Ferrell, Thomas L.

2008-03-01

Sensitive and inexpensive sensors play a significant role in the analysis of drugs and drug metabolites. Specifically, reliable in vivo detection of cocaine and cocaine metabolites serves as a useful tool in research of the body's reaction to the drug and in the treatment of the drug addiction. We present here a promising cocaine biosensor to be used in the human body. The sensor's active element consists of piezoresistive microcantilevers coated with an oligonucleotide-based aptamer as the cocaine binder. In vitro cocaine detection was carried out by flowing a cocaine solution over the microcantilevers. Advantages of this device are its low power consumption, its high sensitivity, and its potential for miniaturization into an implantable capsule. The limit of detection for cocaine in distilled water was found to be 1 ng/ml.

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

PubMed Central

Ramakrishnan, Muthu; Kinsey, Berma M.; Singh, Rana A.; Kosten, Thomas R.; Orson, Frank M.

2014-01-01

In the absence of any effective pharmacotherapy for cocaine addiction, immunotherapy is being actively pursued as a therapeutic intervention. While several different cocaine haptens have been explored to develop anti-cocaine antibodies, none of the hapten was successfully designed which had a protonated tropane nitrogen as is found in native cocaine under physiological conditions, including the succinyl norcocaine (SNC) hapten that has been tested in phase II clinical trials. Herein, we discuss three different cocaine haptens: hexyl-norcocaine (HNC), bromoacetamido butyl- norcocaine (BNC), and succinyl-butyl- norcocaine (SBNC), each with a tertiary nitrogen structure mimicking that of native cocaine which could optimize the specificity of anti-cocaine antibodies for better cocaine recognition. Mice immunized with these haptens conjugated to immunogenic proteins produced high titer anti-cocaine antibodies. However, during chemical conjugation of HNC and BNC haptens to carrier proteins, the 2β methyl ester group is hydrolyzed and immunizing mice with these conjugate vaccines in mice produced antibodies that bound both cocaine and the inactive benzoylecgonine metabolite. While in the case of the SBNC conjugate vaccine hydrolysis of the methyl ester did not appear to occur, leading to antibodies with high specificity to cocaine over BE. Though we observed similar specificity with a SNC hapten, the striking difference is that SBNC carries a positive charge on the tropane nitrogen atom, and therefore it is expected to have better binding of cocaine. The 50% cocaine inhibitory concentration (IC50) value for SBNC antibodies (2.8 μM) was significantly better than the SNC antibodies (9.4 μM) when respective hapten-BSA was used as a substrate. In addition, antibodies from both sera had no inhibitory effect from BE. In contrast to BNC and HNC, the SBNC conjugate was also found to be highly stable without any noticeable hydrolysis for several months at 4°C and 2-3 days in pH 10 buffer at 37°C. PMID:24803171

Chronic escalating cocaine exposure, abstinence/withdrawal, and chronic re-exposure: Effects on striatal dopamine and opioid systems in C57BL/6J mice

PubMed Central

Zhang, Yong; Schlussman, Stefan D.; Rabkin, Jacqui; Butelman, Eduardo R.; Ho, Ann; Kreek, Mary Jeanne

2013-01-01

Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an “addiction-like cycle” in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal /13-day saline + 1-day cocaine), chronic cocaine exposure (14 day cocaine) or chronic re-exposure (14-day cocaine/14-day withdrawal /14-day cocaine). Escalating-dose binge cocaine (15-30 mg/kg/injection x 3/day, i.p. at hourly intervals) or saline (14-day saline) was administered, modeling initial exposure. In “re-exposure” groups, after a 14-day injection-free period (modeling abstinence/withdrawal), mice that had received cocaine were re-injected with 14-day escalating-dose binge cocaine, whereas controls received saline. Microdialysis was conducted on the 14th day of exposure or re-exposure to determine striatal dopamine content. Messenger RNA levels of preprodynorphin (Pdyn), dopamine D1 (Drd1) and D2 (Drd2) in the caudate putamen were determined by real-time PCR. Basal striatal dopamine levels were lower in mice after 14-day escalating exposure or re-exposure than in those in the acute cocaine group and controls. Pdyn mRNA levels were higher in the cocaine groups than in controls. Long-term adaptation was observed across the stages of this addiction-like cycle, in that the effects of cocaine on dopamine levels were increased after re-exposure compared to exposure. Changes in striatal dopaminergic responses across chronic escalating cocaine exposure and re-exposure are a central feature of the neurobiology of relapsing addictive states. PMID:23164614

Cocaine-induced neuroadaptations in glutamate transmission

PubMed Central

Schmidt, Heath D.; Pierce, R. Christopher

2017-01-01

A growing body of evidence indicates that repeated exposure to cocaine leads to profound changes in glutamate transmission in limbic nuclei, particularly the nucleus accumbens. This review focuses on preclinical studies of cocaine-induced behavioral plasticity, including behavioral sensitization, self-administration, and the reinstatement of cocaine seeking. Behavioral, pharmacological, neurochemical, electrophysiological, biochemical, and molecular biological changes associated with cocaine-induced plasticity in glutamate systems are reviewed. The ultimate goal of these lines of research is to identify novel targets for the development of therapies for cocaine craving and addiction. Therefore, we also outline the progress and prospects of glutamate modulators for the treatment of cocaine addiction. PMID:20201846

The Impact of Disulfiram Treatment on the Reinforcing Effects of Cocaine: A Randomized Clinical Trial

PubMed Central

Haile, Colin N.; De La Garza, Richard; Mahoney, James J.; Nielsen, David A.; Kosten, Thomas R.; Newton, Thomas F.

2012-01-01

Background Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users. Methods Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebo-controlled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05–16) and in the other cocaine (20 mg) or money. Results Participants chose cocaine more than saline under both disulfiram and placebo conditions (p<0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p<0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p<0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's<0.05–0.01). Conclusions Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research. Trial Registration Clinicaltrials.gov NCT00729300 PMID:23144826

The effects of prenatal cocaine, post-weaning housing and sex on conditioned place preference in adolescent rats.

PubMed

Dow-Edwards, Diana; Iijima, Maiko; Stephenson, Stacy; Jackson, April; Weedon, Jeremy

2014-04-01

Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual's tendency to take and/or abuse drugs is still a matter of debate. This study sought to answer the question "Does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat?" Further, we wanted to assess the possible sex differences and the role of being raised in an enriched versus impoverished environment. Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30 mg/kg (C30), 60 mg/kg (C60), or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and, on postnatal day (PND) 23, placed into isolation cages or enriched cages with three same-sex littermates and stimulus objects. On PND43-47, CPP was determined across a range of cocaine doses. C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males, and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment. These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP mostly in adolescent males prenatally exposed to moderate cocaine doses.

[The history of cocaine in medicine and its importance to the discovery of the different forms of anaesthesia].

PubMed

Grzybowski, Andrzej

2007-01-01

The first description of the use of cocaine by humans can be found in the memoirs of the Florentine traveller Amerigo Vespucci (1451-1512). For the next 300 years mostly the advantages of cocaine use, also as a medication, were emphasized. In 1860 Albert Niemann (1834-1861) isolated an active ingredient of coca leaves, which he named cocaine. After his death, his work was carried on by his disciple Wilhelm Lossen (1838-1906), who finally, in 1865, determined its proper chemical formula. Although the first observations concerning the effect of cocaine on mucous membranes were made by Niemann and Lossen, the first experimental studies involving the application of cocaine to animals were performed by the Peruvian surgeon Moréno y Maïz. In 1880 Basil von Anrep (1852-1925) published the results of his studies concerning the application of cocaine to humans. In the conclusion of his work he recommended cocaine as a surgical anaesthesia. But it was finally Carl Koller (1857-1944) who, in 1884, empirically demonstrated the benefits of cocaine use in medicine, most of all in ophthalmology. Subsequently, within a couple of months, the medical world learnt about and got interested in the use of cocaine for local anaesthesia. William Stewart Halsted (1852-1922) and his collaborator Richard John Hall (1856-1897) began their own research on cocaine injections. Eventually they developed the nerve and regional blocking techniques. Nowadays, due to the potential harmful effects of cocaine and the risk of addiction, the indications for the use of cocaine as an anaesthetic are strictly limited.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration.

PubMed

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-07-01

There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

Cue-induced craving in patients with cocaine use disorder predicts cognitive control deficits toward cocaine cues.

PubMed

DiGirolamo, Gregory J; Smelson, David; Guevremont, Nathan

2015-08-01

Cue-induced craving is a clinically important aspect of cocaine addiction influencing ongoing use and sobriety. However, little is known about the relationship between cue-induced craving and cognitive control toward cocaine cues. While studies suggest that cocaine users have an attentional bias toward cocaine cues, the present study extends this research by testing if cocaine use disorder patients (CDPs) can control their eye movements toward cocaine cues and whether their response varied by cue-induced craving intensity. Thirty CDPs underwent a cue exposure procedure to dichotomize them into high and low craving groups followed by a modified antisaccade task in which subjects were asked to control their eye movements toward either a cocaine or neutral drug cue by looking away from the suddenly presented cue. The relationship between breakdowns in cognitive control (as measured by eye errors) and cue-induced craving (changes in self-reported craving following cocaine cue exposure) was investigated. CDPs overall made significantly more errors toward cocaine cues compared to neutral cues, with higher cravers making significantly more errors than lower cravers even though they did not differ significantly in addiction severity, impulsivity, anxiety, or depression levels. Cue-induced craving was the only specific and significant predictor of subsequent errors toward cocaine cues. Cue-induced craving directly and specifically relates to breakdowns of cognitive control toward cocaine cues in CDPs, with higher cravers being more susceptible. Hence, it may be useful identifying high cravers and target treatment toward curbing craving to decrease the likelihood of a subsequent breakdown in control. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cocaine behavioral economics: From the naturalistic environment to the controlled laboratory setting

PubMed Central

Greenwald, Mark K.; Steinmiller, Caren L.

2017-01-01

Background We previously observed that behavioral economic factors predict naturalistic heroin seeking behavior that correlates with opioid seeking in the experimental laboratory. The present study sought to replicate and extend these prior findings with regular cocaine users. Methods Participants (N = 83) completed a semi-structured interview to establish income-generating and cocaine-purchasing/use repertoire during the past month. Questions addressed sources/amounts of income and expenditures; price (money and time) per purchase; and frequency/amounts of cocaine purchased and consumed. Naturalistic cocaine purchasing and use patterns were: (1) analyzed as a function of income quartile, (2) perturbed by hypothetical changes in cost factors to assess changes in purchasing/use habits, and (3) correlated with experimental cocaine seeking. Results Income was positively related to naturalistic cocaine seeking/use pattern (i.e., income elastic), and behaviors were cost-efficient and sensitive to supply chain. Income was unrelated to proportional expenditure on cocaine (≈55%) but inversely related to food expenditure. In all hypothetical scenarios (changes in income or dealer, loss of income assistance from government or family/friends, and increasing arrest risk when purchasing), the high-income group reported they would continue to use more cocaine daily than other groups. Number of laboratory cocaine choices significantly correlated with cocaine purchase time (positively) and purity of cocaine (negatively) in the naturalistic setting. Conclusions These results replicate and extend findings with regular heroin users, demonstrate the importance of income, cost-efficiency and supply-mindedness in cocaine seeking/use, and suggest that this interview-based approach has good external validity. PMID:24878248

Suppression of Cocaine Self-Administration in Monkeys: Effects of Delayed Punishment

PubMed Central

Woolverton, William L.; Freeman, Kevin B.; Myerson, Joel; Green, Leonard

2014-01-01

Rationale Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. Objective This study examined whether a histamine injection could punish cocaine self-administration in a drug-drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Methods Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37–50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. Results When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to > 80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the non-preferred position, preference for that option increased with delay from ≤ 30% to > 85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Conclusions Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework. PMID:21956240

Suppression of cocaine self-administration in monkeys: effects of delayed punishment.

PubMed

Woolverton, William L; Freeman, Kevin B; Myerson, Joel; Green, Leonard

2012-04-01

Delaying presentation of a drug can decrease its effectiveness as a reinforcer, but the effect of delaying punishment of drug self-administration is unknown. This study examined whether a histamine injection could punish cocaine self-administration in a drug-drug choice, whether delaying histamine would decrease its effectiveness, and whether the effects of delay could be described within a delay discounting framework. Monkeys were implanted with double-lumen catheters to allow separate injection of cocaine and histamine. In discrete trials, subjects first chose between cocaine (50 or 100 μg/kg/inj) alone and an injection of the same dose of cocaine followed immediately by an injection of histamine (0.37-50 μg/kg). Next, they chose between cocaine followed immediately by histamine and cocaine followed by an equal but delayed dose of histamine. When choosing between cocaine alone and cocaine followed immediately by histamine, preference increased with histamine dose from indifference to >80% choice of cocaine alone. When choosing between cocaine followed by immediate histamine and cocaine followed by delayed histamine, monkeys showed strong position preferences. When delayed histamine was associated with the nonpreferred position, preference for that option increased with delay from ≤30% to >85%. The corresponding decrease in choice of the preferred position was well described by a hyperboloid discounting function. Histamine can function as a punisher in the choice between injections of cocaine and delay can decrease its effectiveness as a punisher. The effects of delaying punishment of drug self-administration can be conceptualized within the delay discounting framework.

Constitutive Knockout of Kalirin-7 Leads to Increased Rates of Cocaine Self-Administration

PubMed Central

Kiraly, Drew D.; Nemirovsky, Natali E.; LaRese, Taylor P.; Tomek, Seven E.; Yahn, Stephanie L.; Olive, M. Foster; Eipper, Betty A.

2013-01-01

Kalirin-7 (Kal7) is a Rho-guanine nucleotide exchange factor that is localized in neuronal postsynaptic densities. Kal7 interacts with the NR2B subunit of the NMDA receptor and regulates aspects of dendritic spine dynamics both in vitro and in vivo. Chronic treatment with cocaine increases dendritic spine density in the nucleus accumbens (NAc) of rodents and primates. Kal7 mRNA and protein are upregulated in the NAc following cocaine treatment, and the presence of Kal7 is necessary for the normal proliferation of dendritic spines following cocaine use. Mice that constitutively lack Kal7 [Kalirin-7 knockout mice (Kal7KO)] demonstrate increased locomotor sensitization to cocaine and a decreased place preference for cocaine. Here, using an intravenous cocaine self-administration paradigm, Kal7KO mice exhibit increased administration of cocaine at lower doses as compared with wild-type (Wt) mice. Analyses of mRNA transcript levels from the NAc of mice that self-administered saline or cocaine reveal that larger splice variants of the Kalrn gene are increased by cocaine more dramatically in Kal7KO mice than in Wt mice. Additionally, transcripts encoding the NR2B subunit of the NMDA receptor increased in Wt mice that self-administered cocaine but were unchanged in similarly experienced Kal7KO mice. These findings suggest that Kal7 participates in the reinforcing effects of cocaine, and that Kal7 and cocaine interact to alter the expression of genes related to critical glutamatergic signaling pathways in the NAc. PMID:23894151

Differential vulnerability to the punishment of cocaine related behaviours: effects of locus of punishment, cocaine taking history and alternative reinforcer availability.

PubMed

Pelloux, Yann; Murray, Jennifer E; Everitt, Barry J

2015-01-01

The availability of alternative reinforcement has been shown to reduce drug use, but it remains unclear whether it facilitates a reduction or cessation of drug seeking or taking. We compared the effects of punishment of cocaine seeking or taking behaviour after brief or extended cocaine-taking histories when behavioural reallocation was facilitated or not by making available an alternative ingestive reinforcer (sucrose). In the first experiment, punishment of either seeking or taking responses was introduced immediately after training on the seeking-taking chained schedule. In the second experiment, punishment of cocaine seeking was introduced after 12 additional days of either 1 or 6 h daily access to cocaine self-administration. In both experiments, beginning 1 week before the introduction of punishment, a subset of rats had concurrent nose poke access to sucrose while seeking or taking cocaine. The presence of an alternative source of reinforcement markedly facilitated behavioural reallocation from punished cocaine taking after acquisition. It also facilitated punishment-induced suppression of cocaine seeking after an extensive cocaine self-administration history likely by prompting goal-directed motivational control over drug use. However, a significant proportion of rats were deemed compulsive-maintaining drug use after an extensive cocaine history despite the presence of abstinence-promoting positive and negative incentives. Making available an alternative reinforcer facilitates disengagement from punished cocaine use through at least two different processes but remains ineffective in a subpopulation of vulnerable animals, which continued to seek cocaine despite the aversive consequence of punishment and the presence of the alternative positive reinforcer.

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans

PubMed Central

Newton, Thomas F.; Haile, Colin N.; Mahoney, James J.; Shah, Ravi; Verrico, Christopher D.; De La Garza, Richard; Kosten, Thomas R.

2015-01-01

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine’s reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0 mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40 mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. PMID:26239766

Dissociable effects of cocaine and yohimbine on impulsive action and relapse to cocaine seeking.

PubMed

Broos, Nienke; van Mourik, Yvar; Schetters, Dustin; De Vries, Taco J; Pattij, Tommy

2017-11-01

A strong association has been demonstrated between various forms of impulsivity and addiction-like behavior in both humans and rats. In this study, we investigated how impulsive action, as measured in the 5-choice serial reaction time task (5-CSRTT), is affected during various stages of cocaine taking and seeking and by relapse-provoking stimuli in animals that were trained both in an intravenous cocaine self-administration paradigm and in the 5-CSRTT. Rats were concurrently trained in the 5-CSRTT and cocaine self-administration protocol, and subsequently, the effects of cocaine (7.5 mg/kg) and the pharmacological stressor yohimbine (1.25 mg/kg) were tested in both paradigms. Cocaine self-administration (5 h/day) transiently altered impulsive action and increased errors of omission in the 5-CSRTT. Pharmacological challenges with cocaine and yohimbine induced increments in impulsive action and reinstated cocaine-seeking responses within the same animals. Further analyses revealed that the effects of cocaine and yohimbine on impulsive action did not correlate with their effects on reinstatement of cocaine seeking. These data suggest that although impulsive action and relapse can be pharmacologically modulated in the same direction within individuals, these effects appear not to be directly coupled.

Exploring the feasibility of an anti-idiotypic cocaine vaccine: analysis of the specificity of anticocaine antibodies (Ab1) capable of inducing Ab2beta anti-idiotypic antibodies.

PubMed

Schabacker, D S; Kirschbaum, K S; Segre, M

2000-05-01

Conventional vaccination with the cocaine molecule conjugated to a protein carrier is a new approach in the treatment of addiction. Experimentally, this strategy has been shown to alter the pharmacokinetics as well as the psychostimulant effect of a cocaine challenge. The purpose of this study was to investigate whether a more stable and less controversial molecule, an anti-idiotypic antibody, which mimics the configuration of the cocaine molecule (Ab2beta), could be successfully used instead of cocaine. Two cocaine conjugates that presented different areas of the cocaine molecule to the immune system were used to produce monoclonal antibodies specific for cocaine (Ab1). Several anti-idiotypic antibodies were then produced. Four were identified as Ab2beta, or internal images of the antigen; when injected into BALB/c mice, they elicited an anticocaine response. The anticocaine response elicited by one of the four Ab2beta (K1-4c) was sufficient to significantly reduce the level of cocaine that targeted the brain following cocaine challenge, compared with the level of cocaine found in the brain of control animals immunized with irrelevant antibody. In conclusion, the possibility of an anti-idiotypic vaccine seems to be worth pursuing.

Using a Novel Alternative to Drug Choice in a Human Laboratory Model of a Cocaine Binge: A Game of Chance

PubMed Central

Vosburg, Suzanne K.; Haney, Margaret; Rubin, Eric; Foltin, Richard W.

2010-01-01

Human laboratory studies have shown that, once initiated, cocaine self-administration is difficult to disrupt using non-drug alternatives. This inpatient study examined whether binge self-administration of cocaine could be altered by an immediate, non-drug reinforcer. Ten cocaine-dependent participants completed 5 consecutive laboratory session days with 2 sessions per day (a model binge), 9 days where cocaine was not available, and subsequent 2 laboratory session days where cocaine was again available (a second model binge). In each laboratory session, participants could choose to either self-administer smoked cocaine or play a game of chance by drawing a pre-determined number of balls from a bingo wheel. Balls were worth monetary amounts from $0 – $20. Participants’ choice to smoke cocaine varied as a function of number of balls drawn. Thus, this game of chance served as an alternative reinforcer to smoking cocaine. Choice varied lawfully as a function of the number of opportunities to earn money indicating that an immediate behavioral alternative can reduce cocaine self-administration after initiation of use. The current model could be used to evaluate whether behavioral and pharmacological manipulations shift choice from cocaine to a non-drug alternative. PMID:20346597

Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine.

PubMed

Thomsen, Morgane; Barrett, Andrew C; Negus, S Stevens; Caine, S Barak

2013-03-01

We have adapted a nonhuman primate model of cocaine versus food choice to the rat species. To evaluate the procedure, we tested cocaine versus food choice under a variety of environmental manipulations as well as pharmacological pretreatments. Complete cocaine-choice dose-effect curves (0-1.0 mg/kg/infusion) were obtained for each condition under concurrent fixed ratio schedules of reinforcement. Percentage of responding emitted on the cocaine-reinforced lever was not affected significantly by removal of cocaine-associated visual or auditory cues, but it was decreased after removal of response-contingent or response-independent cocaine infusions. Cocaine choice was sensitive to the magnitude and fixed ratio requirement of both the cocaine and food reinforcers. We also tested the effects of acute (0.32, 0.56, 1.0, 1.8 mg/kg) and chronic (0.1, 0.32 mg/kg/hr) d-amphetamine treatment on cocaine choice. Acute and chronic d-amphetamine had opposite effects, with acute increasing and chronic decreasing cocaine choice, similar to observations in humans and in nonhuman primates. The results suggest feasibility and utility of the choice procedure in rats and support its comparability to similar procedures used in humans and monkeys. © Society for the Experimental Analysis of Behavior.

Prenatal and postnatal cocaine exposure predict teen cocaine use

PubMed Central

Delaney-Black, Virginia; Chiodo, Lisa M.; Hannigan, John H.; Greenwald, Mark K.; Janisse, James; Patterson, Grace; Huestis, Marilyn A.; Partridge, Robert T.; Ager, Joel; Sokol, Robert J.

2015-01-01

Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n = 316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use. PMID:20609384

Prenatal and postnatal cocaine exposure predict teen cocaine use.

PubMed

Delaney-Black, Virginia; Chiodo, Lisa M; Hannigan, John H; Greenwald, Mark K; Janisse, James; Patterson, Grace; Huestis, Marilyn A; Partridge, Robert T; Ager, Joel; Sokol, Robert J

2011-01-01

Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n=316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use. Copyright © 2010 Elsevier Inc. All rights reserved.

Passive inhalation of cocaine.

PubMed

Cone, E J; Yousefnejad, D; Hillsgrove, M J; Holicky, B; Darwin, W D

1995-10-01

Six healthy male volunteers were exposed to the vapor of 100 and 200 mg freebase cocaine heated to a temperature of 200 degrees C in an unventilated room (12,600-L volume) for a period of 1 h. No pharmacological effects were detected as a result of the exposure. Blood specimens collected immediately following exposure were negative for cocaine and metabolites. Urine specimens analyzed by gas chromatography-mass spectrometry contained peak concentrations of benzoylecgonine that ranged from 22 to 123 ng/mL. The peak excretion time for benzoylecgonine following passive exposure was approximately 5 h. The amount of cocaine inhaled by the subjects during passive exposure was estimated from room air measurements of cocaine to be approximately 0.25 mg. The total amount of cocaine (cocaine plus metabolites) excreted in urine by the six subjects ranged from 0.04 to 0.21 mg. For comparison, the six subjects also received an intravenous injection of 1 mg cocaine hydrochloride. Four of six subjects screened positive (300-ng/mL cutoff concentration) following the injection, indicating that the minimum amount of cocaine in these subjects necessary to produce positive results was approximately 1 mg. A second passive inhalation study was undertaken in which specimens were collected from research staff who assisted in a series of experimental studies with "crack" (freebase cocaine) smokers. The research staff remained in close vicinity while the crack smokers smoked three doses of freebase cocaine (12.5, 25, and 50 mg) over a period of 4 h. As a result, staff members were passively exposed to sidestream smoke from crack pipes and to breath exhalation from the crack smokers. Urine specimens from the staff members contained a maximum of 6 ng/mL benzoylecgonine. Only traces (less than 1 ng/mL) of cocaine were detected in any specimen. Overall, these studies demonstrated that individuals exposed to cocaine smoke under naturalistic or artificial conditions absorbed small amounts of cocaine that were insufficient to produce positive urine specimens at standard Department of Health and Human Services cutoffs. However, passive exposure conditions that would result in absorption of cocaine in amounts exceeding 1 mg could result in the production of cocaine-positive urine specimens.

Dissociable Effects of Cocaine Dependence on Reward Processes: The Role of Acute Cocaine and Craving.

PubMed

Rose, Emma Jane; Salmeron, Betty Jo; Ross, Thomas J; Waltz, James; Schweitzer, Julie B; Stein, Elliot A

2017-02-01

The relative impact of chronic vs acute cocaine on dependence-related variability in reward processing in cocaine-dependent individuals (CD) is not well understood, despite the relevance of such effects to long-term outcomes. To dissociate these effects, CD (N=15) and healthy controls (HC; N=15) underwent MRI two times while performing a monetary incentive delay task. Both scans were identical across subjects/groups, except that, in a single-blind, counterbalanced design, CD received intravenous cocaine (30 mg/70 kg) before one session (CD+cocaine) and saline in another (CD+saline). Imaging analyses focused on activity related to anticipatory valence (gain/loss), anticipatory magnitude (small/medium/large), and reinforcing outcomes (successful/unsuccessful). Drug condition (cocaine vs saline) and group (HC vs CD+cocaine or CD+saline) did not influence valence-related activity. However, compared with HC, magnitude-related activity for gains was reduced in CD in the left cingulate gyrus post-cocaine and in the left putamen in the abstinence/saline condition. In contrast, magnitude-dependent activity for losses increased in CD vs HC in the right inferior parietal lobe post-cocaine and in the left superior frontal gyrus post-saline. Across outcomes (ie, successful and unsuccessful) activity in the right habenula decreased in CD in the abstinence/saline condition vs acute cocaine and HC. Cocaine-dependent variability in outcome- and loss-magnitude activity correlated negatively with ratings of cocaine craving and positively with how high subjects felt during the scanning session. Collectively, these data suggest dissociable effects of acute cocaine on non-drug reward processes, with cocaine consumption partially ameliorating dependence-related insensitivity to reinforcing outcomes/'liking', but having no discernible effect on dependence-related alterations in incentive salience/'wanting'. The relationship of drug-related affective sequelae to non-drug reward processing suggests that CD experience a general alteration of reward function and may be motivated to continue using cocaine for reasons beyond desired drug-related effects. This may have implications for individual differences in treatment efficacy for approaches that rely on reinforcement strategies (eg, contingency management) and for the long-term success of treatment.

Decreased Cocaine Motor Sensitization and Self-Administration in Mice Overexpressing Cannabinoid CB2 Receptors

PubMed Central

Aracil-Fernández, Auxiliadora; Trigo, José M; García-Gutiérrez, María S; Ortega-Álvaro, Antonio; Ternianov, Alexander; Navarro, Daniela; Robledo, Patricia; Berbel, Pere; Maldonado, Rafael; Manzanares, Jorge

2012-01-01

The potential involvement of the cannabinoid CB2 receptors (CB2r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB2r (CB2xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB2r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB1 receptors in the NAcc were also studied in both genotypes. CB2xP mice showed decreased motor response to acute administration of cocaine (10–20 mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB2xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB2r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB2xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB2xP than in cocaine-pretreated WT mice. These results revealed that CB2r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction. PMID:22414816

Promising medications for cocaine dependence treatment.

PubMed

Somaini, Lorenzo; Donnini, Claudia; Raggi, Maria A; Amore, Mario; Ciccocioppo, Roberto; Saracino, Maria A; Kalluppi, Marsida; Malagoli, Marco; Gerra, Maria L; Gerra, Gilberto

2011-05-01

Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents.

Cocaine-and-Amphetamine-Regulated-Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: lack of sex differences

PubMed Central

Job, Martin O.; Perry, JoAnna; Shen, Li L.; Kuhar, Michael J.

2014-01-01

Cocaine-and-Amphetamine Regulated Transcript peptide (CART peptide) is known for having an inhibitory effect on dopamine (DA)- and cocaine-mediated actions and is postulated to be a homeostatic, regulatory factor in the nucleus accumbens (NAc). Some sex differences in cocaine-mediated LMA and in the expression and function of CART peptide have been reported. However, it is not known if the inhibitory effect of CART peptide on cocaine-mediated locomotor activity (LMA) is sexually dimorphic. In this study, the effect of CART 55-102 on LMA due to intra-NAc DA and i.p. cocaine were determined in male and female Sprague-Dawley rats. The results show that CART 55-102 blunted or reduced both the DA- and cocaine-induced LMA in both males and females. In conclusion, CART peptide is effective in blunting DA- and cocaine-mediated LMA in both males and females. PMID:24630272

Recent advances for the treatment of cocaine abuse: central nervous system immunopharmacotherapy.

PubMed

Dickerson, Tobin J; Janda, Kim D

2005-10-19

Cocaine addiction continues to be a major health and societal problem in spite of governmental efforts devoted toward educating the public of the dangers of illicit drug use. A variety of pharmacotherapies and psychosocial programs have been proposed in an effort to provide a method for alleviation of the physical and psychological symptoms of cocaine abuse. Unfortunately, these methods have been met with limited success, illustrating a critical need for new effective approaches for the treatment of cocaine addiction. Recently an alternative cocaine abuse treatment strategy was proposed using intranasal administration of an engineered filamentous bacteriophage displaying cocaine-sequestering antibodies on its surface. These phage particles are an effective vector for CNS penetration and are capable of binding cocaine, thereby blocking its behavioral effects in a rodent model. The convergence of phage display and immunopharmacotherapy has allowed for an investigation of the efficacy of protein-based therapeutics acting within the CNS on the effects of cocaine in animal models and has uncovered a new tool in the battle against cocaine addiction.

THE MEDIAL PREOPTIC AREA MODULATES COCAINE-INDUCED LOCOMOTION IN MALE RATS

PubMed Central

Will, Ryan G.; Martz, Julia R.; Dominguez, Juan M.

2016-01-01

Cocaine-induced locomotion is mediated by dopamine in the nucleus accumbens (NAc). Recent evidence indicates that the medial preoptic area (mPOA), a region in the rostral hypothalamus, modulates cocaine-induced dopamine in the NAc. Specifically, rats with lesions of the mPOA experienced a greater increase in dopamine following cocaine administration than rats with sham lesions. Whether the mPOA similarly influences cocaine-induced locomotion is not known. Here we examined whether radiofrequency or neurotoxic lesions of the mPOA in male rats influence changes in locomotion that follow cocaine administration. Locomotion was measured following cocaine administration in male rats with neurotoxic, radiofrequency, or sham lesions of the mPOA. Results indicate that bilateral lesions of the mPOA facilitated cocaine-induced locomotion. This facilitation was independent of lesion type, as increased locomotion was observed with either approach. These findings support a role for the mPOA as an integral region in the processing of cocaine-induced behavioral response, in this case locomotor activity. PMID:26947755

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

Wood, Suzanne C; Fay, Jonathan; Sage, Jennifer R; Anagnostaras, Stephan G

2007-01-25

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

Subtypes of cocaine abusers.

PubMed

Weiss, R D; Mirin, S M

1986-09-01

We have characterized five subtypes of cocaine abusers on the basis of clinical presentation, family history data, and response to specific treatment interventions. These include depressed patients who value the euphorigenic effects of the drug, patients with bipolar or cyclothymic disorder who use cocaine to augment manic or hypomanic symptoms or to alleviate depression, adults with ADD, residual type, who find that cocaine has a paradoxical effect of increasing attention span and decreasing motor restlessness, patients with narcissistic and borderline personality disorders who use cocaine for its social prestige and because it bolsters self-esteem, and patients with antisocial personality disorder who use cocaine as part of an overall pattern of antisocial behavior. Although not all cocaine abusers fit neatly into these categories, careful psychiatric evaluation and subtyping is essential in designing a specific treatment program for these patients. As the prevalence rate of cocaine abuse increases, studies that examine the efficacy of various treatment approaches for specific subtypes of cocaine abusers will be essential. It is hoped that our work will be a step in that direction.

Evidence on unusual way of cocaine smuggling: cocaine-polymethyl methacrylate (PMMA) solid solution--study of clandestine laboratory samples.

PubMed

Gostic, T; Klemenc, S

2007-07-04

An abandoned clandestine laboratory was seized in Slovenia. All confiscated exhibits were analysed in a forensic laboratory, where the following analytical methods were applied: capillary gas chromatography coupled with mass spectrometry (GC-MS) combined also by solid-phase micro extraction (SPME) and pyrolysis (Py) technique, Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy with energy dispersive X-ray detector (SEM-EDX). The most interesting analytical findings can be summarised as follows: at the crime scene some plastic pieces, which contained cocaine dissolved (as solid solution) in polymethyl methacrylate-plexiglass (PMMA), were found. The highest cocaine concentration measured in the plastic sample was about 15% by weight. Two larger lumps of material (12 and 3 kg) were composed mainly of PMMA and CaCO3 and contained only 0.4 and 0.5% of cocaine, respectively. As for the low cocaine concentration, we assume that those two lumps of material represent discarded waste product--residue after the isolation of cocaine from plastic. Higher quantities of pure solvents (41 l) and solvent mixtures (87 l) were seized. We identified three types of pure solvents (acetone, gasoline and benzine) and two different types of solvent mixtures (benzine/acetone and gasoline/acetone). The total seized volume (87 l) of solvent mixtures holds approximately 395 g of solid residue formed mainly of PMMA and cocaine. Obviously solvent mixtures were used for isolation of cocaine from the plastic. Small quantities of relatively pure cocaine base were identified on different objects. There were two cotton sheets, most probably used for filtration. One sheet had traces of cocaine base (76% purity) on the surface, while cocaine in hydrochloride form (96%) was identified on the other sheet. GC-MS analyses of micro traces isolated from analytical balances showed the presence of cocaine and some common adulterants: phenacetine, lidocaine and procaine. A cocaine sample compressed in the shape of block was also seized. The above analytical findings inferred us to the conclusion that the illicit laboratory was used for the isolation of cocaine from PMMA resin. Further more, analyses confirm that not only isolation but also further manipulation of cocaine, i.e. adulteration/dilution, as well as the formation of cocaine blocks took place in the house. The information obtained through analyses also allowed us to make some hypotheses about possible multistage isolation procedure.

Positional linker effects in haptens for cocaine immunopharmacotherapy.

PubMed

Ino, Akira; Dickerson, Tobin J; Janda, Kim D

2007-08-01

Cocaine use remains a serious problem, despite intensive efforts to curb abuse. Given the lack of effective pharmacotherapeutics for the treatment of cocaine addiction, research groups have targeted immunopharmacotherapy in which the drug user's immune system is trained to recognize and remove cocaine prior to entry into the central nervous system. Antibody cocaine esterases and simple binders have been procured, however, rates and/or affinities still need improvement before clinical trials are warranted. Herein, we report the synthesis and testing of two new haptens for the procurement of cocaine binding antibodies and cocaine esterase catalytic antibodies. Central in the design of these haptens was the placement of the linker functionality distal from the anticipated cocaine epitopes in an attempt to bury the hapten deep within an antibody combining site to gain possible entropic and enthalpic advantages.

The Development of a Preference for Cocaine over Food Identifies Individual Rats with Addiction-Like Behaviors

PubMed Central

Perry, Adam N.; Westenbroek, Christel; Becker, Jill B.

2013-01-01

Rationale Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards. Objectives To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this “addicted” phenotype. Methods Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward. Results Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic. Conclusions The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex. PMID:24260227

Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity[S

PubMed Central

Shi, Xiaolei; Yao, Dan; Gosnell, Blake A.; Chen, Chi

2012-01-01

During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. PMID:22904346

Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ΔFosB.

PubMed

Hasbi, Ahmed; Perreault, Melissa L; Shen, Maurice Y F; Fan, Theresa; Nguyen, Tuan; Alijaniaram, Mohammed; Banasikowski, Tomek J; Grace, Anthony A; O'Dowd, Brian F; Fletcher, Paul J; George, Susan R

2017-01-01

A significant subpopulation of neurons in rat nucleus accumbens (NAc) coexpress dopamine D1 and D2 receptors, which can form a D1-D2 receptor complex, but their relevance in addiction is not known. The existence of the D1-D2 heteromer in the striatum of rat and monkey was established using in situ PLA, in situ FRET and co-immunoprecipitation. In rat, D1-D2 receptor heteromer activation led to place aversion and abolished cocaine CPP and locomotor sensitization, cocaine intravenous self-administration and reinstatement of cocaine seeking, as well as inhibited sucrose preference and abolished the motivation to seek palatable food. Selective disruption of this heteromer by a specific interfering peptide induced reward-like effects and enhanced the above cocaine-induced effects, including at a subthreshold dose of cocaine. The D1-D2 heteromer activated Cdk5/Thr75-DARPP-32 and attenuated cocaine-induced pERK and ΔFosB accumulation, together with inhibition of cocaine-enhanced local field potentials in NAc, blocking thus the signaling pathway activated by cocaine: D1R/cAMP/PKA/Thr34-DARPP-32/pERK with ΔFosB accumulation. In conclusion, our results show that the D1-D2 heteromer exerted tonic inhibitory control of basal natural and cocaine reward, and therefore initiates a fundamental physiologic function that limits the liability to develop cocaine addiction.

Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ΔFosB

PubMed Central

Hasbi, Ahmed; Perreault, Melissa L.; Shen, Maurice Y. F.; Fan, Theresa; Nguyen, Tuan; Alijaniaram, Mohammed; Banasikowski, Tomek J.; Grace, Anthony A.; O'Dowd, Brian F.; Fletcher, Paul J.; George, Susan R.

2018-01-01

A significant subpopulation of neurons in rat nucleus accumbens (NAc) coexpress dopamine D1 and D2 receptors, which can form a D1-D2 receptor complex, but their relevance in addiction is not known. The existence of the D1-D2 heteromer in the striatum of rat and monkey was established using in situ PLA, in situ FRET and co-immunoprecipitation. In rat, D1-D2 receptor heteromer activation led to place aversion and abolished cocaine CPP and locomotor sensitization, cocaine intravenous self-administration and reinstatement of cocaine seeking, as well as inhibited sucrose preference and abolished the motivation to seek palatable food. Selective disruption of this heteromer by a specific interfering peptide induced reward-like effects and enhanced the above cocaine-induced effects, including at a subthreshold dose of cocaine. The D1-D2 heteromer activated Cdk5/Thr75-DARPP-32 and attenuated cocaine-induced pERK and ΔFosB accumulation, together with inhibition of cocaine-enhanced local field potentials in NAc, blocking thus the signaling pathway activated by cocaine: D1R/cAMP/PKA/Thr34-DARPP-32/pERK with ΔFosB accumulation. In conclusion, our results show that the D1-D2 heteromer exerted tonic inhibitory control of basal natural and cocaine reward, and therefore initiates a fundamental physiologic function that limits the liability to develop cocaine addiction. PMID:29354053

A Combination of Buprenorphine and Naltrexone Blocks Compulsive Cocaine Intake in Rodents Without Producing Dependence

PubMed Central

Wee, Sunmee; Vendruscolo, Leandro F.; Misra, Kaushik K.; Schlosburg, Joel E.; Koob, George F.

2012-01-01

Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non–opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist–induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction. PMID:22875830

A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence.

PubMed

Wee, Sunmee; Vendruscolo, Leandro F; Misra, Kaushik K; Schlosburg, Joel E; Koob, George F

2012-08-08

Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non-opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist-induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction.

Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences

PubMed Central

DePoy, L M; Allen, A G; Gourley, S L

2016-01-01

Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called ‘reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, ‘stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in ‘stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure. PMID:27576164

Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons

PubMed Central

Ka, Minhan; Kook, Yeon-Hee; Liao, Ke; Buch, Shilpa; Kim, Woo-Yang

2016-01-01

Cocaine is a highly addictive narcotic associated with dendritic spine plasticity in the striatum. However, it remains elusive whether cocaine modifies spines in a cell type-specific or region-specific manner or whether it alters different types of synapses in the brain. In addition, there is a paucity of data on the regulatory mechanism(s) involved in cocaine-induced modification of spine density. In the current study, we report that cocaine exposure differentially alters spine density, spine morphology, and the types of synapses in hippocampal and cortical neurons. Cocaine exposure in the hippocampus resulted in increased spine density, but had no significant effect on cortical neurons. Although cocaine exposure altered spine morphology in both cell types, the patterns of spine morphology were distinct for each cell type. Furthermore, we observed that cocaine selectively affects the density of excitatory synapses. Intriguingly, in hippocampal neurons cocaine-mediated effects on spine density and morphology involved sigma-1 receptor (Sig-1 R) and its downstream TrkB signaling, which were not the case in cortical neurons. Furthermore, pharmacological inhibition of Sig-1 R prevented cocaine-induced TrkB activation in hippocampal neurons. Our findings reveal a novel mechanism by which cocaine induces selective changes in spine morphology, spine density, and synapse formation, and could provide insights into the cellular basis for the cognitive impairment observed in cocaine addicts. PMID:27735948

The long-term effects of cocaine use on cognitive functioning: A systematic critical review.

PubMed

Frazer, Kirsten M; Richards, Qwynten; Keith, Diana R

2018-08-01

The predominant view of chronic cocaine use maintains that it causes a broad range of cognitive deficits. However, concerns about the possibly deleterious impact of cocaine on cognitive functioning have yet to be thoroughly vetted. This review addresses the impact of cocaine use on such cognitive domains as executive function, memory, language, and psychomotor speed. Additionally, relevant neuroimaging data is considered to understand the neural basis underlying cocaine-related effects on cognitive functioning. We searched PubMed, Google Scholar, and Embase using the search terms "cocaine and cognition," "cocaine and cognitive functioning," and "cocaine and cognitive deficits or impairment." To meet inclusion criteria we evaluated only cognitive and neuroimaging studies describing the long-term effects of cocaine on cognitive functioning published from 1999 to 2016. The majority of studies reported statistically significant differences between cocaine users and non-drug-using controls in brain structures, blood-oxygen-level dependent signals, and brain metabolism. However, differences in cognitive performance were observed on a minority of measures. Additionally, the majority of studies were not compared against normative data. The current evidence does not support the view that chronic cocaine use is associated with broad cognitive deficits. The view that cocaine users have broad cognitive deficits is inaccurate based upon current evidence, and the perpetuation of this view may have negative implications for treatment programs and development of public policies. Copyright © 2018 Elsevier B.V. All rights reserved.

Electrochemical, photoelectrochemical, and surface plasmon resonance detection of cocaine using supramolecular aptamer complexes and metallic or semiconductor nanoparticles.

PubMed

Golub, Eyal; Pelossof, Gilad; Freeman, Ronit; Zhang, Hong; Willner, Itamar

2009-11-15

Metallic or semiconductor nanoparticles (NPs) are used as labels for the electrochemical, photoelectrochemical, or surface plasmon resonance (SPR) detection of cocaine using a common aptasensor configuration. The aptasensors are based on the use of two anticocaine aptamer subunits, where one subunit is assembled on a Au support, acting as an electrode or a SPR-active surface, and the second aptamer subunit is labeled with Pt-NPs, CdS-NPs, or Au-NPs. In the different aptasensor configurations, the addition of cocaine results in the formation of supramolecular complexes between the NPs-labeled aptamer subunits and cocaine on the metallic surface, allowing the quantitative analysis of cocaine. The supramolecular Pt-NPs-aptamer subunits-cocaine complex allows the detection of cocaine by the electrocatalyzed reduction of H(2)O(2). The photocurrents generated by the CdS-NPs-labeled aptamer subunits-cocaine complex, in the presence of triethanol amine as a hole scavenger, allows the photoelectrochemical detection of cocaine. The supramolecular Au-NPs-aptamer subunits-cocaine complex generated on the Au support allows the SPR detection of cocaine through the reflectance changes stimulated by the electronic coupling between the localized plasmon of the Au-NPs and the surface plasmon wave. All aptasensor configurations enable the analysis of cocaine with a detection limit in the range of 10(-6) to 10(-5) M. The major advantage of the sensing platform is the lack of background interfering signals.

A cocaine context renews drug seeking preferentially in a subset of individuals.

PubMed

Saunders, Benjamin T; O'Donnell, Elizabeth G; Aurbach, Elyse L; Robinson, Terry E

2014-11-01

Addiction is characterized by a high propensity for relapse, in part because cues associated with drugs can acquire Pavlovian incentive motivational properties, and acting as incentive stimuli, such cues can instigate and invigorate drug-seeking behavior. There is, however, considerable individual variation in the propensity to attribute incentive salience to reward cues. Discrete and localizable reward cues act as much more effective incentive stimuli in some rats ('sign-trackers', STs), than others ('goal-trackers', GTs). We asked whether similar individual variation exists for contextual cues associated with cocaine. Cocaine context conditioned motivation was quantified in two ways: (1) the ability of a cocaine context to evoke conditioned hyperactivity and (2) the ability of a context in which cocaine was previously self-administered to renew cocaine-seeking behavior. Finally, we assessed the effects of intra-accumbens core flupenthixol, a nonselective dopamine receptor antagonist, on context renewal. In contrast to studies using discrete cues, a cocaine context spurred greater conditioned hyperactivity, and more robustly renewed extinguished cocaine seeking in GTs than STs. In addition, cocaine context renewal was blocked by antagonism of dopamine receptors in the accumbens core. Thus, contextual cues associated with cocaine preferentially acquire motivational control over behavior in different individuals than do discrete cues, and in these individuals the ability of a cocaine context to create conditioned motivation for cocaine requires dopamine in the core of the nucleus accumbens. We speculate that different individuals may be preferentially sensitive to different 'triggers' of relapse.

A generalized matching law analysis of cocaine vs. food choice in rhesus monkeys: effects of candidate 'agonist-based' medications on sensitivity to reinforcement.

PubMed

Hutsell, Blake A; Negus, S Stevens; Banks, Matthew L

2015-01-01

We have previously demonstrated reductions in cocaine choice produced by either continuous 14-day phendimetrazine and d-amphetamine treatment or removing cocaine availability under a cocaine vs. food choice procedure in rhesus monkeys. The aim of the present investigation was to apply the concatenated generalized matching law (GML) to cocaine vs. food choice dose-effect functions incorporating sensitivity to both the relative magnitude and price of each reinforcer. Our goal was to determine potential behavioral mechanisms underlying pharmacological treatment efficacy to decrease cocaine choice. A multi-model comparison approach was used to characterize dose- and time-course effects of both pharmacological and environmental manipulations on sensitivity to reinforcement. GML models provided an excellent fit of the cocaine choice dose-effect functions in individual monkeys. Reductions in cocaine choice by both pharmacological and environmental manipulations were principally produced by systematic decreases in sensitivity to reinforcer price and non-systematic changes in sensitivity to reinforcer magnitude. The modeling approach used provides a theoretical link between the experimental analysis of choice and pharmacological treatments being evaluated as candidate 'agonist-based' medications for cocaine addiction. The analysis suggests that monoamine releaser treatment efficacy to decrease cocaine choice was mediated by selectively increasing the relative price of cocaine. Overall, the net behavioral effect of these pharmacological treatments was to increase substitutability of food pellets, a nondrug reinforcer, for cocaine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences.

PubMed

Cosgrove, Kelly P; Hunter, Robb G; Carroll, Marilyn E

2002-10-01

This experiment examines the effect of access to a running-wheel on intravenous cocaine self-administration in male and female rats. Rats maintained at 85% of their free-feeding body weight were first exposed to the running-wheel alone during the 6-h sessions until behavior stabilized for 14 days. Intravenous cannulae were then implanted, and the rats were trained to self-administer a low dose of cocaine (0.2 mg/kg) under a fixed-ratio (FR 1) schedule during the 6-h sessions, while the wheel remained inactive and cocaine self-administration stabilized (cocaine-only condition). Next, the wheel access and cocaine self-administration were concurrently available followed by a period of cocaine-only. Behavior was allowed to stabilize for 10 days at each phase. During wheel access, cocaine infusions decreased by 21.9% in males and 70.6% in females compared to the cocaine-only condition; the effect was statistically significant in females. Infusions increased to baseline levels when wheel access was terminated. When cocaine infusions were concurrently available, wheel revolutions were reduced by 63.7% and 61.5% in males and females, respectively, compared to the wheel-only condition. This result did not differ due to sex, but it was statistically significant when data from males and females were combined. These results indicate that wheel-running activity had a greater suppressant effect on cocaine self-administration in females than in males, and in females, wheel-running and cocaine self-administration are substitutable as reinforcers.

Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats.

PubMed

Zlebnik, Natalie E; Anker, Justin J; Carroll, Marilyn E

2012-12-01

Concurrent access to an exercise wheel decreases cocaine self-administration under short access (5 h/day for 5 days) conditions and suppresses cocaine-primed reinstatement in adult rats. The effect of exercise (wheel running) on the escalation of cocaine intake during long access (LgA, 6 h/day for 26 days) conditions was evaluated. Adolescent and adult female rats acquired wheel running, and behavior was allowed to stabilize for 3 days. They were then implanted with an iv catheter and allowed to self-administer cocaine (0.4 mg/kg, iv) during 6-h daily sessions for 16 days with concurrent access to either an unlocked or a locked running wheel. Subsequently, for ten additional sessions, wheel access conditions during cocaine self-administration sessions were reversed (i.e., locked wheels became unlocked and vice versa). In the adolescents, concurrent access to the unlocked exercise wheel decreased responding for cocaine and attenuated escalation of cocaine intake irrespective of whether the locked or unlocked condition came first. However, cocaine intake increased when the wheel was subsequently locked for the adolescents that had initial access to an unlocked wheel. Concurrent wheel access either before or after the locked wheel access did not reduce cocaine intake in adults. Wheel running reduced cocaine intake during LgA conditions in adolescent but not adult rats, and concurrent access to the running wheel was necessary. These results suggest that exercise prevents cocaine seeking and that this effect is more pronounced in adolescents than adults.

The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors.

PubMed

Perry, Adam N; Westenbroek, Christel; Becker, Jill B

2013-01-01

Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards. To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this "addicted" phenotype. Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward. Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic. The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.

Intracellular mechanisms of cocaine-memory reconsolidation in the basolateral amygdala and dorsal hippocampus

NASA Astrophysics Data System (ADS)

Wells, Audrey Marie

The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U0126 was administered after exposure to an unpaired context), suggesting that ERK in the BLA plays a critical role in restabilizing contextual cocaine-related memories. Next, Experiment 2 evaluated the hypothesis that the transcription factor (TF) nuclear factor-kappaB (NF-kappaB) would also critically mediate instrumental cocaine-memory reconsolidation in the BLA. Remarkably, the NF-kappaB inhibitor, sulfasalazine (SSZ), administered bilaterally into the BLA following cocaine-memory reactivation, did not significantly alter subsequent cocaine-seeking behavior, relative to VEH, despite producing an observable trend for an enhancement in this behavior. Future studies will be needed to further examine this relationship, but the present findings may suggest that NF-kappaB TFs acts as negative regulators of cocaine-memory reconsolidation. Finally, Experiment 3 tested the hypothesis that members of the Src family of tyrosine kinases (SFKs) are obligatory for instrumental cocaine-memory reconsolidation. Consistent with our hypothesis, PP2, a nonspecific inhibitor of SFKs, administered bilaterally into the DH after cocaine-memory reactivation, attenuated subsequent drug-context induced motivation for cocaine, relative to VEH, in a memory reactivation-dependent manner. This effect was associated with a preferential disruption of SFK-mediated phosphorylation of the NR2a N-methyl-D-aspartate receptor (NMDAR) subunit. Together, these findings begin to illuminate how the BLA and DH may subserve the long-term stability of maladaptive cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior.

Cocaine-related deaths.

PubMed

Lora-Tamayo, C; Tena, T; Rodriguez, A

1994-07-15

Cocaine availability has been increasing in Spain in the past few years. A review of all the toxicological analyses carried out at the Madrid Department of the Instituto Nacional de Toxicología, with subjects who had died of drugs from 1990 to 1992, found 533 persons who had cocaine in their blood and/or tissues; 450 (84%) deaths involved cocaine and heroin together whereas 83 (16%) deaths involved cocaine with an absence of heroin. This paper reports the circumstances, cocaine and benzoylecgonine concentrations in the blood and other toxicological findings for the two major groups of deaths where cocaine was found with an absence of heroin, i.e., possible overdose cases (35 cases) and traffic accidents (23 cases).

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

PubMed Central

Brimijoin, Stephen; Gao, Yang; Anker, Justin J; Gliddon, Luke A; LaFleur, David; Shah, R; Zhao, Qinghai; Singh, M; Carroll, Marilyn E

2008-01-01

Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans. PMID:18199998

A human recombinant monoclonal antibody to cocaine: Preparation, characterization and behavioral studies

PubMed Central

Eubanks, Lisa M.; Ellis, Beverly A.; Cai, Xiaoqing; Schlosburg, Joel E.; Janda, Kim D.

2014-01-01

Cocaine abuse remains prevalent worldwide and continues to be a major health concern; nonetheless, there is no effective therapy. Immunopharmacothery has emerged as a promising treatment strategy by which anti-cocaine antibodies bind to the drug blunting its effects. Previous passive immunization studies using our human monoclonal antibody, GNCgzk, resulted in protection against cocaine overdose and acute toxicity. To further realize the clinical potential of this antibody, a recombinant IgG form of the antibody has been produced in mammalian cells. This antibody displayed a high binding affinity for cocaine (low nanomolar) in line with the superior attributes of the GNCgzk antibody and reduced cocaine-induced ataxia in a cocaine overdose model. PMID:25205191

Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn.

PubMed

Carey, A N; Borozny, K; Aldrich, J V; McLaughlin, J P

2007-08-13

Stress contributes to the reinstatement of cocaine-seeking behavior in abstinent subjects. Kappa-opioid receptor antagonists attenuate the behavioral effects of stress, potentially providing therapeutic value in treating cocaine abuse. Presently, the peptide arodyn produced long-lasting kappa-opioid receptor antagonism, suppressing kappa-opioid receptor agonist-induced antinociception at least 3 days after intracerebroventricular administration of 0.3 nmol. C57Bl/6J mice demonstrated cocaine-conditioned place preference, extinction over 3 weeks, and a subsequent reinstatement of place preference. Arodyn pretreatment suppressed stress-induced, but not cocaine-exposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappa-opioid receptor antagonists may be useful therapeutics for cocaine abuse.

Dopaminergic sensitivity and cocaine abuse: response to apomorphine.

PubMed

Hollander, E; Nunes, E; DeCaria, C M; Quitkin, F M; Cooper, T; Wager, S; Klein, D F

1990-08-01

Ten male patients with chronic cocaine abuse received a single dose of the dopamine agonist apomorphine. Self-ratings of cocaine craving, depression, and anxiety decreased in response to apomorphine. Neuroendocrine response was consistent with central dopaminergic stimulation. Patients in the "craving" phase of the cocaine abuse cycle differed in behavioral but not neuroendocrine response to apomorphine from patients in the "crash" phase. Decrease in cocaine craving correlated with decrease in plasma homovanillic acid (pHVA). Total cocaine consumption correlated negatively with baseline prolactin and pHVA levels and inversely with peak change in prolactin following apomorphine. Patients had blunted neuroendocrine response to apomorphine in comparison to historical normal controls. Implications for the "dopamine" hypothesis of cocaine abuse are discussed.

Differential Antagonism of Cocaine Self-Administration and Cocaine-Induced Disruptions of Learning by Haloperidol in Rhesus Monkeys

ERIC Educational Resources Information Center

Winsauer, Peter J.; Moerschbaecher, Joseph M.; Roussell, Alison M.

2008-01-01

Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032 - 0.032 mg/kg/infusion of cocaine increased response…

Longitudinal Effects of Embryonic Exposure to Cocaine on Morphology, Cardiovascular Physiology, and Behavior in Zebrafish.

PubMed

Mersereau, Eric J; Boyle, Cody A; Poitra, Shelby; Espinoza, Ana; Seiler, Joclyn; Longie, Robert; Delvo, Lisa; Szarkowski, Megan; Maliske, Joshua; Chalmers, Sarah; Darland, Diane C; Darland, Tristan

2016-05-31

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.

A molecular model for cocaine binding by the immunotherapeutic human/mouse chimeric monoclonal antibody 2E2.

PubMed

Lape, Michael; Paula, Stefan; Ball, William J

2010-06-01

Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (gamma1 heavy chain)/murine (lambda light chain) chimeric mAb 2E2 has excellent affinity and specificity for cocaine and recent animal studies have demonstrated 2E2's ability in vivo to reduce cocaine levels in the brain as well as alter cocaine self-administration behavior in rats. In this study, we used mAb 2E2 amino acid sequence information to create a homology model for the 3-D structure of its Fv fragment. Subsequent computational docking studies revealed the intermolecular interactions potentially responsible for mAb 2E2's cocaine binding properties. The driving force of cocaine binding was identified as a combination of hydrophobic interactions and a single hydrogen bond between a light chain tyrosine residue and a carbonyl oxygen atom of cocaine. The model also allowed for an in silico evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2's cocaine binding properties. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

A Molecular Model for Cocaine Binding by the Immunotherapeutic Human/Mouse Chimeric Monoclonal Antibody 2E2

PubMed Central

Lape, Michael; Paula, Stefan; Ball, William J.

2010-01-01

Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (γ1 heavy chain)/murine (λ light chain) chimeric mAb 2E2 has excellent affinity and specificity for cocaine and recent animal studies have demonstrated 2E2’s ability in vivo to reduce cocaine levels in the brain as well as alter cocaine self-administration behavior in rats. In this study, we used mAb 2E2 amino acid sequence information to create a homology model for the 3-D structure of its Fv fragment. Subsequent computational docking studies revealed the intermolecular interactions potentially responsible for mAb 2E2’s cocaine binding properties. The driving force of cocaine binding was identified as a combination of hydrophobic interactions and a single hydrogen bond between a light chain tyrosine residue and a carbonyl oxygen atom of cocaine. The model also allowed for an in silico evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2’s cocaine binding properties. PMID:20185210

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction.

PubMed

Schmoutz, Christopher D; Guerin, Glenn F; Goeders, Nicholas E

2014-09-01

Previous research has demonstrated a complicated role for stress and HPA axis activation in potentiating various cocaine-related behaviors in preclinical models of drug dependence. However, the investigation of several antiglucocorticoid therapies has yielded equivocal results in reducing cocaine-related behaviors, possibly because of varying mechanisms of actions. Specifically, research suggests that metyrapone (a corticosterone synthesis inhibitor) may reduce cocaine self-administration in rats via a nongenomic, extra-adrenal mechanism without altering plasma corticosterone. In the current experiments, male rats were trained to self-administer cocaine infusions and food pellets in a multiple, alternating schedule of reinforcement. Metyrapone pretreatment dose-dependently decreased cocaine self-administration as demonstrated previously. Pharmacological inhibition of neurosteroid production by finasteride had significant effects on cocaine self-administration, regardless of metyrapone pretreatment. However, metyrapone's effects on cocaine self-administration were significantly attenuated with bicuculline pretreatment, suggesting a role for GABA-active neurosteroids in cocaine-reinforced behaviors. In vitro binding data also confirmed that metyrapone does not selectively bind to GABA-related proteins. The results of these experiments support the hypothesis that metyrapone may increase neurosteroidogenesis to produce effects on cocaine-related behaviors. Copyright © 2014 Elsevier B.V. All rights reserved.

Environmental enrichment reduces cocaine neurotoxicity during cocaine-conditioned place preference in male rats.

PubMed

Freese, Luana; Almeida, Felipe Borges; Heidrich, Nubia; Hansen, Alana Witt; Steffens, Luiza; Steinmetz, Aline; Moura, Dinara Jaqueline; Gomez, Rosane; Barros, Helena Maria Tannhauser

2018-06-01

Environmental enrichment (EE) has a neuroprotective role and prevents the development of cocaine addiction behavior in rats. Studies showing the role of EE in cocaine toxicity are nonexistent. We hypothesized that rats exposed to EE are protected from cocaine-induced changes in the redox profile and DNA damage after undergoing conditioned place preference (CPP). Ten male Wistar rats were placed in EE cages equipped with toys, a ladder and tunnels, and ten were provided clean, standard laboratory housing (non-EE). EE and non-EE rats were randomly allocated to the classical CPP cocaine vs. saline (COC/Saline) group, where cocaine (15 mg/kg; i.p.) was tested alternately with saline. Afterwards, intracellular reactive species and antioxidant enzymes were evaluated and the comet essay was performed in the prefrontal cortex and hippocampus of rats. As expected, EE rats spent less time in the cocaine-paired chamber, and as a new result, less cocaine-induced DNA damage was observed in the two brain structures. Altogether, our results demonstrate that EE decreases neurotoxicity in brain regions linked to cocaine addiction but does not extinguish it completely. Copyright © 2018. Published by Elsevier Inc.

Ion mobility spectrometry evaluation of cocaine occupational exposure in forensic laboratories.

PubMed

Armenta, Sergio; de la Guardia, Miguel; Alcalà, Manel; Blanco, Marcelo; Perez-Alfonso, Clara; Galipienso, Nieves

2014-12-01

An approach, based on ion mobility spectrometry (IMS) has been developed for the control of cocaine in air of the breathing zone of operators, in laboratory surfaces and in nasal mucus of employees to evaluate cocaine exposure in a forensic laboratory. The analytical methodology has been validated in terms of accuracy, precision and limits of detection and results obtained were statistically comparable with those obtained by liquid chromatography. Cocaine concentration in laboratory air increases from 100 ± 35 ng m(-3) of a normal day to 10,000 ng m(-3) during the manipulation of cocaine seizures. The occupational exposure limit (OEL) for cocaine has not been established which difficult the evaluation of the health effects of continuous exposition to very small doses of cocaine. Cocaine was also found in almost all the analyzed sample surfaces and also was found in nasal mucus of the police officers that were present during the manipulation of cocaine seizures without using a face mask. In summary, cocaine concentrations could present a health hazard to the employees and therefore warrants remediation and some modifications of the manipulation operations have been proposed. Copyright © 2014 Elsevier B.V. All rights reserved.

Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats

PubMed Central

Eagle, Andrew L.; Singh, Robby; Kohler, Robert J.; Friedman, Amy L.; Liebowitz, Chelsea P.; Galloway, Matthew P.; Enman, Nicole M.; Jutkiewicz, Emily M.; Perrine, Shane A.

2017-01-01

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague–Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0,10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, asexpected. However, compared to control ratson Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. PMID:25712697

Characterization of Differential Cocaine Metabolism in Mouse and Rat through Metabolomics-Guided Metabolite Profiling

PubMed Central

Yao, Dan; Shi, Xiaolei; Wang, Lei; Gosnell, Blake A.

2013-01-01

Rodent animal models have been widely used for studying neurologic and toxicological events associated with cocaine abuse. It is known that the mouse is more susceptible to cocaine-induced hepatotoxicity (CIH) than the rat. However, the causes behind this species-dependent sensitivity to cocaine have not been elucidated. In this study, cocaine metabolism in the mouse and rat was characterized through LC-MS-based metabolomic analysis of urine samples and were further compared through calculating the relative abundance of individual cocaine metabolites. The results showed that the levels of benzoylecgonine, a major cocaine metabolite from ester hydrolysis, were comparable in the urine from the mice and rats treated with the same dose of cocaine. However, the levels of the cocaine metabolites from oxidative metabolism, such as N-hydroxybenzoylnorecgonine and hydroxybenzoylecgonine, differed dramatically between the two species, indicating species-dependent cocaine metabolism. Subsequent structural analysis through accurate mass analysis and LC-MS/MS fragmentation revealed that N-oxidation reactions, including N-demethylation and N-hydroxylation, are preferred metabolic routes in the mouse, while extensive aryl hydroxylation reactions occur in the rat. Through stable isotope tracing and in vitro enzyme reactions, a mouse-specific α-glucoside of N-hydroxybenzoylnorecgonine and a group of aryl hydroxy glucuronides high in the rat were identified and structurally elucidated. The differences in the in vivo oxidative metabolism of cocaine between the two rodent species were confirmed by the in vitro microsomal incubations. Chemical inhibition of P450 enzymes further revealed that different P450-mediated oxidative reactions in the ecgonine and benzoic acid moieties of cocaine contribute to the species-dependent biotransformation of cocaine. PMID:23034697

Action of Pitolisant on the stimulant and rewarding effects of cocaine in mice.

PubMed

Brabant, Christian; Charlier, Yana; Navacerrada, Maria Elisa Serrano; Alleva, Livia; Tirelli, Ezio

2016-11-15

Previous studies have demonstrated that the histamine H3 receptor inverse agonist thioperamide potentiates the stimulant and rewarding effects of cocaine. However, these potentiating effects of thioperamide do not necessarily result from H3 receptor blockade since thioperamide is an imidazole-based compound capable of enhancing plasma cocaine concentrations by blocking cytochrome P450 activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist that has already been tested in clinical trials but it remains to be determined whether this compound also potentiates the behavioral effects of cocaine. The present study tested the effects of Pitolisant on locomotion, on cocaine-induced hyperactivity and on the development of conditioned place preference induced by cocaine (2 and 8mg/kg, i.p.) in male C57BL/6J mice. Pitolisant was injected 30min before each cocaine-pairing session. Locomotion recorded on the first cocaine-pairing session was used to test the effects of Pitolisant on the locomotor effects of cocaine. Our results show that doses of Pitolisant higher than 10mg/kg depressed locomotion. When injected alone at doses that did not affect locomotion, Pitolisant (2.5-10mg/kg, i.p.) had no rewarding properties in the place conditioning technique. Additionally, Pitolisant did not significantly alter cocaine-induced hyperactivity and cocaine-induced conditioned place preference. Taken together, our study indicates that Pitolisant has no addictive properties alone. Moreover, this compound does not significantly affect the stimulant and rewarding effects of cocaine. These results add further evidence to support the hypothesis that a pharmacokinetic interaction is involved in the ability of thioperamide to potentiate cocaine's psychomotor effects. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of ethanol on cocaine self-administration in monkeys responding under a second-order schedule of reinforcement.

PubMed

John, William S; Nader, Michael A

2017-01-01

Concurrent alcohol use among cocaine abusers is common but the behavioral variables that promote co-abuse are not well understood. The present study examined the effects of intragastric (i.g.) ethanol (EtOH) administration in monkeys responding under a schedule of cocaine reinforcement in which extensive drug seeking was maintained by conditioned stimuli. Four adult male cynomolgus monkeys (Macaca fascicularis) were trained to respond under a second-order fixed-interval (FI) 600s (fixed-ratio (FR) 30:S) schedule of cocaine (0.003-0.56mg/kg/injection) presentation. Sessions ended after 5 injections or 90min had elapsed. Different EtOH doses (0.5-2.0g/kg, i.g.) were administered 30min before the session, typically on Tuesdays and Fridays. Blood ethanol concentrations (BECs) were also assessed. Pattern of FI responding was assessed by determining quarter-life (QL) values. Cocaine self-administration was characterized as an inverted U-shaped function of dose; QL values increased monotonically with dose. EtOH pretreatments dose-dependently decreased self-administration at several cocaine doses in 3 of 4 monkeys. In one animal, EtOH increased low-dose cocaine-maintained responding. For all monkeys, QL values were increased by EtOH when low- and high-cocaine doses were self-administered, suggesting additive effects of EtOH and cocaine. Furthermore, BECs were not altered following cocaine self-administration. The reductions in cocaine self-administration and the increases in QL values following EtOH, suggest that EtOH was enhancing cocaine-related conditioned reinforcement. A better understanding of the behavioral mechanisms that mediate the co-abuse of alcohol and cocaine will lead to improved treatments for both drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice.

PubMed

Wetzel, Hanna N; Zhang, Tongli; Norman, Andrew B

2017-09-01

A recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. A three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over 1h in the presence and absence of h2E2. The mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. This model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs. Copyright © 2017 Elsevier Inc. All rights reserved.

Muscarinic receptor M4 positive allosteric modulators attenuate central effects of cocaine.

PubMed

Dall, Camilla; Weikop, Pia; Dencker, Ditte; Molander, Anna C; Wörtwein, Gitta; Conn, P Jeffrey; Fink-Jensen, Anders; Thomsen, Morgane

2017-07-01

Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M 4 receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking. We tested the M 4 -selective positive allosteric modulators VU0152100 and VU0467154 in a drug discrimination assay and a conditioned place preference assay, including extinction and reinstatement of place preference. Specificity of the cocaine discrimination effect was verified using knockout mice lacking either M 1 or M 4 receptors (M 1 -/- , M 4 -/- ). We also replicated previous findings in cocaine-induced locomotor hyperactivity and striatal dopamine microdialysis assays. VU0152100 attenuated the discriminative stimulus effect of cocaine in wild-type mice and M 1 -/- mice, but not in M 4 -/- mice, without affecting rates of responding. As previously shown with VU0152100, VU0467154 almost eliminated cocaine-induced hyperactivity and striatal dopamine efflux. VU0467154 failed to attenuate acquisition of cocaine-conditioned place preference, but facilitated extinction and prevented reinstatement of the conditioned place preference. These findings further support the notion that M 4 receptors are promising targets for the treatment of cocaine addiction, by showing that results can be replicated using distinct ligands, and that in addition to blocking reinforcing effects of cocaine relevant to ongoing drug taking, M 4 positive allosteric modulators can also attenuate subjective and conditioned effects relevant to relapse. Copyright © 2017. Published by Elsevier B.V.

Carbon-11-cocaine binding compared at subpharmacological and pharmacological doses: A PET study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Fowler, J.S.; Logan, J.

The authors have characterized cocaine binding in the brain to a high-affinity site on the dopamine transporter using PET and tracer doses of [{sup 11}C]cocaine in the baboon in vivo. The binding pattern, however, of cocaine at tracer (subpharmacological) doses may differ from that observed when the drug is taken in behaviorally active doses, particularly since in vitro studies have shown that cocaine also binds to low affinity binding sites. PET was used to compare and characterize [{sup 11}C]cocaine binding in the baboon brain at low subpharmacological (18 {mu}g average dose) and at pharmacological (8000 {mu}g) doses. Serial studies onmore » the same day in the same baboon were used to assess the reproducibility of repeated measures and to assess the effects of drugs which inhibit the dopamine, norepinephrine and serotonin transporters. Time-activity curves from brain and the arterial plasma input function were used to calculate the steady-state distribution volume (DV). At subpharmacological doses, [{sup 11}C]cocaine had a more homogeneous distribution. Bmax/Kd for sub-pharmacological [{sup 11}C]cocaine corresponded to 0.5-0.6 and for pharmacological [{sup 11}C]cocaine it corresponded to 0.1-0.2. Two-point Scatchard analysis gave Bmax = 2300 pmole/g and Kd = 3600 nM. Bmax/Kd for sub-pharmacological doses of [{sup 11}C]cocaine was decreased by cocaine and drugs that inhibit the dopamine transporter, to 0.1-0.2, but not by drugs that inhibit the serotonin or the norepinephrine transporter. None of these drugs changed Bmax/Kd for a pharmacological dose of [{sup 11}C]cocaine. At subpharmacological doses, [{sup 11}C]cocaine binds predominantly to a high-affinity site on the dopamine transporter. 36 refs., 4 figs., 5 tabs.« less

The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine.

PubMed

Karkhanis, Anushree N; Beveridge, Thomas J R; Blough, Bruce E; Jones, Sara R; Ferris, Mark J

2016-09-01

The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75mg/kg/infusion), and following LY379268 (0.03 or 0.30mg/kg; i.p.), phenmetrazine (25mg/kg/day; osmotic minipump), and a combination of the two drugs. LY379268 and phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%. These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cocaine administration dose-dependently increases sexual desire and decreases condom use likelihood: The role of delay and probability discounting in connecting cocaine with HIV.

PubMed

Johnson, Matthew W; Herrmann, Evan S; Sweeney, Mary M; LeComte, Robert S; Johnson, Patrick S

2017-02-01

Although cocaine use has been linked to sexual HIV risk behavior for decades, the direct effects of cocaine on sexual desire and sexual decision-making are unexamined. Research suggests delay discounting (devaluation of future outcomes) and probability discounting (devaluation of uncertain outcomes) play roles in condom use decisions. This study examined the effect of cocaine administration on sexual desire, hypothetical condom use, and discounting tasks. This double-blind, within-subjects study compared the effects of 0, 125, and 250 mg/70 kg oral cocaine HCl in 12 cocaine users. Measures included sexual desire and other subjective ratings, the Sexual Delay Discounting Task, the Sexual Probability Discounting Task, and monetary delay and probability discounting tasks. Cocaine caused dose-related increases in sexual desire and prototypical stimulant abuse-liability ratings. Relative to placebo, cocaine did not significantly alter condom use likelihood when condoms were immediately available or when sex was associated with 100% certainty of sexually transmitted infection (STI). In contrast, cocaine dose-dependently strengthened the effect of delay (sexual delay discounting) and STI uncertainty (sexual probability discounting) in decreasing condom use likelihood. Cocaine caused no significant change in monetary delay and probability discounting. This is the first study showing that cocaine administration increases sexual desire. Detrimental effects of cocaine on sexual risk were only observed when safer sex required delay, or STI risk was uncertain (representative of many real-world scenarios), suggesting a critical role of discounting processes. Lack of monetary effects highlights the importance of studying clinically relevant outcomes when examining drug effects on behavioral processes.

Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

PubMed Central

Madayag, Aric; Lobner, Doug; Kau, Kristen S.; Mantsch, John R.; Abdulhameed, Omer; Hearing, Matthew; Grier, Mark D.; Baker, David A.

2010-01-01

Cocaine produces a persistent reduction in cystine-glutamate exchange via system xc- in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System xc- influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system xc- activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered prior to daily cocaine to determine the impact of increased cystine-glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered prior to cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2–3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered prior to daily cocaine also prevented the persistent reduction in system xc- activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in 35S cystine transport via system xc-, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least three weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system xc- activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking. PMID:18094234

Three-dimensional quantitative structure-activity relationship modeling of cocaine binding by a novel human monoclonal antibody.

PubMed

Paula, Stefan; Tabet, Michael R; Farr, Carol D; Norman, Andrew B; Ball, W James

2004-01-01

Human monoclonal antibodies (mAbs) designed for immunotherapy have a high potential for avoiding the complications that may result from human immune system responses to the introduction of nonhuman mAbs into patients. This study presents a characterization of cocaine/antibody interactions that determine the binding properties of the novel human sequence mAb 2E2 using three-dimensional quantitative structure-activity relationship (3D-QSAR) methodology. We have experimentally determined the binding affinities of mAb 2E2 for cocaine and 38 cocaine analogues. The K(d) of mAb 2E2 for cocaine was 4 nM, indicating a high affinity. Also, mAb 2E2 displayed good cocaine specificity, as reflected in its 10-, 1500-, and 25000-fold lower binding affinities for the three physiologically relevant cocaine metabolites benzoylecgonine, ecgonine methyl ester, and ecgonine, respectively. 3D-QSAR models of cocaine binding were developed by comparative molecular similarity index analysis (CoMSIA). A model of high statistical quality was generated showing that cocaine binds to mAb 2E2 in a sterically restricted binding site that leaves the methyl group attached to the ring nitrogen of cocaine solvent-exposed. The methyl ester group of cocaine appears to engage in attractive van der Waals interactions with mAb 2E2, whereas the phenyl group contributes to the binding primarily via hydrophobic interactions. The model further indicated that an increase in partial positive charge near the nitrogen proton and methyl ester carbonyl group enhances binding affinity and that the ester oxygen likely forms an intermolecular hydrogen bond with mAb 2E2. Overall, the cocaine binding properties of mAb 2E2 support its clinical potential for development as a treatment of cocaine overdose and addiction.

Cocaine hydrolase encoded in viral vector blocks the reinstatement of cocaine seeking in rats for 6 months

PubMed Central

Anker, Justin J.; Brimijoin, Stephen; Gao, Yang; Geng, Liyi; Zlebnik, Natalie E.; Parks, Robin J.; Carroll, Marilyn E.

2011-01-01

Background Cocaine dependence is a pervasive disorder with high rates of relapse. In a previous study, direct administration of a quadruple mutant albumin-fused butyrylcholinesterase (BChE) that efficiently catalyzes hydrolysis of cocaine to benzoic acid and ecgonine methyl ester acutely blocked cocaine seeking in an animal model of relapse. In the present experiments these results were extended to achieve a long duration blockade of cocaine seeking with a gene transfer paradigm using a related BChE-based cocaine hydrolase, termed “CocH”. Methods Male and female rats were allowed to self-administer cocaine under a fixed-ratio 1 schedule of reinforcement for approximately 14 days. Following the final self-administration session, rats were injected with CocH vector or a control injection (empty vector or saline), and their cocaine solutions were replaced with saline for 14 days to allow for extinction of lever pressing. Subsequently, they were tested for drug-primed reinstatement by administering i.p. injections of saline (S), cocaine (5, 10, and 15 mg/kg, C), and d-amphetamine (A) according to the following sequence: S, C, S, C, S, C, S, A. Rats then received cocaine-priming injections once weekly for 4 weeks, and subsequently, once monthly for up to 6 months. Results Administration of CocH vector produced substantial and sustained CocH activity in plasma that corresponded with diminished cocaine- (but not amphetamine-) induced reinstatement responding for up to 6 months following treatment (compared to high responding controls). Conclusion These results demonstrate that viral transfer of CocH may be useful in promoting long-term resistance to relapse to cocaine addiction. PMID:22209637

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration

PubMed Central

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-01-01

There are ∼1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy. PMID:25689882

Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel

PubMed Central

Dickson, Price E.; Miller, Mellessa M.; Calton, Michele A.; Bubier, Jason A.; Cook, Melloni N.; Goldowitz, Daniel; Chesler, Elissa J.; Mittleman, Guy

2015-01-01

Rationale Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underling cocaine use in mice. Methods Mice from 39 BXD strains acquired cocaine IVSA (0.56 mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032 – 1.8 mg/kg/infusion). Results We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant QTL on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-naïve mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome-wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use. Conclusions These data provide novel candidate genes underlying cocaine IVSA in mice, and suggest mechanisms driving human cocaine use. PMID:26581503

Analysis of Urinary Biomarkers for Smoking Crack Cocaine: Results of a Danish Laboratory Study.

PubMed

Jeppesen, Hans Henrik; Busch-Nielsen, Malthe; Larsen, Anders Nørgaard; Breindahl, Torben

2015-01-01

Crack cocaine (free-base cocaine) smokers belong to a subgroup of marginalized drug users exposed to severe health risks and great social harm. Detection of the urinary, pyrolytic biomarker methylecgonidine (MED) and its metabolite ecgonidine (ED) secures an unambiguous confirmation of crack cocaine smoking. Although prevalence studies of cocaine based upon self-reporting may not be accurate, laboratory analysis is seldom used for neither diagnostic purpose nor early identification of crack cocaine smoking, which is far more severe than snorting cocaine. A new analytical method was validated for MED, ED and other relevant cocaine metabolites using automated liquid handling and column switching coupled to liquid chromatography and tandem mass spectrometry. Limit of quantification was 30 ng/mL for ED and MED. This method was applied in a laboratory study of urine samples (n = 110) from cocaine users in Denmark subjected to routine drugs-of-abuse testing. Crack cocaine smoking was confirmed by the presence of MED and/or ED. Eighty-four samples (76.4%) were found positive for crack cocaine smoking in this group of problematic cocaine users. MED was only detected in 5.9% of the positive samples. The study shows a prevalence 3-fold higher to that recently suggested by European Monitoring Centre for Drugs and Drug Addiction. We therefore advocate that the urinary biomarkers MED and ED are included in routine testing methods for clinical toxicology. This may lead to an earlier identification of crack cocaine smoking and possibly prevent a more severe drug use. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Extrasynaptic targeting of NMDA receptors following D1 dopamine receptor activation and cocaine self-administration

PubMed Central

Ortinski, Pavel I.; Turner, Jill R.; Pierce, R. Christopher

2013-01-01

We previously showed that after repeated exposure to cocaine, D1-like dopamine receptor (D1DR) stimulation reverses plastic changes of AMPA receptor-mediated signaling in the nucleus accumbens shell. However, there is little information on the impact of cocaine self-administration on D1-NMDA receptor interactions in this brain region. Here, we assessed whether cocaine self-administration alters the effects of D1DR stimulation on synaptic and extrasynaptic NMDA receptors (NMDARs) using whole-cell patch-clamp recordings. In slices from cocaine-naïve rats, pre-treatment with a D1DR agonist decreased synaptic NMDAR receptor-mediated currents and increased the contribution of extrasynaptic NMDARs. In contrast, neither cocaine self-administration alone nor cocaine experience followed by D1DR stimulation had an effect on synaptic or extrasynaptic NMDAR signaling. Activation of extrasynaptic NMDARs relies on the availability of extracellular glutamate, which is regulated primarily by glutamate transporters. In cocaine-experienced animals, administration of a glutamate re-uptake blocker, DL-threo-β-benzyloxyaspartic acid (TBOA), revealed increased extrasynaptic NMDAR activity and stronger baseline activity of glutamate uptake transporters relative to cocaine-naïve rats. In cocaine-naïve rats, the D1DR-mediated increase in extrasynaptic NMDAR signaling was independent of the activity of glutamate re-uptake transporters. Taken together, these results indicate that cocaine experience blunts the influence of D1DRs on synaptic and extrasynaptic NMDAR signaling. Additionally, prior cocaine self-administration limits activation of the extrasynaptic NMDAR pool by increasing glutamate re-uptake. These findings outline a pattern of adaptive interactions between D1DRs and NMDARs in the nucleus accumbens shell and demonstrate up-regulation of extrasynaptic NMDAR signaling as a novel consequence of cocaine self-administration. PMID:23719812

Orexin / hypocretin signaling at the OX1 receptor regulates cue-elicited cocaine-seeking

PubMed Central

Smith, Rachel J.; See, Ronald E.; Aston-Jones, Gary

2009-01-01

The orexin / hypocretin system has recently been implicated in reward-processing and addiction. We examined the involvement of the orexin system in cue-induced reinstatement of extinguished cocaine-seeking by administering the orexin 1 receptor (OX1R) antagonist SB-334867, or the orexin 2 receptor (OX2R) antagonist 4-pyridylmethyl (S)-tert-leucyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4PT), prior to reinstatement testing. Male Sprague-Dawley rats self-administered cocaine in 2-hour sessions for 10 days, followed by extinction training. Reinstatement of cocaine-seeking was elicited by presentation of tone + light cues previously paired with cocaine infusions. SB-334867 (10, 20, 30 mg/kg) dose-dependently decreased cue-induced reinstatement of cocaine-seeking without significantly affecting responding during late extinction. 4PT (10, 30 mg/kg) did not significantly alter cue-induced reinstatement. In separate experiments, the highest doses of SB-334867 and 4PT had no significant effect on established cocaine self-administration, and 4PT reduced spontaneous activity in a locomotor test to a greater extent than SB-334867. Finally, SB-334867 (30 mg/kg) had no effect on the acquisition of cocaine-paired cues during a Pavlovian cocaine-stimulus conditioning session in the operant chamber. Pretreatment with SB-334867 prior to the Pavlovian acquisition session had no effect on subsequent cue-induced reinstatement of cocaine-seeking elicited by those cues. However, pretreatment with SB-334867 prior to a second reinstatement session significantly attenuated the expression of cue-induced reinstatement. These results show that orexin transmission at OX1R, but not OX2R, is necessary for the reinstatement of cocaine-seeking elicited by drug-paired cues, and that orexin signaling is not critical for cocaine reinforcement or cocaine-stimulus conditioning. PMID:19656173

High and escalating levels of cocaine intake are dissociable from subsequent incentive motivation for the drug in rats.

PubMed

Allain, Florence; Bouayad-Gervais, Karim; Samaha, Anne-Noël

2018-01-01

Taking high and increasing amounts of cocaine is thought to be necessary for the development of addiction. Consequently, a widely used animal model of drug self-administration involves giving animals continuous drug access during long sessions (LgA), as this produces high and escalating levels of intake. However, human cocaine addicts likely use the drug with an intermittent rather than continuous pattern, producing spiking brain cocaine levels. Using an intermittent-access (IntA) cocaine self-administration procedure in rats, we studied the relationship between escalation of cocaine intake and later incentive motivation for the drug, as measured by responding under a progressive ratio schedule of cocaine reinforcement. First, under IntA, rats escalated their cocaine use both within and between sessions. However, escalation did not predict later incentive motivation for the drug. Second, incentive motivation for cocaine was similar in IntA-rats limited to low- and non-escalating levels of drug intake (IntA-Lim) and in IntA-rats that took high and escalating levels of drug. Finally, IntA-Lim rats took much less cocaine than rats given continuous drug access during each self-administration session (LgA-rats). However, IntA-Lim rats later responded more for cocaine under a progressive ratio schedule of reinforcement. Taking large and escalating quantities of cocaine does not appear necessary to increase incentive motivation for the drug. Taking cocaine in an intermittent pattern-even in small amounts-is more effective in producing this addiction-relevant change. Thus, beyond the amount of drug taken, the temporal kinetics of drug use predict change in drug use over time.

Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats.

PubMed

Eagle, Andrew L; Singh, Robby; Kohler, Robert J; Friedman, Amy L; Liebowitz, Chelsea P; Galloway, Matthew P; Enman, Nicole M; Jutkiewicz, Emily M; Perrine, Shane A

2015-05-01

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. Copyright © 2015. Published by Elsevier B.V.

The effects of prenatal cocaine, post-weaning housing and sex on conditioned place preference in adolescent rats

PubMed Central

Dow-Edwards, Diana; Iijima, Maiko; Stephenson, Stacy; Jackson, April; Weedon, Jeremy

2014-01-01

Rationale Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual's tendency to take and/or abuse drugs is still a matter of debate. Objectives This study sought to answer the question does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat. Further, we wanted to assess possible sex differences and the role of being raised in an enriched vs impoverished environment. Methods Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30mg/kg (C30), 60mg/kg (C60) or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and on postnatal day (PND) 23 placed into isolation cages or enriched cages with 3 same-sex littermates and stimulus objects. On PND43-47, CPP was determined across a range of cocaine doses. Results C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment. Conclusions These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses, and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP most in adolescent males prenatally exposed to moderate cocaine doses. PMID:24435324

Brain mu-opioid receptor binding predicts treatment outcome in cocaine-abusing outpatients

PubMed Central

Ghitza, Udi E.; Preston, Kenzie L.; Epstein, David H.; Kuwabara, Hiroto; Endres, Christopher J.; Bencherif, Badreddine; Boyd, Susan J.; Copersino, Marc L.; Frost, J. James; Gorelick, David A.

2010-01-01

Background Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown. Methods We determined whether regional brain mOR binding before treatment correlates with outcome and compared it to standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine-abstinence reinforcement whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography (PET) with [11C] carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment, 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology. Results Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sub-lobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use. Conclusions Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction. PMID:20579973

Distinct Contributions of Dopamine in the Dorsolateral Striatum and Nucleus Accumbens Shell to the Reinforcing Properties of Cocaine

PubMed Central

Veeneman, Maartje M J; Broekhoven, Mark H; Damsteegt, Ruth; Vanderschuren, Louk J M J

2012-01-01

Dopaminergic neurotransmission in the dorsal and ventral striatum is thought to be involved in distinct aspects of cocaine addiction. Ventral striatal dopamine mediates the acute reinforcing properties of cocaine, whereas dopamine in the dorsolateral striatum (DLS) is thought to become involved in later stages of the addiction process to mediate well-established cue-controlled drug seeking. However, it is unclear whether the DLS also has a role in the reinforcing properties of cocaine itself. Therefore, we systematically investigated the involvement of dopamine in dorsal and ventral striatal regions in cocaine self-administration, using various schedules of reinforcement in animals with limited drug taking experience. Intra-DLS infusion of the dopamine receptor antagonist α-flupenthixol did not affect the acquisition of cocaine self-administration, increased cocaine self-administration under a fixed ratio-1 (FR-1) schedule of reinforcement, caused a rightward and downward shift of the dose–response curve of cocaine under an FR-1 schedule of reinforcement and decreased responding for cocaine under a progressive ratio (PR) schedule of reinforcement. Infusion of α-flupenthixol into the ventral nucleus accumbens (NAcc) shell inhibited the acquisition of cocaine self-administration, reduced responding for the drug under FR-1 and PR schedules of reinforcement, and caused a downward shift of the dose–response curve of cocaine self-administration under an FR-1 schedule of reinforcement. These data show that dopamine in both the DLS and NAcc shell is involved in cocaine reinforcement. We suggest that the DLS and the NAcc shell mediate somewhat distinct facets of the reinforcing properties of cocaine, related to its rewarding and motivational aspects, respectively. PMID:21918505

Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

PubMed

Porrino, Linda J; Beveridge, Thomas J R; Smith, Hilary R; Nader, Michael A

2016-05-01

Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure. © 2015 Society for the Study of Addiction.

Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.

PubMed

Larson, Erin B; Graham, Danielle L; Arzaga, Rose R; Buzin, Nicole; Webb, Joseph; Green, Thomas A; Bass, Caroline E; Neve, Rachael L; Terwilliger, Ernest F; Nestler, Eric J; Self, David W

2011-11-09

Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

Rational design of an enzyme mutant for anti-cocaine therapeutics

NASA Astrophysics Data System (ADS)

Zheng, Fang; Zhan, Chang-Guo

2008-09-01

(-)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (-)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (-)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants (i.e., A199S/S287G/A328W/Y332G) has a ˜456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.

Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse.

PubMed

García-Fuster, M J; Perez, J A; Clinton, S M; Watson, S J; Akil, H

2010-01-01

Hippocampal plasticity (e.g. neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and 5-bromo-2'-deoxyuridine for older cells born prior to sensitization. Results show that: (i) bHRs exhibited greater psychomotor response to cocaine than bLRs; (ii) acute cocaine did not alter cell proliferation in bLR/bHR rats; (iii) chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence; (iv) neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype; (v) cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine; and (vi) cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR vs. bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs, which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization.

Fluorescence Immunoassay for Cocaine Detection.

PubMed

Nakayama, Hiroshi; Kenjjou, Noriko; Shigetoh, Nobuyuki; Ito, Yuji

2016-04-01

A fluorescence immunoassay (FIA) has been developed for the detection of cocaine using norcocaine labeled with merocyanine dye and a monoclonal antibody specific to cocaine. Using this FIA, the detection range for cocaine was between 20.0 and 1700 μg/L with a limit of detection of 20.0 μg/L. Other cocaine derivatives did not interfere significantly with the detection when using this immunoassay technique with cross-reactivity values of less than 20%. Thus this FIA could be considered a useful tool for the detection of cocaine.

Clinical ratings and plasma HVA during cocaine abstinence.

PubMed

Martin, S D; Yeragani, V K; Lodhi, R; Galloway, M P

1989-08-01

Six patients were evaluated over a 21-day period during inpatient recovery from chronic repeated cocaine use. Serial evaluations of Hamilton depression rating, cocaine craving, plasma homovanillic acid (pHVA), and plasma 3-methoxy-4-hydroxyphenylethyleneglycol (pMHPG) concentrations were determined. There was a distinct increase in cocaine craving between 1 and 2 weeks after the last cocaine use. Levels of pHVA also increased at the time of heightened craving. The data provide preliminary evidence to suggest that changes in cocaine craving during abstinence are positively correlated with changes in dopamine turnover.

Absence of age-related dopamine transporter loss in current cocaine abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.J.; Volkow, N.D.; Fischman, M.

The brain dopamine (DA) system appears to play a crucial role in the reinforcing properties of cocaine. Using PET we had previously shown significant decreases in DA D2 receptors but no changes in DA transporters (DAT) in detoxified cocaine abusers (>1 month after last cocaine use). This study evaluates DAT availability in current cocaine abusers (15 male and 5 female; age = 36.2{+-}5.3 years old) using PET and [C-11]cocaine, as a DAT ligand, and compares it to that in 18 male and 2 female age matched normal controls. Cocaine abusers had a history of abusing 4.2{+-}2.8 gm /week of cocainemore » for an average of 11.0{+-}4.9 years and their last use of cocaine was 5.4{+-}8 days prior to PET study. DAT availability was obtained using the ratio of the distribution volume in the region of interest (caudate, pulamen) to that in cerebellum which is a function of Bmax./Kd.+1. DAT availability in cocaine abusers did not differ to that in normals (N) (C= 1.78{+-}0.14, N= 1.77{+-}0.13). In addition, there were no differences between the groups in the distribution volume or the Kl (plasma to brain transfer constant) measures for [C-11]cocaine. However, in the normals but not in the abusers striatal DAT availability decreased with age (C: r = -0.07, p = 0.76; N: r = -0.55, p < 0.01). Though this study fails to show group differences in DAT availability between normals and current cocaine abusers it indicates a blunting of the age-related decline in DAT availability in the cocaine abusers. Future studies in older cocaine abusers at different time after detoxification arc required in order to assess if cocaine slows the loss of DAT with age or whether these changes reflect compensation to increased DAT blockade and recover with detoxification.« less

Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice.

PubMed

Joseph, Lauren; Thomsen, Morgane

2017-06-30

Muscarinic M 1 /M 4 receptor stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (S D ) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M 1 , M 2 , or M 4 receptors (M 1 -/- , M 2 -/- , M 4 -/- ), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M 1 , M 2 , or M 4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M 1 /M 4 receptors partially substituted for cocaine and increased the S D effect of cocaine, while M 2 -preferring antagonists did not substitute, and reduced the S D effect of cocaine. The cocaine-like effects of scopolamine were absent in M 1 -/- mice. The cocaine S D attenuating effects of methoctramine were absent in M 2 -/- mice and almost absent in M 1 -/- mice. The findings indicate that the cocaine-like S D effects of muscarinic antagonists are primarily mediated through M 1 receptors, with a minor contribution of M 4 receptors. The data also support our previous findings that stimulation of M 1 receptors and M 4 receptors can each attenuate the S D effect of cocaine, and show that this can also be achieved by blocking M 2 autoreceptors, likely via increased acetylcholine release. Copyright © 2017 Elsevier B.V. All rights reserved.

A Recombinant Humanized Anti-Cocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Rats

PubMed Central

Gooden, Felicia C. T.; Tabet, Michael R.; Ball, William J.

2014-01-01

The monoclonal antibody (mAb), h2E2, is a humanized version of the chimeric human/murine anti-cocaine mAb 2E2. The recombinant h2E2 protein was produced in vitro from a transfected mammalian cell line and retained high affinity (4 nM Kd) and specificity for cocaine over its inactive metabolites benzoylecgonine (BE) and ecgonine methyl ester. In rats, pharmacokinetic studies of h2E2 (120 mg/kg i.v.) showed a long terminal elimination half-life of 9.0 days and a low volume of distribution at steady state (Vdss) of 0.3 l/kg. Pretreatment with h2E2 produced a dramatic 8.8-fold increase in the area under the plasma cocaine concentration-time curve (AUC) and in brain a concomitant decrease of 68% of cocaine’s AUC following an i.v. injection of an equimolar cocaine dose. Sequestration of cocaine in plasma by h2E2, shown via reduction of cocaine’s Vdss, indicates potential clinical efficacy. Although the binding of cocaine to h2E2 in plasma should inhibit distribution and metabolism, the elimination of cocaine remained multicompartmental and was still rapidly eliminated from plasma despite the presence of h2E2. BE was the major cocaine metabolite, and brain BE concentrations were sixfold higher than in plasma, indicating that cocaine is normally metabolized in the brain. In the presence of h2E2, brain BE concentrations were decreased and plasma BE was increased, consistent with the observed h2E2-induced changes in cocaine disposition. The inhibition of cocaine distribution to the brain confirms the humanized mAb, h2E2, as a lead candidate for development as an immunotherapy for cocaine abuse. PMID:24733787

Effects of Dopamine D2/D3 Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

PubMed Central

Czoty, Paul W.

2013-01-01

Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. The present experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of whether social status, known to alter D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(−)−norpropylapomorphine [(−)−NPA], low-efficacy agonist aripiprazole (ARI), and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (−)−NPA were characterized under conditions in which monkeys did (ARI) or did not [ARI and (−)−NPA] self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased the choice of low cocaine doses, and only (−)−NPA decreased the choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self administration occurred only on days 1 and 5 of treatment, ARI, but not (−)−NPA, decreased cocaine choice in dominant monkeys, whereas (−)−NPA, but not ARI, did so in subordinates. When dominant monkeys self-administered cocaine on all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine. PMID:23211363

Obesity-resistant S5B rats showed great cocaine conditioned place preference than the obesity-prone OM rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thanos, P.K.; Wang, G.; Thanos, P.K..

Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, wemore » then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains. OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions. OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine. Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.« less

Substance P and cocaine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro.

PubMed

Kombian, Samuel B; Ananthalakshmi, Kethireddy V V; Zidichouski, Jeffrey A; Saleh, Tarek M

2009-04-01

Substance P (SP) has been reported to produce effects on excitatory synaptic transmission in the nucleus accumbens (NAc) that are similar to those induced by cocaine. To address the question of whether SP serves as an endogenous mediator producing cocaine-like effects that are known to be D1-receptor-mediated, we tested the hypothesis that the effects of SP and cocaine on excitatory postsynaptic currents (EPSCs) in the NAc occlude one another. We report here that SP and SP(5-11) actions occlude the effect of cocaine and vice versa. SP, SP(5-11) and cocaine all depressed evoked, non-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents in a concentration-dependent manner, with EC50 values of 0.12, 0.17 and 8.3 microm, respectively. Although cocaine was the least potent, it was most efficacious. SP, SP(5-11) and cocaine all suppressed isolated NMDA receptor-mediated evoked EPSCs. SP(5-11) (1 microm)-induced EPSC depression was blocked by the neurokinin-1 antagonist L732138 and by the D1-like receptor antagonist SCH23390. Pretreatment of slices with cocaine (30 microm) depressed the EPSC by 39.1% +/- 4.8%. Application of SP or SP(5-11) (1 microm) at the peak of the cocaine depressive effect on the EPSC did not produce any additional diminution of the response (5.7% +/- 2.8%). In the reverse experiments, in which either SP or SP(5-11) was applied first, subsequent application of cocaine at the peak of the peptide's effect (30.3% +/- 2.3%) produced a further but smaller depression (15.5% +/- 3.6%) of the remaining EPSC. These data indicate that cocaine and SP produce similar effects on excitatory synaptic transmission in the NAc, and that their actions occlude one another. This suggests that SP may act like cocaine in its absence, and may be an endogenous trigger for the reward and behaviors associated with cocaine.

Stable self-serving personality traits in recreational and dependent cocaine users

PubMed Central

Quednow, Boris B.; Hulka, Lea M.; Preller, Katrin H.; Baumgartner, Markus R.; Eisenegger, Christoph; Vonmoos, Matthias

2017-01-01

Chronic cocaine use has been associated with impairments in social cognition, self-serving and antisocial behavior, and socially relevant personality disorders (PD). Despite the apparent relationship between Machiavellianism and stimulant use, no study has explicitly examined this personality concept in cocaine users so far. In the frame of the longitudinal Zurich Cocaine Cognition Study, the Machiavellianism Questionnaire (MACH-IV) was assessed in 68 recreational and 30 dependent cocaine users as well as in 68 psychostimulant-naïve controls at baseline. Additionally, three closely related personality dimensions from the Temperament and Character Inventory (TCI)–cooperativeness, (social) reward dependence, and self-directedness–and the screening questionnaire of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) were acquired. At the one-year follow-up, 57 cocaine users and 48 controls were reassessed with the MACH-IV. Finally, MACH-IV scores were correlated with measures of social cognition and interaction (cognitive/emotional empathy, Theory-of-Mind, prosocial behavior) and with SCID-II PD scores assessed at baseline. Both recreational and dependent cocaine users showed significantly higher Machiavellianism than controls, while dependent cocaine users additionally displayed significantly lower levels of TCI cooperativeness and self-directedness. During the one-year interval, MACH-IV scores showed high test-retest reliability and also the significant gap between cocaine users and controls remained. Moreover, in cocaine users, higher Machiavellianism correlated significantly with lower levels of cooperativeness and self-directedness, with less prosocial behavior, and with higher cluster B PD scores. However, Machiavellianism was not correlated with measures of cocaine use severity (r<-.15). Both recreational and dependent cocaine users display pronounced and stable Machiavellian personality traits. The lack of correlations with severity of cocaine use and its temporal stability indicates that a Machiavellian personality trait might represent a predisposition for cocaine use that potentially serves as a predictor for stimulant addiction. PMID:28253291

Cocaine abuse or dependency and other pyschiatric disorders. Madrid study on dual pathology.

PubMed

Arias, Francisco; Szerman, Nestor; Vega, Pablo; Mesias, Beatriz; Basurte, Ignacio; Morant, Consuelo; Ochoa, Enriqueta; Poyo, Félix; Babin, Francisco

2013-01-01

The main objective of this study was to analyse the cocaine addict subgroup from the Madrid study of prevalence of dual disorders in community mental health and substance misuse services. The sample consisted of 837 outpatients from Madrid, Spain. We compared 488 subjects who had a lifetime diagnosis of cocaine abuse or dependence, and 222 subjects who did not have a cocaine substance use disorder. We used the Mini International Neuropsychiatric Interview to evaluate axis I mental disorders, and the Personality Disorder Questionnaire to evaluate personality disorders. Almost three-quarters (73.4%) of cocaine addicts had a current dual disorder. Most prevalent were mood and anxiety disorders. Almost half (49.6%) had a personality disorder. Most of them (94.9%) had other substance use disorders. Cocaine addicts did not have higher prevalence rates of dual pathology than addicts with no cocaine abuse or dependence. Cocaine addicts were associated to a diagnosis of antisocial personality disorder, agoraphobia, and post-traumatic stress disorder, and they had an early age of onset of alcohol and cannabis use. Dual pathology is no higher in cocaine addicts in treatment than in addicts who do not use cocaine, however cocaine addicts started other drugs earlier, and were associated with specific mental disorders. Copyright © 2012 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

Effect of experimental analogs of contingency management treatment on cocaine seeking behavior.

PubMed

Greenwald, Mark K; Ledgerwood, David M; Lundahl, Leslie H; Steinmiller, Caren L

2014-06-01

Contingency management (CM) treatment is effective for treating cocaine dependence but further mechanistic studies of its efficacy are warranted. This study aimed to determine whether: (a) higher vs. lower predictable money amounts ($3 vs. $1; analogs of standard voucher-based CM) increase cocaine demand elasticity; and (b) probabilistic amounts matched for expected value with the $3-predictable amount (50% chance of $6; 25% chance of $12; and 12.5% chance of $24; analogs of prize CM) similarly affect cocaine choice. Each of 15 cocaine-dependent participants first completed a qualifying session to ensure that intranasal cocaine functioned as a reinforcer, then completed a 10-session, within-subject, randomized crossover study. During each of the 10 sessions, the participant responded on a progressive ratio schedule to earn units of cocaine (5-mg or 10-mg) and/or money (five monetary conditions above). During the reinforcement qualifying session (10-mg vs. 0-mg units; no money alternative), cocaine choice was high. The $3-predictable amount significantly decreased cocaine choice relative to both the $1-predictable amount and the qualifying session. Cocaine-choices in the probabilistic conditions were similar to the $3 predictable condition. These findings indicate that CM interventions targeted at reducing cocaine self-administration are more likely to succeed with higher value non-drug reinforcement. Copyright © 2014. Published by Elsevier Ireland Ltd.

Multiple faces of BDNF in cocaine addiction

PubMed Central

Li, Xuan; Wolf, Marina E.

2014-01-01

Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self-administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the “addiction phase” examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF’s potential relevance to treating cocaine addiction. PMID:25449839

Signs of Cocaine Abuse and Addiction

MedlinePlus

... Signs of Cocaine Use and Addiction Signs of Cocaine Use and Addiction Listen ©istock.com/ AntonioGuillern After ... English Español "My life was built around getting cocaine and getting high." ©istock.com/ Marjot Stacey is ...

The effect of nicotine pre-exposure on demand for cocaine and sucrose in male rats.

PubMed

Schwartz, Lindsay P; Kearns, David N; Silberberg, Alan

2018-06-01

The aim of the present study was to determine how nicotine pre-exposure affects the elasticity of demand for intravenous cocaine and for sucrose pellets in adult male rats. In Experiment 1, demand for cocaine was assessed in rats that had nicotine in their drinking water. Nicotine pre-exposure significantly decreased rats' willingness to defend cocaine consumption as the price (measured as the number of responses per cocaine infusion) increased compared with a control group with no nicotine pre-exposure. That is, nicotine increased the elasticity of demand for cocaine infusions. Experiment 2 repeated the first experiment, but with rats working for sucrose pellets instead of cocaine. Nicotine pre-exposure had no effect on the elasticity of demand for sucrose. This pattern of results suggests that nicotine pre-exposure can reduce the reinforcing effects of cocaine, but not sucrose, in adult male rats.

Three-dimensional structure-activity relationship modeling of cocaine binding to two monoclonal antibodies by comparative molecular field analysis.

PubMed

Paula, Stefan; Tabet, Michael R; Keenan, Susan M; Welsh, William J; Ball, W James

2003-01-17

Successful immunotherapy of cocaine addiction and overdoses requires cocaine-binding antibodies with specific properties, such as high affinity and selectivity for cocaine. We have determined the affinities of two cocaine-binding murine monoclonal antibodies (mAb: clones 3P1A6 and MM0240PA) for cocaine and its metabolites by [3H]-radioligand binding assays. mAb 3P1A6 (K(d) = 0.22 nM) displayed a 50-fold higher affinity for cocaine than mAb MM0240PA (K(d) = 11 nM) and also had a greater specificity for cocaine. For the systematic exploration of both antibodies' binding specificities, we used a set of approximately 35 cocaine analogues as structural probes by determining their relative binding affinities (RBAs) using an enzyme-linked immunosorbent competition assay. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models on the basis of comparative molecular field analysis (CoMFA) techniques correlated the binding data with structural features of the ligands. The analysis indicated that despite the mAbs' differing specificities for cocaine, the relative contributions of the steric (approximately 80%) and electrostatic (approximately 20%) field interactions to ligand-binding were similar. Generated three-dimensional CoMFA contour plots then located the specific regions about cocaine where the ligand/receptor interactions occurred. While the overall binding patterns of the two mAbs had many features in common, distinct differences were observed about the phenyl ring and the methylester group of cocaine. Furthermore, using previously published data, a 3D-QSAR model was developed for cocaine binding to the dopamine reuptake transporter (DAT) that was compared to the mAb models. Although the relative steric and electrostatic field contributions were similar to those of the mAbs, the DAT cocaine-binding site showed a preference for negatively charged ligands. Besides establishing molecular level insight into the interactions that govern cocaine binding specificity by biopolymers, the three-dimensional images obtained reflect the properties of the mAbs binding pockets and provide the initial information needed for the possible design of novel antibodies with properties optimized for immunotherapy. Copyright 2003 Elsevier Science Ltd.

Cocaine and coronary calcification in young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

PubMed

Pletcher, Mark J; Kiefe, Catarina I; Sidney, Steve; Carr, J Jeffrey; Lewis, Cora E; Hulley, Stephen B

2005-11-01

Cocaine use is associated with myocardial ischemia and infarction, but it is unclear whether this is only because of the acute effects of cocaine on heart rate, blood pressure, and vasomotor tone or whether accelerated atherosclerosis from long-term exposure to cocaine also contributes. We sought to measure the association between cocaine exposure and coronary calcification, a marker for atherosclerosis, among participants in the CARDIA Study who received computed tomography scanning and answered questions about illicit drug use at the year 15 examination in 2000-2001. Among 3038 CARDIA participants (age 33-45 years, 55% women and 45% black), past cocaine exposure was reported by 35% and was more common among men, smokers, drinkers, and participants with less education. Powdered cocaine exposure was more common among whites, crack cocaine among blacks. Before adjustment, cocaine exposure was strongly associated with coronary calcification. After adjusting for age, sex, ethnicity, socioeconomic status, family history, and habits, however, these associations disappeared: adjusted odds ratios for coronary calcification were 0.9 (95% CI 0.6-1.3) for 1 to 10, 1.2 (95% CI 0.8-1.7) for 11 to 99, and 1.0 (95% CI 0.6-1.6) for > or =100 lifetime episodes of cocaine use, in comparison with none. Sex, tobacco, and alcohol use appeared to be primarily responsible for the confounding we observed in unadjusted models. We found no evidence of a causal relationship between long-term exposure to cocaine and coronary calcification and conclude that acute nonatherogenic mechanisms probably explain most cocaine-associated myocardial infarction.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys.

PubMed

Collins, Gregory T; Gerak, Lisa R; Javors, Martin A; France, Charles P

2016-01-01

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses.

PubMed

Bouhlal, Sofia; Ellefsen, Kayla N; Sheskier, Mikela B; Singley, Erick; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A; Leggio, Lorenzo

2017-11-01

Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's≫>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations. Published by Elsevier B.V.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

PubMed Central

Collins, Gregory T.; Gerak, Lisa R.; Javors, Martin A.

2016-01-01

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30–60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse. PMID:26534942

Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem.

PubMed

Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J; Roitman, Mitchell F

2017-01-15

Cocaine increases dopamine concentration in the nucleus accumbens through competitive binding to the dopamine transporter (DAT). However, it also increases the frequency of dopamine release events, a finding that cannot be explained by action at the DAT alone. Rather, this effect may be mediated by cocaine-induced modulation of brain regions that project to dopamine neurons. To explore regional contributions of cocaine to dopamine signaling, we administered cocaine to the lateral or fourth ventricles and compared the effects on dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area to that of systemically-delivered cocaine. Stimulation trains caused a sharp rise in dopamine followed by a slower return to baseline. The magnitude of dopamine release ([DA]max) as well as the latency to decay to fifty percent of the maximum (t(1/2); index of DAT activity) by each stimulation train were recorded. All routes of cocaine delivery caused an increase in [DA]max; only systemic cocaine caused an increase in t(1/2). Importantly, these data are the first to show that hindbrain (fourth ventricle)-delivered cocaine modulates phasic dopamine signaling. Fourth ventricular cocaine robustly increased cFos immunoreactivity in the nucleus of the solitary tract (NTS), suggesting a neural substrate for hindbrain cocaine-mediated effects on [DA]max. Together, the data demonstrate that cocaine-induced effects on phasic dopamine signaling are mediated via actions throughout the brain including the hindbrain. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Buspirone Reduces Sexual Risk-Taking Intent but not Cocaine Self-Administration

PubMed Central

Bolin, B. Levi; Lile, Joshua A.; Marks, Katherine R.; Beckmann, Joshua S.; Rush, Craig R.; Stoops, William W.

2016-01-01

Impulsive sexual decision-making may underlie sexual risk-taking behavior that contributes to the disproportionately high prevalence of HIV infection among cocaine users. Delay-discounting procedures measure impulsive decision-making and may provide insight into the underlying mechanisms of sexual risk-taking behavior. The anxiolytic drug buspirone reduces delay discounting in rats and blunts the reinforcing effects of cocaine in some preclinical studies suggesting that it might have utility in the treatment of cocaine-use disorders. This study determined whether buspirone mitigates impulsive risky sexual decision-making in cocaine users on a sexual delay-discounting procedure. The effects of buspirone maintenance on the abuse-related and physiological effects of cocaine were also tested. Nine (N = 9) current cocaine users completed a repeated-measures, inpatient protocol in which sexual delay discounting was assessed following three days of maintenance on placebo and buspirone (30 mg/day) in counterbalanced order. The reinforcing, subject-rated, and physiological effects of placebo and intranasal cocaine (15 and 45 mg) were also assessed during buspirone and placebo maintenance. Buspirone increased the likelihood of condom use for hypothetical sexual partners that were categorized as most likely to have a sexually transmitted infection and least sexually desirable. Cocaine functioned as a reinforcer and increased positive subjective effects ratings, but buspirone maintenance did not impact these effects of cocaine. Buspirone was also safe and tolerable when combined with cocaine and may have blunted some its cardiovascular effects. The results from the sexual delay-discounting procedure indicate that buspirone may reduce preference for riskier sex in cocaine users. PMID:27254258

Highly sensitive and specific on-site detection of serum cocaine by a low cost aptasensor.

PubMed

Oueslati, Rania; Cheng, Cheng; Wu, Jayne; Chen, Jiangang

2018-06-15

Cocaine is one of the most used illegal recreational drugs. Developing an on-site test for cocaine use detection has been a focus of research effort, since it is essential to the control and legal action against drug abuse. Currently most of cocaine detection methods are time-consuming and require special or expensive equipment, and the detection often suffers from high cross-reactivity with cocaine metabolites and relative low sensitivity with the best limit of detection reported at sub nanomolar (nM) level. In this work, an aptasensor has been developed using capacitive monitoring of sensor surface incorporating alternating current electrokinetics effects to speed up molecular transport and minimize matrix effects. The aptasensor is rapid, low cost, highly sensitive and specific as well as simple-to-use for the detection of cocaine from serum. The assay has a sample-to-result time of 30 s, a limit of detection of 7.8 fM, and a linear response for cocaine ranging from 14.5fM to 14.5pM in standard buffer, which are great improvements from other reported cocaine sensors. Special buffer is used for serum cocaine detection, and a limit of detection of 13.4 fM is experimentally demonstrated for cocaine spiked in human serum (equivalent to 1.34pM cocaine in neat serum). The specificity of the biosensor is also demonstrated with structurally similar chemicals, ecgonine ethyl ester and methylecgonidine. This biosensor shows high promise in detection of low levels of cocaine from complex matrices. Copyright © 2018 Elsevier B.V. All rights reserved.

Associations between behavioral disinhibition and cocaine use history in individuals with cocaine dependence.

PubMed

Prisciandaro, James J; Korte, Jeffrey E; McRae-Clark, Aimee L; Brady, Kathleen T

2012-10-01

Behavioral disinhibition has been suggested as both a cause and consequence of substance use disorders. Many studies examining associations between behavioral disinhibition and substance use history have focused on individuals with alcohol dependence or non-dependent college students. In the present study, the relationship between behavioral disinhibition and cocaine use history in individuals with cocaine dependence is examined. Forty-six non-treatment-seeking cocaine-dependent men and women completed impulsivity (Barratt impulsiveness scale; BIS) and novelty seeking (temperament and character inventory; TCI) questionnaires at the baseline visit of an ongoing study. Unadjusted, and adjusted for gender and age, Pearson correlations were calculated between BIS, TCI, and cocaine use variables from the structured clinical interview for DSM-IV and timeline follow-back (age of onset, quantity/frequency of past 30 day cocaine use). As expected, elevated motor impulsivity and novelty seeking were each associated with younger age of dependence onset. Also, individuals with lower levels of persistence on the TCI reported more days of cocaine use over the previous month. Unexpectedly, increased novelty seeking and attentional impulsivity were associated with fewer days of cocaine use and less money spent on cocaine, respectively. Controlling for age and gender did not substantially change the pattern of observed associations. The present study provides preliminary evidence for associations between behavioral disinhibition and cocaine use history in cocaine-dependent individuals. Given our relatively small sample size and the correlational nature of our findings, further research is needed to replicate and extend our results. Copyright © 2012 Elsevier Ltd. All rights reserved.

Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions.

PubMed

Huskinson, Sally L; Freeman, Kevin B; Woolverton, William L

2015-01-01

Cocaine and opioids are often co-abused. Laboratory research has focused largely on the reinforcing effects of mixtures of drugs relative to the drugs alone. Less research has examined drug mixing by the subject under concurrent-access conditions. Self-administration of various doses of cocaine and remifentanil was examined under concurrent-access conditions. It was hypothesized that if cocaine and opioid combinations were more effective reinforcers than the single drugs, subjects would mix the two drugs by adjusting their responding to cocaine and an opioid alternative to maintain an optimal ratio of cocaine/remifentanil intake. Three male rhesus monkeys were allowed to self-administer cocaine (0.05-0.2 mg/kg/inj) or saline on one lever and remifentanil (0.05-0.4 μg/kg/inj) or saline on the other lever under concurrent fixed-ratio (FR) 10 schedules. Daily sessions lasted 2 h, and there was a 1-s timeout after every 10-s injection. When saline and drug were concurrently available, responding on the saline-associated lever was low relative to the drug alternative. When cocaine and remifentanil were concurrently available, both drugs were self-administered above saline levels. Cocaine intake decreased, and remifentanil intake increased as a function of the remifentanil dose that was available. Conversely, cocaine intake and remifentanil intake did not change systematically as a function of the cocaine dose that was available. Monkeys will mix cocaine and an opioid when the two drugs are available concurrently. However, there was no indication that monkeys titrated drug intake to maintain an optimal ratio of intake of the two compounds.

Effect of PTSD diagnosis and contingency management procedures on cocaine use in dually cocaine and opioid-dependent individuals maintained on LAAM: A retrospective analysis

PubMed Central

Mancino, M.; McGaugh, J.; Feldman, Z.; Poling, J.; Oliveto, A.

2012-01-01

This randomized clinical trial retrospectively examined the effect of Post Traumatic Stress Disorder (PTSD) and contingency management (CM) on cocaine use in opioid and cocaine dependent individuals maintained on high or low-dose LAAM randomly assigned to CM or a yoked-control condition. Cocaine-positive urines decreased more rapidly over time in those without PTSD versus those with PTSD in the non-contingency condition. In participants with PTSD, CM resulted in fewer cocaine positive urines compared to the non-contingent condition. This suggests that CM may help improve the potentially worse outcomes in opioid-and cocaine dependent individuals with PTSD compared to those without PTSD. PMID:20163389

Neonatal Neurobehavioral and Neuroanatomic Correlates of Prenatal Cocaine Exposure

PubMed Central

FRANK, DEBORAH A.; AUGUSTYN, MARILYN; ZUCKERMAN, BARRY S.

2008-01-01

Complex methodologic challenges face researchers studying the effects of prenatal cocaine exposure on infant outcome. These include unavoidable imprecision in ascertaining the gestational timing and dose of cocaine to which the fetus was exposed and difficulties in identifying and quantifying the confounding, mediating, and moderating variables. Review of research on neonatal behavioral and cranial ultrasound findings following in utero cocaine exposure is used to illustrate these issues. We conclude that there are measurable but not dramatic dose-related effects of prenatal cocaine exposure on infant central nervous system structure and function. The effects of dose of prenatal cocaine exposure on later child development remain to be determined. Such research would be facilitated by a scientific consensus delineating relative doses of prenatal cocaine exposure. PMID:9668396

Plasma concentrations of BDNF and IGF-1 in abstinent cocaine users with high prevalence of substance use disorders: relationship to psychiatric comorbidity.

PubMed

Pedraz, María; Martín-Velasco, Ana Isabel; García-Marchena, Nuria; Araos, Pedro; Serrano, Antonia; Romero-Sanchiz, Pablo; Suárez, Juan; Castilla-Ortega, Estela; Barrios, Vicente; Campos-Cloute, Rafael; Ruiz, Juan Jesús; Torrens, Marta; Chowen, Julie Ann; Argente, Jesús; de la Torre, Rafael; Santín, Luis Javier; Villanúa, María Ángeles; Rodríguez de Fonseca, Fernando; Pavón, Francisco Javier

2015-01-01

Recent studies have identified biomarkers related to the severity and pathogenesis of cocaine addiction and common comorbid psychiatric disorders. Monitoring these plasma mediators may improve the stratification of cocaine users seeking treatment. Because the neurotrophic factors are involved in neural plasticity, neurogenesis and neuronal survival, we have determined plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 3 (IGFBP-3) in a cross-sectional study with abstinent cocaine users who sought outpatient treatment for cocaine (n = 100) and age/body mass matched controls (n = 85). Participants were assessed with the diagnostic interview 'Psychiatric Research Interview for Substance and Mental Disorders'. Plasma concentrations of these peptides were not different in cocaine users and controls. They were not associated with length of abstinence, duration of cocaine use or cocaine symptom severity. The pathological use of cocaine did not influence the association of IGF-1 with age observed in healthy subjects, but the correlation between IGF-1 and IGFBP-3 was not significantly detected. Correlation analyses were performed between these peptides and other molecules sensitive to addiction: BDNF concentrations were not associated with inflammatory mediators, lipid derivatives or IGF-1 in cocaine users, but correlated with chemokines (fractalkine/CX3CL1 and SDF-1/CXCL12) and N-acyl-ethanolamines (N-palmitoyl-, N-oleoyl-, N-arachidonoyl-, N-linoleoyl- and N-dihomo-γ-linolenoyl-ethanolamine) in controls; IGF-1 concentrations only showed association with IGFBP-3 concentrations in controls; and IGFBP-3 was only correlated with N-stearoyl-ethanolamine concentrations in cocaine users. Multiple substance use disorders and life-time comorbid psychopathologies were common in abstinent cocaine users. Interestingly, plasma BDNF concentrations were exclusively found to be decreased in users diagnosed with both primary and cocaine-induced disorders for mood and anxiety disorders. In summary, BDNF, IGF-1 and IGFBP-3 were not affected by a history of pathological use of cocaine supported by the absence of associations with other molecules sensitive to cocaine addiction. However, BDNF was affected by comorbid mood disorders. Further research is necessary to elucidate the role of BDNF and IGF-1 in the transition to cocaine addiction and associated psychiatric comorbidity.

Plasma Concentrations of BDNF and IGF-1 in Abstinent Cocaine Users with High Prevalence of Substance Use Disorders: Relationship to Psychiatric Comorbidity

PubMed Central

Araos, Pedro; Serrano, Antonia; Romero-Sanchiz, Pablo; Suárez, Juan; Castilla-Ortega, Estela; Barrios, Vicente; Campos-Cloute, Rafael; Ruiz, Juan Jesús; Torrens, Marta; Chowen, Julie Ann; Argente, Jesús; de la Torre, Rafael; Santín, Luis Javier; Villanúa, María Ángeles; Rodríguez de Fonseca, Fernando; Pavón, Francisco Javier

2015-01-01

Recent studies have identified biomarkers related to the severity and pathogenesis of cocaine addiction and common comorbid psychiatric disorders. Monitoring these plasma mediators may improve the stratification of cocaine users seeking treatment. Because the neurotrophic factors are involved in neural plasticity, neurogenesis and neuronal survival, we have determined plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 3 (IGFBP-3) in a cross-sectional study with abstinent cocaine users who sought outpatient treatment for cocaine (n = 100) and age/body mass matched controls (n = 85). Participants were assessed with the diagnostic interview ‘Psychiatric Research Interview for Substance and Mental Disorders’. Plasma concentrations of these peptides were not different in cocaine users and controls. They were not associated with length of abstinence, duration of cocaine use or cocaine symptom severity. The pathological use of cocaine did not influence the association of IGF-1 with age observed in healthy subjects, but the correlation between IGF-1 and IGFBP-3 was not significantly detected. Correlation analyses were performed between these peptides and other molecules sensitive to addiction: BDNF concentrations were not associated with inflammatory mediators, lipid derivatives or IGF-1 in cocaine users, but correlated with chemokines (fractalkine/CX3CL1 and SDF-1/CXCL12) and N-acyl-ethanolamines (N-palmitoyl-, N-oleoyl-, N-arachidonoyl-, N-linoleoyl- and N-dihomo-γ-linolenoyl-ethanolamine) in controls; IGF-1 concentrations only showed association with IGFBP-3 concentrations in controls; and IGFBP-3 was only correlated with N-stearoyl-ethanolamine concentrations in cocaine users. Multiple substance use disorders and life-time comorbid psychopathologies were common in abstinent cocaine users. Interestingly, plasma BDNF concentrations were exclusively found to be decreased in users diagnosed with both primary and cocaine-induced disorders for mood and anxiety disorders. In summary, BDNF, IGF-1 and IGFBP-3 were not affected by a history of pathological use of cocaine supported by the absence of associations with other molecules sensitive to cocaine addiction. However, BDNF was affected by comorbid mood disorders. Further research is necessary to elucidate the role of BDNF and IGF-1 in the transition to cocaine addiction and associated psychiatric comorbidity. PMID:25734326

Comparative effects of sodium bicarbonate and sodium chloride on reversing cocaine-induced changes in the electrocardiogram.

PubMed

Parker, R B; Perry, G Y; Horan, L G; Flowers, N C

1999-12-01

Cocaine abuse is associated with a number of cardiovascular complications that include arrhythmias and sudden cardiac death. Although the mechanism(s) remain unclear, cocaine-induced block of sodium channels resulting in slowed cardiac conduction is thought to play an important role. Several reports suggest that the effects of cocaine effects on cardiac sodium channels can be reversed by administration of sodium bicarbonate. Whether the beneficial effects of sodium bicarbonate are due to sodium ions or an increase in blood pH is unknown. Therefore the purpose of this study was to compare the effects of sodium loading alone (by using sodium chloride) versus sodium loading with an associated increase in arterial pH (by using sodium bicarbonate) on reversing cocaine-induced effects on the electrocardiogram (ECG) in a canine model. Seventeen anesthetized dogs received three i.v. injections of cocaine, 5 mg/kg, with each dose separated by 15 min. Two minutes after the third cocaine dose, each dog was randomly assigned to receive 2 mEq/kg i.v. sodium bicarbonate (1 mEq/ml) or 2 mEq/kg i.v. sodium chloride (1 mEq/ml). ECG, electrophysiologic, and hemodynamic data were recorded at baseline, after each cocaine injection, and after administration of sodium bicarbonate or sodium chloride. In both groups of animals, the first cocaine injection significantly (p < 0.05) prolonged the PR, QTc, AH, and HV intervals, and QRS duration compared with baseline. All intervals continued to lengthen in a dose-dependent manner after the second and third cocaine doses. Sodium bicarbonate significantly (p < 0.05) reduced cocaine-induced prolongation of PR [(147 +/- 5-130 +/- 5 ms), AH (81 +/- 6 - 72 +/- 6 ms), and HV intervals (55 +/- 2 - 39 +/- 1 ms). and QRS duration (96 +/- 6 - 66 +/- 4 ms), peak effect after third cocaine dose versus after sodium bicarbonate, respectively]. Sodium chloride had no effect on reversing cocaine-induced effects on the ECG. Cocaine produces dose-dependent slowing of cardiac conduction that is effectively reversed by sodium bicarbonate. The lack of efficacy of sodium chloride suggests that the increase in arterial pH associated with sodium bicarbonate is responsible for reversal of the effects of cocaine on the ECG. Therefore sodium bicarbonate may be clinically useful in the treatment of cocaine-induced cardiac arrhythmias, primarily as a result of its effects on arterial pH.

[Sucrose reward promotes rats' motivation for cocaine].

PubMed

Li, Yan-Qing; LE, Qiu-Min; Yu, Xiang-Chen; Ma, Lan; Wang, Fei-Fei

2016-06-25

Caloric diet, such as fat and sugar intake, has rewarding effects, and has been indicated to affect the responses to addictive substances in animal experiments. However, the possible association between sucrose reward and the motivation for addictive drugs remains to be elucidated. Thus, we carried out behavioral tests after sucrose self-administration training to determine the effects of sucrose experience on rats' motivation for cocaine, locomotor sensitivity to cocaine, basal locomotor activity, anxiety level, and associative learning ability. The sucrose-experienced (sucrose) group exhibited higher lever press, cocaine infusion and break point, as well as upshift of cocaine dose-response curve in cocaine self-administration test, as compared with the control (chow) group. Additionally, despite similar locomotor activity in open field test and comparable score in cocaine-induced conditioned place preference, the sucrose group showed higher cocaine-induced locomotor sensitivity as compared with the chow group. The anxiety level and the performance in vocal-cue induced fear memory were similar between these two groups in elevated plus maze and fear conditioning tests, respectively. Taken together, our work indicates that sucrose experience promotes the rats' motivation for cocaine.

Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: Focus on dopamine, norepinephrine and glutamate

PubMed Central

Haile, Colin N.; Mahoney, James J.; Newton, Thomas F.; De La Garza, Richard

2012-01-01

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine. PMID:22327234

Psychometric properties of the Spanish version of the Cocaine Selective Severity Assessment to evaluate cocaine withdrawal in treatment-seeking individuals.

PubMed

Pérez de los Cobos, José; Trujols, Joan; Siñol, Núria; Vasconcelos e Rego, Lisiane; Iraurgi, Ioseba; Batlle, Francesca

2014-09-01

Reliable and valid assessment of cocaine withdrawal is relevant for treating cocaine-dependent patients. This study examined the psychometric properties of the Spanish version of the Cocaine Selective Severity Assessment (CSSA), an instrument that measures cocaine withdrawal. Participants were 170 cocaine-dependent inpatients receiving detoxification treatment. Principal component analysis revealed a 4-factor structure for CSSA that included the following components: 'Cocaine Craving and Psychological Distress', 'Lethargy', 'Carbohydrate Craving and Irritability', and 'Somatic Depressive Symptoms'. These 4 components accounted for 56.0% of total variance. Internal reliability for these components ranged from unacceptable to good (Chronbach's alpha: 0.87, 0.65, 0.55, and 0.22, respectively). All components except Somatic Depressive Symptoms presented concurrent validity with cocaine use. In summary, while some properties of the Spanish version of the CSSA are satisfactory, such as interpretability of factor structure and test-retest reliability, other properties, such as internal reliability and concurrent validity of some factors, are inadequate. Copyright © 2014 Elsevier Inc. All rights reserved.

Paradoxical Abatement of Striatal Dopaminergic Transmission by Cocaine and Methylphenidate*

PubMed Central

Federici, Mauro; Latagliata, Emanuele Claudio; Ledonne, Ada; Rizzo, Francesca R.; Feligioni, Marco; Sulzer, Dave; Dunn, Matthew; Sames, Dalibor; Gu, Howard; Nisticò, Robert; Puglisi-Allegra, Stefano; Mercuri, Nicola B.

2014-01-01

We combined in vitro amperometric, optical analysis of fluorescent false neurotransmitters and microdialysis techniques to unveil that cocaine and methylphenidate induced a marked depression of the synaptic release of dopamine (DA) in mouse striatum. In contrast to the classical dopamine transporter (DAT)-dependent enhancement of the dopaminergic signal observed at concentrations of cocaine lower than 3 μm, the inhibitory effect of cocaine was found at concentrations higher than 3 μm. The paradoxical inhibitory effect of cocaine and methylphenidate was associated with a decrease in synapsin phosphorylation. Interestingly, a cocaine-induced depression of DA release was only present in cocaine-insensitive animals (DAT-CI). Similar effects of cocaine were produced by methylphenidate in both wild-type and DAT-CI mice. On the other hand, nomifensine only enhanced the dopaminergic signal either in wild-type or in DAT-CI mice. Overall, these results indicate that cocaine and methylphenidate can increase or decrease DA neurotransmission by blocking reuptake and reducing the exocytotic release, respectively. The biphasic reshaping of DA neurotransmission could contribute to different behavioral effects of psychostimulants, including the calming ones, in attention deficit hyperactivity disorder. PMID:24280216

Cocaine's appetite for fat and the consequences on body weight.

PubMed

Billing, Lawrence; Ersche, Karen D

2015-03-01

For many individuals in treatment for cocaine dependence, weight gain is a substantial problem during recovery. This weight gain causes significant distress and seems to increase the risk of relapse. The mechanisms underlying cocaine's effects on weight remain elusive. It is widely assumed that this weight gain reflects a metabolic or behavioural compensatory response to the cessation of cocaine use. Here we challenge this assumption and outline potential mechanisms by which chronic cocaine use produces disturbances in the regulation of fat intake and storage, through its effects on the central and peripheral nervous systems, specifically the sympathetic nervous system. We hypothesize that the cocaine-induced alteration in fat regulation results in cocaine users developing a pronounced appetite for fatty food but keeps their fat mass low. This altered fat appetite subsequently leads to excessive weight gain when individuals enter treatment and stop using cocaine. Our aim is to shed light on the neurobiological mechanisms that may underlie the alterations in eating and fat regulation in cocaine-dependent individuals, to open up potential new avenues to support these individuals in recovery.

Cocaine use and syphilis trends: findings from the arrestee drug abuse monitoring (ADAM) program and syphilis epidemiology in Houston.

PubMed

Ross, Michael W; Risser, Jan; Peters, Ronald J; Johnson, Regina J

2006-01-01

There has been speculation that trends in syphilis have been fueled by crack cocaine use. This study examined the data on syphilis notifications and arrestee drug abuse monitoring (ADAM) to ascertain the relationships between syphilis and cocaine use trends in three racial/ethnic groups. Syphilis notifications and data from the ADAM project were compared in Houston/Harris County, Texas, from 1991-1998 using a linear regression equation. Data indicated significant relationships between the data for cocaine use and syphilis in African Americans but not Hispanics or non-Hispanic whites. For African Americans, 58% of the variance between cocaine use and syphilis was explained. When data limited to jail syphilis notifications and ADAM cocaine in African Americans were examined, the association was stronger for males than for females. For African Americans, cocaine (probably crack cocaine) use trends were significantly associated with syphilis trends in this population. These data suggest that control of crack cocaine may have an impact on syphilis rates and that there may be close relationships between some STDs and drug abuse.

Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

PubMed

Wiskerke, Joost; Schoffelmeer, Anton N M; De Vries, Taco J

2016-10-01

Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Xiuwu; Mi Jing; Wetsel, William C.

Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85{alpha}/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naive rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or salinemore » for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D{sub 1}/D{sub 2} agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT{sub 3} antagonist ondansetron (0.2 mg/kg, s.c., 3.5 h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85{alpha}/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5 h after pergolide. The present study suggests that selective enhancement of the PI3K activity in the NAc shell may be one of key alterations underlying the long-term cocaine sensitization. To the extent cocaine sensitization is an important factor in human cocaine abuse, pharmacological interventions targeted toward the NAc shell PI3K alteration may be useful in cocaine abuse treatment.« less

Optogenetic Central Amygdala Stimulation Intensifies and Narrows Motivation for Cocaine.

PubMed

Warlow, Shelley M; Robinson, Mike J F; Berridge, Kent C

2017-08-30

Addiction is often characterized by intense motivation for a drug, which may be narrowly focused at the expense of other rewards. Here, we examined the role of amygdala-related circuitry in the amplification and narrowing of motivation focus for intravenous cocaine. We paired optogenetic channelrhodopsin (ChR2) stimulation in either central nucleus of amygdala (CeA) or basolateral amygdala (BLA) of female rats with one particular nose-poke porthole option for earning cocaine infusions (0.3 mg/kg, i.v.). A second alternative porthole earned identical cocaine but without ChR2 stimulation. Consequently, CeA rats quickly came to pursue their CeA ChR2-paired cocaine option intensely and exclusively, elevating cocaine intake while ignoring their alternative cocaine alone option. By comparison, BLA ChR2 pairing failed to enhance cocaine motivation. CeA rats also emitted consummatory bites toward their laser-paired porthole, suggesting that higher incentive salience made that cue more attractive. A separate progressive ratio test of incentive motivation confirmed that CeA ChR2 amplified rats' motivation, raising their breakpoint effort price for cocaine by 10-fold. However, CeA ChR2 laser on its own lacked any reinforcement value: laser by itself was never self-stimulated, not even by the same rats in which it amplified motivation for cocaine. Conversely, CeA inhibition by muscimol/baclofen microinjections prevented acquisition of cocaine self-administration and laser preference, whereas CeA inhibition by optogenetic halorhodopsin suppressed cocaine intake, indicating that CeA circuitry is needed for ordinary cocaine motivation. We conclude that CeA ChR2 excitation paired with a cocaine option specifically focuses and amplifies motivation to produce intense pursuit and consumption focused on that single target. SIGNIFICANCE STATEMENT In addiction, intense incentive motivation often becomes narrowly focused on a particular drug of abuse. Here we show that pairing central nucleus of amygdala (CeA) optogenetic stimulation with one option for earning intravenous cocaine makes that option almost the exclusive focus of intense pursuit and consumption. CeA stimulation also elevated the effort cost rats were willing to pay for cocaine and made associated cues become intensely attractive. However, we also show that CeA laser had no reinforcing properties at all when given alone for the same rats. Therefore, CeA laser pairing makes its associated cocaine option and cues become powerfully attractive in a nearly addictive fashion. Copyright © 2017 the authors 0270-6474/17/378330-19$15.00/0.

Optogenetic Central Amygdala Stimulation Intensifies and Narrows Motivation for Cocaine

PubMed Central

2017-01-01

Addiction is often characterized by intense motivation for a drug, which may be narrowly focused at the expense of other rewards. Here, we examined the role of amygdala-related circuitry in the amplification and narrowing of motivation focus for intravenous cocaine. We paired optogenetic channelrhodopsin (ChR2) stimulation in either central nucleus of amygdala (CeA) or basolateral amygdala (BLA) of female rats with one particular nose-poke porthole option for earning cocaine infusions (0.3 mg/kg, i.v.). A second alternative porthole earned identical cocaine but without ChR2 stimulation. Consequently, CeA rats quickly came to pursue their CeA ChR2-paired cocaine option intensely and exclusively, elevating cocaine intake while ignoring their alternative cocaine alone option. By comparison, BLA ChR2 pairing failed to enhance cocaine motivation. CeA rats also emitted consummatory bites toward their laser-paired porthole, suggesting that higher incentive salience made that cue more attractive. A separate progressive ratio test of incentive motivation confirmed that CeA ChR2 amplified rats' motivation, raising their breakpoint effort price for cocaine by 10-fold. However, CeA ChR2 laser on its own lacked any reinforcement value: laser by itself was never self-stimulated, not even by the same rats in which it amplified motivation for cocaine. Conversely, CeA inhibition by muscimol/baclofen microinjections prevented acquisition of cocaine self-administration and laser preference, whereas CeA inhibition by optogenetic halorhodopsin suppressed cocaine intake, indicating that CeA circuitry is needed for ordinary cocaine motivation. We conclude that CeA ChR2 excitation paired with a cocaine option specifically focuses and amplifies motivation to produce intense pursuit and consumption focused on that single target. SIGNIFICANCE STATEMENT In addiction, intense incentive motivation often becomes narrowly focused on a particular drug of abuse. Here we show that pairing central nucleus of amygdala (CeA) optogenetic stimulation with one option for earning intravenous cocaine makes that option almost the exclusive focus of intense pursuit and consumption. CeA stimulation also elevated the effort cost rats were willing to pay for cocaine and made associated cues become intensely attractive. However, we also show that CeA laser had no reinforcing properties at all when given alone for the same rats. Therefore, CeA laser pairing makes its associated cocaine option and cues become powerfully attractive in a nearly addictive fashion. PMID:28751460

Cocaine

MedlinePlus

Cocaine is a white powder. It can be snorted up the nose or mixed with water and injected with a needle. Cocaine can also be made into small white rocks, ... Crack is smoked in a small glass pipe. Cocaine speeds up your whole body. You may feel ...

Photoletter to the editor: Diffuse cocaine-related purpura.

PubMed

Sarkar, Debjeet; Kammona, Hussein A; Lamsen, Leonard N; McAbee, Bradley A; Clark, Christopher T; Lee, Solomon S; Kelley, Shane E

2013-01-01

Diffuse purpura is an uncommon skin manifestation found in platelet and coagulation disorders, meningococcemia, vasculitides and cocaine use. Reports of cocaine-related purpura predominantly involve adulteration with the anti-helminthic, levamisole. Levamisole enhances the effects of cocaine and is known to cause vasculitis. Recently, the CDC also released an advisory of oxymorphone being used intravenously causing thrombogenic thrombocytopenic purpura (TTP). We report the case of a patient with diffuse purpura ultimately diagnosed with cocaine-related thrombogenic vasculopathy. In the current environment of adulterated cocaine usage and increased prescription narcotic abuse, it is crucial to investigate substance abuse as a cause of diffuse purpura.

Analysis of volatile organic compounds from illicit cocaine samples

NASA Astrophysics Data System (ADS)

Robins, W. H.; Wright, Bob W.

1994-10-01

Detection of illicit cocaine hydrochloride shipments can be improved if there is a greater understanding of the identity and quantity of volatile compounds present. This study provides preliminary data concerning the volatile organic compounds detected in a limited set of cocaine hydrochloride samples. In all cases, cocaine was one of the major volatile compounds detected. Other tropeines were detected in almost all samples. Low concentrations of compounds which may be residues of processing solvents were observed in some samples. The equilibrium emissivity of cocaine from cocaine hydrochloride was investigated and a value of 83 parts-per-trillion was determined.

MDMA reinstates cocaine-seeking behaviour in mice.

PubMed

Trigo, José Manuel; Orejarena, Maria Juliana; Maldonado, Rafael; Robledo, Patricia

2009-06-01

MDMA effects are mediated by monoaminergic systems, which seem to play a central role in cocaine craving and relapse. CD1 mice trained to self-administer cocaine (1 mg/kg/infusion) underwent an extinction procedure in which the cues contingent with drug self-administration remained present. Mice achieving extinction were injected with MDMA (10 mg/kg), d-amphetamine (1 and 2 mg/kg) or saline and tested for reinstatement. Acute MDMA, but not d-amphetamine or saline reinstated cocaine-seeking behaviour in mice in which cocaine self-administration and contingent cues were previously extinguished. Acute MDMA can reinstate cocaine-seeking behaviour in mice.

Alternative Reinforcer Response Cost Impacts Cocaine Choice in Humans

PubMed Central

Stoops, William W.; Lile, Joshua A.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

2011-01-01

Cocaine use disorders are an unrelenting public health concern. Behavioral treatments reduce cocaine use by providing non-drug alternative reinforcers. The purpose of this human laboratory experiment was to determine how response cost for non-drug alternative reinforcers influenced cocaine choice. Seven cocaine-using, non-treatment-seeking subjects completed a crossover, double-blind protocol in which they first sampled doses of intranasal cocaine (5, 10, 20 or 30 mg) and completed a battery of subject-rated and physiological measures. Subjects then made eight discrete choices between the sampled dose and an alternative reinforce (US$0.25). The response cost to earn a cocaine dose was always a fixed ratio (FR) of 100 responses. The response cost for the alternative reinforcer varied across sessions (FR1, FR10, FR100, FR1000). Dose-related increases were observed for cocaine choice. Subjects made fewer drug choices when the FR requirements for the alternative reinforcers were lower than that for drug relative to when the FR requirements were equal to or higher than that for drug. Intranasal cocaine also produced prototypical stimulant-like subject-rated and physiological effects (e.g., increased ratings of Like Drug; elevated blood pressure). These data demonstrate that making alternative reinforcers easier to earn reduces cocaine self-administration, which has implications for treatment efforts. PMID:22015480

Influences on cocaine tolerance assessed under a multiple conjunctive schedule of reinforcement.

PubMed

Yoon, Jin Ho; Branch, Marc N

2009-11-01

Under multiple schedules of reinforcement, previous research has generally observed tolerance to the rate-decreasing effects of cocaine that has been dependent on schedule-parameter size in the context of fixed-ratio (FR) schedules, but not under the context of fixed-interval (FI) schedules of reinforcement. The current experiment examined the effects of cocaine on key-pecking responses of White Carneau pigeons maintained under a three-component multiple conjunctive FI (10 s, 30 s, & 120 s) FR (5 responses) schedule of food presentation. Dose-effect curves representing the effects of presession cocaine on responding were assessed in the context of (1) acute administration of cocaine (2) chronic administration of cocaine and (3) daily administration of saline. Chronic administration of cocaine generally resulted in tolerance to the response-rate decreasing effects of cocaine, and that tolerance was generally independent of relative FI value, as measured by changes in ED50 values. Daily administration of saline decreased ED50 values to those observed when cocaine was administered acutely. The results show that adding a FR requirement to FI schedules is not sufficient to produce schedule-parameter-specific tolerance. Tolerance to cocaine was generally independent of FI-parameter under the present conjunctive schedules, indicating that a ratio requirement, per se, is not sufficient for tolerance to be dependent on FI parameter.

Extinction and Reinstatement of Cocaine-seeking in Self-administering Mice is Associated with Bidirectional AMPAR-mediated Plasticity in the Nucleus Accumbens Shell.

PubMed

Ebner, Stephanie R; Larson, Erin B; Hearing, Matthew C; Ingebretson, Anna E; Thomas, Mark J

2018-06-07

Experience-dependent synaptic plasticity is an important component of both learning and motivational disturbances found in addicted individuals. Here, we investigated the role of cocaine experience-dependent plasticity at excitatory synapses in the nucleus accumbens shell (NAcSh) in relapse-related behavior in mice with a history of volitional cocaine self-administration. Using an extinction/reinstatement paradigm of cocaine-seeking behavior, we demonstrate that cocaine-experienced mice with extinguished cocaine-seeking behavior show potentiation of synaptic strength at excitatory inputs onto NAcSh medium spiny neurons (MSNs). Conversely, we found that exposure to various distinct types of reinstating stimuli (cocaine, cocaine-associated cues, yohimbine "stress") after extinction can produce a relative depotentiation of NAcSh synapses that is strongly associated with the magnitude of cocaine-seeking behavior exhibited in response to these challenges. Furthermore, we show that these effects are due to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-specific mechanisms that differ depending on the nature and context of the reinstatement-inducing stimuli. Together, our findings identify common themes as well as differential mechanisms that are likely important for the ability of diverse environmental stimuli to drive relapse to addictive-like cocaine-seeking behavior. Copyright © 2018. Published by Elsevier Ltd.

Gender differences in cocaine pharmacokinetics in CF-1 mice.

PubMed

Visalli, Thomas; Turkall, Rita; Abdel-Rahman, Mohamed S

2005-01-15

Hepatocellular damage is thought to occur as a result of cytochrome P450-mediated oxidation of cocaine to norcocaine (NC), a precursor of the hepatotoxic nitrosonium ion. However, this damage occurs only in male mice, with females exhibiting minimal biochemical and histological signs of hepatocellular stress. The objective of this study was to determine the plasma time course and tissue disposition of cocaine and its metabolites to further investigate the role that metabolism may play in the gender difference observed. Male and female CF-1 mice were orally administered 20mg/kg cocaine hydrochloride once daily for 7 days. Blood samples were withdrawn at various time points post-injection and analyzed for cocaine and its metabolites benzoylecgonine (BE), norcocaine, ecgonine methyl ester (EME), and ecgonine (E). In addition, tissue concentrations of cocaine and its metabolites were determined in liver, heart, brain, and kidney tissue. The results demonstrated that the plasma elimination half-life of cocaine is nearly three times longer in males versus females. Non-hepatotoxic hydrolysis metabolites BE, EME, and E were higher in female tissues while norcocaine was detected in tissues of male animals only. This study revealed that differences in cocaine pharmacokinetics and the resultant differences in the biodisposition of cocaine and its metabolites in tissues contribute to the mechanism of gender difference seen in cocaine hepatotoxicity.

Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.

PubMed

Schank, Jesse R; Liles, L Cameron; Weinshenker, David

2008-06-01

Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.

Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans.

PubMed

Javaid, J I; Notorangelo, M P; Pandey, S C; Reddy, P L; Pandey, G N; Davis, J M

1994-07-01

In the present study, homovanillic acid in plasma (pHVA) and benzodiazepine receptors (3H-PK11195 binding) in neutrophil membranes were determined in blood obtained from cocaine-dependent (DSM-III-R) adult male inpatients at baseline-(within 72 hr of last cocaine use) and after 3 weeks of cocaine abstinence, and normal controls. The mean (+/- SEM) pHVA at baseline (10.3 ng/ml +/- 1.1) was similar to normals and did not change after 3 weeks of cocaine abstinence. Similarly, the binding indices of benzodiazepine receptors in cocaine-dependent subjects as a group were not significantly different than in normal controls. In 10 cocaine-dependent subjects, however, where both blood samples were available, the number of 3H-PK11195 binding sites was significantly (p < 0.05) decreased after 3 weeks of cocaine abstinence (mean +/- sem: Bmax = 6371 +/- 657 fmol/mg protein) compared with baseline (Bmax = 7553 +/- 925 fmol/mg protein), although there were no differences in the binding affinity (mean +/- sem: KD = 8.6 +/- 1.2 nmol/L after 3 weeks of abstinence compared with 8.1 +/- 1.0 nmol/L at baseline). These preliminary results suggest that peripheral benzodiazepine receptors may play an important role in the pathophysiology of cocaine withdrawal in cocaine-dependent human subjects.

Effects of Chronic Buspirone Treatment on Cocaine Self-Administration

PubMed Central

Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J; Bergman, Jack

2013-01-01

Cocaine abuse and dependence is a major public health problem that continues to challenge medication-based treatment. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on both serotonin and dopamine systems. In recent preclinical studies, acute buspirone treatment reduced cocaine self-administration at doses that did not also decrease food-reinforced behavior in rhesus monkeys (Bergman et al, 2012). The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of cocaine and food. Five adult rhesus monkeys (Macaca mulatta) were trained to self-administer cocaine and food during four 1-h daily sessions under a second-order schedule of reinforcement (FR2 [VR 16:S]). Buspirone (0.32 and 0.56 mg/kg/h) was administered intravenously through one lumen of a double-lumen catheter every 20 min for 23 h each day for 7–10 consecutive days. Each buspirone treatment period was followed by saline control treatment until drug- and food-maintained responding returned to baseline levels. Buspirone significantly reduced responding maintained by cocaine, and shifted the dose–effect curve downwards. Buspirone had minimal effects on food-maintained responding. In cocaine discrimination studies, buspirone (0.1–0.32 mg/kg, IM) did not antagonize the discriminative stimulus and rate-altering effects of cocaine in four of six monkeys. These findings indicate that buspirone selectively attenuates the reinforcing effects of cocaine in a nonhuman primate model of cocaine self-administration, and has variable effects on cocaine discrimination. PMID:23072835

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward.

PubMed

Carroll, Marilyn E; Collins, Molly; Kohl, Emily A; Johnson, Seth; Dougen, Ben

2016-08-01

In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. Cocaine deliveries were similar in males and females in the females' luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females' follicular and luteal phases. Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females' follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine's rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females' luteal phase.

Cocaine affects foraging behaviour and biogenic amine modulated behavioural reflexes in honey bees.

PubMed

Søvik, Eirik; Even, Naïla; Radford, Catherine W; Barron, Andrew B

2014-01-01

In humans and other mammals, drugs of abuse alter the function of biogenic amine pathways in the brain leading to the subjective experience of reward and euphoria. Biogenic amine pathways are involved in reward processing across diverse animal phyla, however whether cocaine acts on these neurochemical pathways to cause similar rewarding behavioural effects in animal phyla other than mammals is unclear. Previously, it has been shown that bees are more likely to dance (a signal of perceived reward) when returning from a sucrose feeder after cocaine treatment. Here we examined more broadly whether cocaine altered reward-related behaviour, and biogenic amine modulated behavioural responses in bees. Bees developed a preference for locations at which they received cocaine, and when foraging at low quality sucrose feeders increase their foraging rate in response to cocaine treatment. Cocaine also increased reflexive proboscis extension to sucrose, and sting extension to electric shock. Both of these simple reflexes are modulated by biogenic amines. This shows that systemic cocaine treatment alters behavioural responses that are modulated by biogenic amines in insects. Since insect reward responses involve both octopamine and dopamine signalling, we conclude that cocaine treatment altered diverse reward-related aspects of behaviour in bees. We discuss the implications of these results for understanding the ecology of cocaine as a plant defence compound. Our findings further validate the honey bee as a model system for understanding the behavioural impacts of cocaine, and potentially other drugs of abuse.

Rating the severity and character of transient cocaine-induced delusions and hallucinations with a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP).

PubMed

Cubells, Joseph F; Feinn, Richard; Pearson, Deborah; Burda, Jeffrey; Tang, Yilang; Farrer, Lindsay A; Gelernter, Joel; Kranzler, Henry R

2005-10-01

Cocaine can induce transient psychotic symptoms. We examined the phenomenology of such cocaine-induced psychosis (CIP) using a modified version of the Scale for Assessment of Positive Symptoms (SAPS), a well-validated instrument for the assessment of schizophrenic psychosis. We developed a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP), based on the well-validated SAPS. We interviewed 243 unrelated cocaine-dependent adults using both the SAPS-CIP and an instrument for the identification of cocaine-induced paranoia, the Cocaine Experience Questionnaire (CEQ). One hundred and eighty-one (75%) of the subjects endorsed CIP using the CEQ. With the SAPS-CIP, hallucination (HAL) and delusion (DEL) scores correlated strongly, and the DEL domain showed excellent concurrent validity with the CEQ. We observed significant positive correlations, respectively, between severity of HAL and DEL, and lifetime number of episodes of cocaine use, and negative correlations with age at onset of cocaine use. The results suggest that CIP consists of transient delusional and hallucinatory symptoms, which tend to occur together and co-vary in severity. It appears that rating cocaine-induced paranoia alone (e.g., with the CEQ) can identify most subjects experiencing CIP. However, the SAPS-CIP is useful for quantifying the severity of CIP according to operational criteria. Our data provide additional evidence that CIP is a sensitizing response.

Gestational treatment with methylazoxymethanol (MAM) that disrupts hippocampal-dependent memory does not alter behavioural response to cocaine.

PubMed

Featherstone, Robert E; Burton, Christie L; Coppa-Hopman, Romina; Rizos, Zoë; Sinyard, Judy; Kapur, Shitij; Fletcher, Paul J

2009-10-01

Schizophrenia is associated with increased rates of substance abuse that are thought to be the result of changes in cortical and mesolimbic dopamine activity. Previous work has shown that gestational methylazoxymethanol acetate (MAM) treatment induces increased mesolimbic dopamine activity when given around the time of embryonic day 17 (ED17), suggesting that MAM treatment may model some aspects of schizophrenia. Given that increased dopaminergic activity facilitates aspects of drug self-administration and reinstatement of drug seeking, the current experiments sought to assess cocaine self-administration in MAM treated animals. Experiment 1 examined the acquisition of cocaine self-administration in ED17 MAM and saline treated rats using a sub-threshold dose of cocaine. In experiment 2 ED17 MAM and saline treated animals were trained to self-administer cocaine and were then assessed under varying doses of cocaine (dose-response), followed by extinction and drug-induced reinstatement of responding. A subset of these animals was trained on a win-shift radial maze task, designed to detect impairments in hippocampal-dependent memory. In experiment 3, MAM and saline treated animals were assessed on a progressive ratio schedule of cocaine delivery. Finally, in experiment 4 MAM and saline treated animals were assessed on cocaine-induced locomotor activity across a range of doses of cocaine. MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed.

A MAOA gene*cocaine severity interaction on impulsivity and neuropsychological measures of orbitofrontal dysfunction: preliminary results.

PubMed

Verdejo-García, Antonio; Albein-Urios, Natalia; Molina, Esther; Ching-López, Ana; Martínez-González, José M; Gutiérrez, Blanca

2013-11-01

Based on previous evidence of a MAOA gene*cocaine use interaction on orbitofrontal cortex volume attrition, we tested whether the MAOA low activity variant and cocaine use severity are interactively associated with impulsivity and behavioral indices of orbitofrontal dysfunction: emotion recognition and decision-making. 72 cocaine dependent individuals and 52 non-drug using controls (including healthy individuals and problem gamblers) were genotyped for the MAOA gene and tested using the UPPS-P Impulsive Behavior Scale, the Iowa Gambling Task and the Ekman's Facial Emotions Recognition Test. To test the main hypothesis, we conducted hierarchical multiple regression analyses including three sets of predictors: (1) age, (2) MAOA genotype and severity of cocaine use, and (3) the interaction between MAOA genotype and severity of cocaine use. UPPS-P, Ekman Test and Iowa Gambling Task's scores were the outcome measures. We computed the statistical significance of the prediction change yielded by each consecutive set, with 'a priori' interest in the MAOA*cocaine severity interaction. We found significant effects of the MAOA gene*cocaine use severity interaction on the emotion recognition scores and the UPPS-P's dimensions of Positive Urgency and Sensation Seeking: Low activity carriers with higher cocaine exposure had poorer emotion recognition and higher Positive Urgency and Sensation Seeking. Cocaine users carrying the MAOA low activity show a greater impact of cocaine use on impulsivity and behavioral measures of orbitofrontal cortex dysfunction. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients

PubMed Central

Addai, Amma B.; Pandhare, Jui; Paromov, Victor; Mantri, Chinmay K.; Pratap, Siddharth; Dash, Chandravanu

2015-01-01

Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4+ T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 µM–100 µM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 µM through 50 µM increased HIV-1 integration in CD4+ T cells in a dose-dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4+ T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4+ T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients. PMID:25691383

Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice.

PubMed

Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, J A; Colado, M I; O'Shea, E

2010-01-01

3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Mice received a course of cocaine (20 mg*kg(-1), x2 for 3 days) followed by MDMA (20 mg*kg(-1), x2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.

Alpha 1-acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes.

PubMed

Ma, Yu-Ling; Peters, Nicholas S; Henry, John A

2006-03-01

Alpha 1-acid glycoprotein (AAG) is an acute phase protein capable of binding basic drugs. This action explains its reversal of sodium channel blockade by drugs such as amitriptyline and quinidine. We report here the reversal of cocaine-induced sodium channel blockade by AAG. The sodium channel blocking property of cocaine is a major mechanism behind cocaine-induced sudden cardiac death, since sodium channels play a key role in the initiation and regulation of the heart beat. Voltage-gated sodium current (I(Na)) was recorded using whole-cell patch-clamp techniques. Guinea-pig cardiac ventricular myocytes were isolated and continuously perfused at room temperature with physiological solutions. At concentrations ranging from 5 to 320 microM cocaine showed a dose-dependent and reversible blockade of I(Na) with an IC50 of 45.9 microM. The addition of equimolar amounts of AAG to cocaine produced almost complete reversal of cocaine's effects, suggesting a single binding site for cocaine on the AAG molecule. With changes of peak I(Na) normalized against control as 1, cocaine at 20 and 40 microM reduced I(Na) to 0.62+/-0.042 (n = 6) and 0.57+/-0.052 (n = 9), respectively, and the addition of an equimolar concentration of AAG reversed I(Na) to 0.86+/-0.022 and 0.91+/-0.060, respectively. AAG reverses cocaine-induced sodium channel blockade in a dose-dependent manner, indicating a therapeutic potential to reverse acute cocaine cardiac toxicity.

Inhibitory Motor Control at Five Years as a Function of Prenatal Cocaine Exposure

PubMed Central

BENDERSKY, MARGARET; GAMBINI, GIORGIA; LASTELLA, ANNA; BENNETT, DAVID S.; LEWIS, MICHAEL

2006-01-01

This study examined children’s (n = 140, age 5 years) ability to inhibit a motor response as a function of prenatal cocaine exposure. We hypothesized that cocaine-exposed children would perform worse than unexposed children on the Contrary Tapping task. Results indicated that cocaine exposure, high environmental risk, male gender, and low child IQ each were related to poorer inhibitory control. An interaction indicated that cocaine effects were specific to children who lived in relatively low-risk environments. Cocaine-exposed children made an error sooner than unexposed children if they lived in low-risk environments but not if they lived in high-risk environments. Potential underlying mechanisms and the importance of examining cocaine exposure effects in the context of children’s existing environment are discussed. PMID:14578695

Prolonged withdrawal following cocaine self-administration increases resistance to punishment in a cocaine binge.

PubMed

Gancarz-Kausch, Amy M; Adank, Danielle N; Dietz, David M

2014-11-03

Drug addiction is characterized by compulsive drug-taking behaviors and a high propensity to relapse following drug cessation. Drug craving and seeking can increase during a period of abstinence, but this phenomenon is not observed in drug-induced reinstatement models. To investigate the effect of withdrawal on cocaine relapse, rats were exposed to extended-access cocaine self-administration and subjected to either 1 or 30 d of withdrawal. When tested during 12 h unlimited access to cocaine (binge), the duration of the withdrawal did not influence cocaine intake. However, using a histamine punishment procedure that greatly suppresses drug-taking behavior, we demonstrate that longer periods of abstinence from cocaine induce a greater persistence in responding for drug in the face of negative consequences.

Sinus Bradycardia in Habitual Cocaine Users.

PubMed

Franklin, Sona M; Thihalolipavan, Sudarone; Fontaine, John M

2017-05-15

Common physiological manifestations of cocaine are related to its adrenergic effects, due to inhibition of dopamine and norepinephrine uptake at the postsynaptic terminal. Few studies have documented bradycardia secondary to cocaine use, representing the antithesis of its adrenergic effects. We assessed the prevalence of sinus bradycardia (SB) in habitual cocaine users and postulated a mechanism for this effect. One hundred sixty-two patients with a history of cocaine use were analyzed and compared with age- and gender-matched controls. SB was defined as a rate of <60 beats/min and habitual cocaine use as 2 or more documented uses >30 days apart. Propensity score-matching analysis was applied to balance covariates between cocaine users and nonusers and reduce selection bias. Patients with a history of bradycardia, hypothyroidism, or concomitant beta-blocker use were excluded. Mean age of study patients was 44 ± 8 years. SB was observed in 43 of 162 (27%) cocaine users and in 9 of 149 (6%) nonusers (p = 0.0001). Propensity score-matching analysis matched 218 patients from both groups. Among matched patients SB was observed in 25 of 109 (23%) cocaine users and in 5 of 109 (5%) nonusers (p = 0.0001). Habitual cocaine use was an independent predictor of SB and associated with a sevenfold increase in the risk of SB (95% CI 2.52 to 19.74, p = 0.0002). In conclusion, habitual cocaine use is a strong predictor of SB and was unrelated to recency of use. A potential mechanism for SB may be related to cocaine-induced desensitization of the beta-adrenergic receptor secondary to continuous exposure. Symptomatic SB was not observed; thus, pacemaker therapy was not indicated. Copyright © 2017 Elsevier Inc. All rights reserved.

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration.

PubMed

Werner, Craig T; Milovanovic, Mike; Christian, Daniel T; Loweth, Jessica A; Wolf, Marina E

2015-12-01

The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine- and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine- and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

Enhancement of Behavioral Sensitization, Anxiety-Like Behavior, and Hippocampal and Frontal Cortical CREB Levels Following Cocaine Abstinence in Mice Exposed to Cocaine during Adolescence

PubMed Central

Valzachi, Maria Cristina; Teodorov, Elizabeth; Marcourakis, Tania; Bailey, Alexis; Camarini, Rosana

2013-01-01

Adolescence has been linked to greater risk-taking and novelty-seeking behavior and a higher prevalence of drug abuse and risk of relapse. Decreases in cyclic adenosine monophosphate response element binding protein (CREB) and phosphorylated CREB (pCREB) have been reported after repeated cocaine administration in animal models. We compared the behavioral effects of cocaine and abstinence in adolescent and adult mice and investigated possible age-related differences in CREB and pCREB levels. Adolescent and adult male Swiss mice received one daily injection of saline or cocaine (10 mg/kg, i.p.) for 8 days. On day 9, the mice received a saline injection to evaluate possible environmental conditioning. After 9 days of withdrawal, the mice were tested in the elevated plus maze to evaluate anxiety-like behavior. Twelve days after the last saline/cocaine injection, the mice received a challenge injection of either cocaine or saline, and locomotor activity was assessed. One hour after the last injection, the brains were extracted, and CREB and pCREB levels were evaluated using Western blot in the prefrontal cortex (PFC) and hippocampus. The cocaine-pretreated mice during adolescence exhibited a greater magnitude of the expression of behavioral sensitization and greater cocaine withdrawal-induced anxiety-like behavior compared with the control group. Significant increases in CREB levels in the PFC and hippocampus and pCREB in the hippocampus were observed in cocaine-abstinent animals compared with the animals treated with cocaine in adulthood. Interestingly, significant negative correlations were observed between cocaine sensitization and CREB levels in both regions. These results suggest that the behavioral and neurochemical consequences of psychoactive substances in a still-developing nervous system can be more severe than in an already mature nervous system. PMID:24205196

Adolescent d-Amphetamine Treatment in a Rodent Model of ADHD: Pro-Cognitive Effects in Adolescence without an Impact on Cocaine Cue Reactivity in Adulthood

PubMed Central

Jordan, Chloe J.; Taylor, Danielle M.; Dwoskin, Linda P.; Kantak, Kathleen M.

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model. PMID:26467602

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: Association to striatal D2/D3 receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomasi, Dardo; Wang, Gene -Jack; Wang, Ruiliang

Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [ 11C]raclopride and PET in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal and premotor cortices and insula and disengaged cuneus and defaultmore » mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. In conclusion, these findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.« less

Carrier-Mediated Cocaine Transport at the Blood-Brain Barrier as a Putative Mechanism in Addiction Liability

PubMed Central

Chapy, Hélène; Smirnova, Maria; André, Pascal; Schlatter, Joël; Chiadmi, Fouad; Couraud, Pierre-Olivier; Scherrmann, Jean-Michel; Declèves, Xavier

2015-01-01

Background: The rate of entry of cocaine into the brain is a critical factor that influences neuronal plasticity and the development of cocaine addiction. Until now, passive diffusion has been considered the unique mechanism known by which cocaine crosses the blood-brain barrier. Methods: We reassessed mechanisms of transport of cocaine at the blood-brain barrier using a human cerebral capillary endothelial cell line (hCMEC/D3) and in situ mouse carotid perfusion. Results: Both in vivo and in vitro cocaine transport studies demonstrated the coexistence of a carrier-mediated process with passive diffusion. At pharmacological exposure level, passive diffusion of cocaine accounted for only 22.5% of the total cocaine influx in mice and 5.9% in hCMEC/D3 cells, whereas the carrier-mediated influx rate was 3.4 times greater than its passive diffusion rate in vivo. The functional identification of this carrier-mediated transport demonstrated the involvement of a proton antiporter that shared the properties of the previously characterized clonidine and nicotine transporter. The functionnal characterization suggests that the solute carrier (SLC) transporters Oct (Slc22a1-3), Mate (Slc47a1) and Octn (Slc22a4-5) are not involved in the cocaine transport in vivo and in vitro. Diphenhydramine, heroin, tramadol, cocaethylene, and norcocaine all strongly inhibited cocaine transport, unlike benzoylecgonine. Trans-stimulation studies indicated that diphenhydramine, nicotine, 3,4-methylenedioxyamphetamine (ecstasy) and the cathinone compound 3,4-methylenedioxypyrovalerone (MDPV) were also substrates of the cocaine transporter. Conclusions: Cocaine transport at the BBB involves a proton-antiporter flux that is quantitatively much more important than its passive diffusion. The molecular identification and characterization of this transporter will provide new tools to understand its role in addictive mechanisms. PMID:25539501

Effects of the κ-opioid receptor on the inhibition of 100 Hz electroacupuncture on cocaine-induced conditioned place preference

PubMed Central

Hou, Bingjun

2016-01-01

The administration of 100 Hz electroacupuncture has been demonstrated to suppress cocaine-induced conditioned place preference (CPP) in rats, and there is evidence that the κ-opioid receptor may have a role in cocaine addiction. The present study sought to explore the mechanisms underlying the inhibitory effects of 100 Hz electroacupuncture on cocaine-induced CPP in rats. A rat model of cocaine-induced CPP was used in the present study to investigate the following: i) Naloxone treatment (5 and 10 mg/kg) following 100 Hz electroacupuncture-mediated inhibition on cocaine-induced CPP, revealing that a high dose (10 mg/kg) of naloxone blocked the inhibitory effects of 100 Hz electroacupuncture on cocaine-induced CPP; ii) nor-binaltorphimine (nor-BNI) on 100 Hz electroacupuncture-mediated inhibition on cocaine-induced CPP, which indicated that administration of 10 µg/5 µl and 0.3 µg/1 µl nor-BNI intracerebroventricularly and via the nucleus accumbens, respectively, reversed the inhibitory effects of 100 Hz electroacupuncture on cocaine-induced CPP, and that injection of nor-BNI in different brain areas of rats blocks the inhibitory effects of electroacupuncture on cocaine-induced CPP; and iv) 100 Hz electroacupuncture on the mRNA expression levels of the κ-opioid receptor in the rat nucleus accumbens and amygdala, which established that mRNA expression levels of κ-opioid receptor in the nucleus accumbens were increased with 100 Hz electroacupuncture plus cocaine-induced CPP. Overall, the results of the present study indicated that 100 Hz electroacupuncture was able to suppress cocaine-induced CPP via the κ-opioid receptor in the nucleus accumbens. PMID:27588082

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

PubMed Central

McReynolds, Jayme R; Taylor, Analisa; Vranjkovic, Oliver; Ambrosius, Terra; Derricks, Olivia; Nino, Brittany; Kurtoglu, Beliz; Wheeler, Robert A; Baker, David A; Gasser, Paul J; Mantsch, John R

2017-01-01

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use. PMID:27604564

Escalated cocaine "binges" in rats: enduring effects of social defeat stress or intra-VTA CRF.

PubMed

Leonard, Michael Z; DeBold, Joseph F; Miczek, Klaus A

2017-09-01

Exposure to intermittent social defeat stress elicits corticotropin releasing factor (CRF) release into the VTA and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists. The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake. Male Long-Evans rats were microinjected into the VTA with CRF (50 or 500 ng/side), vehicle, or subjected to social defeat stress, intermittently over 10 days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-h extended access "binge." Rats that experienced social defeat or received intra-VTA CRF microinfusions (50 ng) both took significantly more cocaine than controls over the 24-h binge but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. α) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B. Repeated infusion of CRF into the VTA persistently alters cocaine valuation and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation.

Effects of yohimbine and drug cues on impulsivity and attention in cocaine-dependent men and women and sex-matched controls.

PubMed

Moran-Santa Maria, M M; Baker, N L; McRae-Clark, A L; Prisciandaro, J J; Brady, K T

2016-05-01

Deficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. In a double-blind placebo controlled cross-over study, cocaine-dependent men (n=12), cocaine-dependent women (n=27), control men (n=31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors' Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session Healthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0-1.3), χ(2)1=2.0, p=0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI)=0.6 (0.4-0.8), χ(2)1=8.6, p=0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)=7.2 (3.6-14.7), χ(2)1=30.1, p<0.001]. Cocaine-dependent women exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354 ± 13 vs. Male 415 ± 14; t89=2.6, p=0.012]. These data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cocaine induces astrocytosis through ER stress-mediated activation of autophagy

PubMed Central

Periyasamy, Palsamy; Guo, Ming-Lei; Buch, Shilpa

2016-01-01

ABSTRACT Cocaine is known to induce inflammation, thereby contributing in part, to the pathogenesis of neurodegeneration. A recent study from our lab has revealed a link between macroautophagy/autophagy and microglial activation. The current study was aimed at investigating whether cocaine could also mediate activation of astrocytes and, whether this process involved induction of autophagy. Our findings demonstrated that cocaine mediated the activation of astrocytes by altering the levels of autophagy markers, such as BECN1, ATG5, MAP1LC3B-II, and SQSTM1 in both human A172 astrocytoma cells and primary human astrocytes. Furthermore, cocaine treatment resulted in increased formation of endogenous MAP1LC3B puncta in human astrocytes. Additionally, astrocytes transfected with the GFP-MAP1LC3B plasmid also demonstrated cocaine-mediated upregulation of the green fluorescent MAP1LC3B puncta. Cocaine-mediated induction of autophagy involved upstream activation of ER stress proteins such as EIF2AK3, ERN1, ATF6 since blockage of autophagy using either pharmacological or gene-silencing approaches, had no effect on cocaine-mediated induction of ER stress. Using both pharmacological and gene-silencing approaches to block either ER stress or autophagy, our findings demonstrated that cocaine-induced activation of astrocytes (measured by increased levels of GFAP) involved sequential activation of ER stress and autophagy. Cocaine-mediated-increased upregulation of GFAP correlated with increased expression of proinflammatory mediators such as TNF, IL1B, and IL6. In conclusion, these findings reveal an association between ER stress-mediated autophagy and astrogliosis in cocaine-treated astrocytes. Intervention of ER stress and/or autophagy signaling would thus be promising therapeutic targets for abrogating cocaine-mediated neuroinflammation. PMID:27337297

Effects of repeated cocaine exposure and withdrawal on voluntary ethanol drinking, and the expression of glial glutamate transporters in mesocorticolimbic system of P rats.

PubMed

Hammad, Alaa M; Althobaiti, Yusuf S; Das, Sujan C; Sari, Youssef

2017-07-01

Glutamatergic neurotransmission within the brain's reward circuits plays a major role in the reinforcing properties of both ethanol and cocaine. Glutamate homeostasis is regulated by several glutamate transporters, including glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). Cocaine exposure has been shown to induce a dysregulation in glutamate homeostasis and a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc). In this study, alcohol preferring (P) rats were exposed to free-choice of ethanol (15% and 30%) and/or water for five weeks. On Week 6, rats were administered (i.p.) cocaine (10 and 20mg/kg) or saline for 12 consecutive days. This study tested two groups of rats: the first group was euthanized after seven days of repeated cocaine i.p. injection, and the second group was deprived from cocaine for five days and euthanized at Day 5 after cocaine withdrawal. Only repeated cocaine (20mg/kg, i.p.) exposure decreased ethanol intake from Day 3 through Day 8. Co-exposure of cocaine and ethanol decreased the relative mRNA expression and the expression of GLT-1 in the NAc but not in the medial prefrontal cortex (mPFC). Importantly, co-exposure of cocaine and ethanol decreased relative expression of xCT in the NAc but not in the mPFC. Our findings demonstrated that chronic cocaine exposure affects ethanol intake; and ethanol and cocaine co-abuse alters the expression of glial glutamate transporters. Copyright © 2017 Elsevier Inc. All rights reserved.

A preliminary investigation of Stroop-related intrinsic connectivity in cocaine dependence: Associations with treatment outcomes

PubMed Central

Mitchell, Marci R.; Balodis, Iris M.; DeVito, Elise E.; Lacadie, Cheryl M.; Yeston, Jon; Scheinost, Dustin; Constable, R. Todd; Carroll, Kathleen M.; Potenza, Marc N.

2013-01-01

Background Cocaine-dependent individuals demonstrate neural and behavioral differences compared to healthy comparison subjects when performing the Stroop color-word inference test. Stroop measures also relate to treatment outcome for cocaine dependence. Intrinsic connectivity analyses assess the extent to which task-related regional brain activations are related to each other in the absence of defining a priori regions-of-interest. Objective This study examined: 1) the extent to which cocaine-dependent and non-addicted individuals differed on measures of intrinsic connectivity during fMRI Stroop performance; and, 2) the relationships between fMRI Stroop intrinsic connectivity and treatment outcome in cocaine dependence. Methods Sixteen treatment-seeking cocaine-dependent patients and matched non-addicted comparison subjects completed an fMRI Stroop task. Between-group differences in intrinsic connectivity were assessed and related to self-reported and urine-toxicology-based cocaine-abstinence measures. Results Cocaine-dependent patients vs. comparison subjects showed less intrinsic connectivity in cortical and sub-cortical regions. When adjusting for individual degree of intrinsic connectivity, cocaine-dependent vs. comparison subjects showed relatively greater intrinsic connectivity in the ventral striatum, putamen, inferior frontal gyrus, anterior insula, thalamus, and substantia nigra. Non-mean-adjusted intrinsic-connectivity measures in the midbrain, thalamus, ventral striatum, substantia nigra, insula, and hippocampus negatively correlated with measures of cocaine abstinence. Conclusion The diminished intrinsic connectivity in cocaine-dependent vs. comparison subjects suggests poorer communication across brain regions during cognitive-control processes. In mean-adjusted analyses, the cocaine-dependent group displayed relatively greater Stroop-related connectivity in regions implicated in motivational processes in addictions. The relationships between treatment outcomes and connectivity in the midbrain and basal ganglia suggest that connectivity represents a potential treatment target. PMID:24200209

Norcocaine and cocaethylene distribution patterns in hair samples from light, moderate, and heavy cocaine users

PubMed Central

Rossi, Riccardo; Aroni, Kyriaki; Gili, Alessio; Bacci, Mauro; Pascali, Vincenzo; Fucci, Nadia

2015-01-01

Even though hair analysis often seems to be the best choice for retrospective monitoring of cocaine intake, differentiating between incorporated cocaine and external contamination is widely debated. In this study we report results obtained in 90 hair samples from addicts. All samples were analyzed for cocaine, benzoylecgonine, norcocaine, cocaethylene, and tropococaine by gas chromatography‐mass spectrometry (GC‐MS) techniques coupled with direct immersion solid‐phase micro‐extraction. Cocaine concentrations were stratified into three classes of usage: light (0.5–3 ng/mg), moderate (3.1–10 ng/mg) and heavy (10.1–40 ng/mg). The Substance Abuse and Mental Health Services Administration cut‐off criteria for establishing active cocaine use were applied to the results. For all samples criteria were cocaine levels above 0.5 ng/mg (ranging from 1.63 to 39.29 ng/mg, mean 9.49 ng/mg), benzoylecgonine concentrations ≥ 0.05 ng/mg (ranging from 0.19 to 5.77 ng/mg, mean 1.40), and benzoylecgonine to cocaine % ratio ≥5% (from 6.43 to 26.09%). Norcocaine was present in 58.9% of samples (concentration range: 0.22–3.14 ng/mg) and was strongly predictive only of heavy cocaine use (sensitivity 100% for cocaine concentrations above 9.58 ng/mg). Twenty hair samples from moderate and heavy users tested positive for cocaethylene (concentration range: 0.22–1.98 ng/mg, mean 0.73 ng/mg). This study on hair samples with no chance of false positive cases highlights the very limited applications of testing minor cocaine metabolites for definitive proof of active cocaine consumption. © 2015 The Authors. Drug Testing and Analysis Published by John Wiley & Sons, Ltd. PMID:26621770

Modeling evolution of hydrogen bonding and stabilization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase.

PubMed

Gao, Daquan; Zhan, Chang-Guo

2006-01-01

Molecular dynamics (MD) simulations and quantum mechanical/molecular mechanical (QM/MM) calculations were performed on the prereactive enzyme-substrate complex, transition states, intermediates, and product involved in the process of human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (-)-cocaine. The computational results consistently reveal a unique role of the oxyanion hole (consisting of G116, G117, and A199) in BChE-catalyzed hydrolysis of cocaine, compared to acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylcholine. During BChE-catalyzed hydrolysis of cocaine, only G117 has a hydrogen bond with the carbonyl oxygen (O31) of the cocaine benzoyl ester in the prereactive BChE-cocaine complex, and the NH groups of G117 and A199 are hydrogen-bonded with O31 of cocaine in all of the transition states and intermediates. Surprisingly, the NH hydrogen of G116 forms an unexpected hydrogen bond with the carboxyl group of E197 side chain and, therefore, is not available to form a hydrogen bond with O31 of cocaine in the acylation. The NH hydrogen of G116 is only partially available to form a weak hydrogen bond with O31 of cocaine in some structures involved in the deacylation. The change of the estimated hydrogen-bonding energy between the oxyanion hole and O31 of cocaine during the reaction process demonstrates how the protein environment can affect the energy barrier for each step of the BChE-catalyzed hydrolysis of cocaine. These insights concerning the effects of the oxyanion hole on the energy barriers provide valuable clues on how to rationally design BChE mutants with a higher catalytic activity for the hydrolysis of (-)-cocaine. 2005 Wiley-Liss, Inc.

Modeling Evolution of Hydrogen Bonding and Stabilization of Transition States in the Process of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase

PubMed Central

Gao, Daquan; Zhan, Chang-Guo

2010-01-01

Molecular dynamics (MD) simulations and quantum mechanical/molecular mechanical (QM/MM) calculations were performed on the prereactive enzyme-substrate complex, transition states, intermediates, and product involved in the process of human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (−)-cocaine. The computational results consistently reveal a unique role of the oxyanion hole (consisting of G116, G117, and A199) in BChE-catalyzed hydrolysis of cocaine, as compared to acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylcholine. During BChE-catalyzed hydrolysis of cocaine, only G117 has a hydrogen bond with the carbonyl oxygen (O31) of the cocaine benzoyl ester in the prereactive BChE-cocaine complex, and the NH groups of G117 and A199 are hydrogen-bonded with O31 of cocaine in all of the transition states and intermediates. Surprisingly, the NH hydrogen of G116 forms an unexpected hydrogen bond with the carboxyl group of E197 side chain and, therefore, is not available to form a hydrogen bond with O31 of cocaine in the acylation. The NH hydrogen of G116 is only partially available to form a weak hydrogen bond with O31 of cocaine in some structures involved in the deacylation. The change of the estimated hydrogen bonding energy between the oxyanion hole and O31 of cocaine during the reaction process demonstrates how the protein environment can affect the energy barrier for each step of the BChE-catalyzed hydrolysis of cocaine. These insights concerning the effects of the oxyanion hole on the energy barriers provide valuable clues on how to rationally design BChE mutants with a higher catalytic activity for the hydrolysis of (−)-cocaine. PMID:16288482

Norcocaine and cocaethylene distribution patterns in hair samples from light, moderate, and heavy cocaine users.

PubMed

Gambelunghe, Cristiana; Rossi, Riccardo; Aroni, Kyriaki; Gili, Alessio; Bacci, Mauro; Pascali, Vincenzo; Fucci, Nadia

2017-02-01

Even though hair analysis often seems to be the best choice for retrospective monitoring of cocaine intake, differentiating between incorporated cocaine and external contamination is widely debated. In this study we report results obtained in 90 hair samples from addicts. All samples were analyzed for cocaine, benzoylecgonine, norcocaine, cocaethylene, and tropococaine by gas chromatography-mass spectrometry (GC-MS) techniques coupled with direct immersion solid-phase micro-extraction. Cocaine concentrations were stratified into three classes of usage: light (0.5-3 ng/mg), moderate (3.1-10 ng/mg) and heavy (10.1-40 ng/mg). The Substance Abuse and Mental Health Services Administration cut-off criteria for establishing active cocaine use were applied to the results. For all samples criteria were cocaine levels above 0.5 ng/mg (ranging from 1.63 to 39.29 ng/mg, mean 9.49 ng/mg), benzoylecgonine concentrations ≥ 0.05 ng/mg (ranging from 0.19 to 5.77 ng/mg, mean 1.40), and benzoylecgonine to cocaine % ratio ≥5% (from 6.43 to 26.09%). Norcocaine was present in 58.9% of samples (concentration range: 0.22-3.14 ng/mg) and was strongly predictive only of heavy cocaine use (sensitivity 100% for cocaine concentrations above 9.58 ng/mg). Twenty hair samples from moderate and heavy users tested positive for cocaethylene (concentration range: 0.22-1.98 ng/mg, mean 0.73 ng/mg). This study on hair samples with no chance of false positive cases highlights the very limited applications of testing minor cocaine metabolites for definitive proof of active cocaine consumption. © 2015 The Authors. Drug Testing and Analysis Published by John Wiley & Sons, Ltd. © 2015 The Authors. Drug Testing and Analysis Published by John Wiley & Sons, Ltd.

Effects of chronic buspirone treatment on nicotine and concurrent nicotine+cocaine self-administration.

PubMed

Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J

2013-06-01

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal pharmacotherapy would reduce both cigarette smoking and cocaine abuse. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on serotonin and dopamine systems. In preclinical studies, it reduced cocaine self-administration following both acute and chronic treatment in rhesus monkeys. The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of intravenous (IV) nicotine and IV nicotine+cocaine combinations. Five cocaine-experienced adult rhesus monkeys (Macaca mulatta) were trained to self-administer nicotine or nicotine+cocaine combinations, and food pellets (1 g) during four 1-h daily sessions under a second-order schedule of reinforcement (FR 2 (VR16:S)). Each nicotine+cocaine combination maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Buspirone (0.032-0.56 mg/kg/h) was administered IV through one lumen of a double-lumen catheter every 20 min for 23 h each day, for 7-10 consecutive days. Each 7-10-day sequence of buspirone treatment was followed by saline-control treatment for at least 3 days until food- and drug-maintained responding returned to baseline. Buspirone dose-dependently reduced responding maintained by nicotine alone (0.001-0.1 mg/kg/inj; P<0.01) and by nicotine (0.001 or 0.0032 mg/kg/inj)+cocaine combinations (0.0032 mg/kg/inj; P<0.05-0.001) with no significant effects on food-maintained responding. We conclude that buspirone selectively attenuates the reinforcing effects of nicotine alone and nicotine+cocaine polydrug combinations in a nonhuman primate model of drug self-administration.

Effects of Chronic Buspirone Treatment on Nicotine and Concurrent Nicotine+Cocaine Self-Administration

PubMed Central

Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J

2013-01-01

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal pharmacotherapy would reduce both cigarette smoking and cocaine abuse. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on serotonin and dopamine systems. In preclinical studies, it reduced cocaine self-administration following both acute and chronic treatment in rhesus monkeys. The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of intravenous (IV) nicotine and IV nicotine+cocaine combinations. Five cocaine-experienced adult rhesus monkeys (Macaca mulatta) were trained to self-administer nicotine or nicotine+cocaine combinations, and food pellets (1 g) during four 1-h daily sessions under a second-order schedule of reinforcement (FR 2 (VR16:S)). Each nicotine+cocaine combination maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Buspirone (0.032–0.56 mg/kg/h) was administered IV through one lumen of a double-lumen catheter every 20 min for 23 h each day, for 7–10 consecutive days. Each 7–10-day sequence of buspirone treatment was followed by saline-control treatment for at least 3 days until food- and drug-maintained responding returned to baseline. Buspirone dose-dependently reduced responding maintained by nicotine alone (0.001–0.1 mg/kg/inj; P<0.01) and by nicotine (0.001 or 0.0032 mg/kg/inj)+cocaine combinations (0.0032 mg/kg/inj; P<0.05–0.001) with no significant effects on food-maintained responding. We conclude that buspirone selectively attenuates the reinforcing effects of nicotine alone and nicotine+cocaine polydrug combinations in a nonhuman primate model of drug self-administration. PMID:23337868

The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats

PubMed Central

Wenzel, Jennifer M.; Su, Zu-In; Shelton, Kerisa; Dominguez, Hiram M.; von Furstenberg, Victoria A.; Ettenberg, Aaron

2013-01-01

Human cocaine users report that the initial “high” produced by cocaine administration is followed by an anxiogenic “crash”. Given that cocaine has such robust and opposing properties, it is likely that both the positive and negative effects of cocaine contribute to an individual’s motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine’s dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug’s negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine’s opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1 mg/kg/0.1 ml) three hours after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine’s immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug’s negative/anxiogenic properties. PMID:24012795

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: Association to striatal D2/D3 receptors

DOE PAGES

Tomasi, Dardo; Wang, Gene -Jack; Wang, Ruiliang; ...

2014-08-20

Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [ 11C]raclopride and PET in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal and premotor cortices and insula and disengaged cuneus and defaultmore » mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. In conclusion, these findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.« less

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.

PubMed

Swalve, Natashia; Smethells, John R; Zlebnik, Natalie E; Carroll, Marilyn E

2016-06-01

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes. Copyright © 2016 Elsevier Inc. All rights reserved.

Neuroadaptive changes in NMDAR1 gene expression after extinction of cocaine self-administration.

PubMed

Crespo, José A; Oliva, José M; Ghasemzadeh, M Benham; Kalivas, Peter W; Ambrosio, E

2002-06-01

The aim of the present work was to study the time course effects in levels of mRNA encoding N-methyl-d-aspartate receptor subunit 1 (NMDAR1) after long-term cocaine self-administration (1 mg/kg/ injection) and its extinction using a yoked-box procedure. NMDAR1 content was measured by quantitative in situ hybridization histochemistry in prefrontal cortex, caudate-putamen, nucleus accumbens, olfactory tubercle, and piriform cortex immediately after cessation of the last session of cocaine self-administration (Day 0) and 1, 5, and 10 days after the extinction period. The results show that long-term cocaine self-administration and its extinction alter NMDAR1 gene expression in these forebrain regions, and that the changes depend upon the brain region examined and the type of cocaine administration (contingent, noncontingent, and saline). Compared to saline and noncontingent cocaine administration, contingent cocaine produced an up-regulation in NMDAR1 gene expression on Day 0 in all the brain regions analyzed. NMDAR1 levels of contingent animals decreased progressively in the absence of cocaine, and the decrement persisted 10 days after the extinction of cocaine self-administration behavior in all the forebrain areas, with the exception of olfactory tubercle. In contrast, noncontingent cocaine administration did not produce any change in NMDAR1 gene expression on Day 0, and extinction resulted in an increase of NMDAR1 mRNA content on Days 1 and 5 and returned to control (saline) values on Day 10. These results suggest that an interaction between environmental stimuli and the pharmacological action of cocaine during drug self-administration and its extinction may represent an important factor in the regulation of cocaine effects on NMDAR1 gene expression.

SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

PubMed Central

Weed, Michael; Adams, Robert J.; Hienz, Robert D.; Meulendyke, Kelly A.; Linde, Michael E.; Clements, Janice E.; Mankowski, Joseph L.; Zink, M. Christine

2011-01-01

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals. PMID:21626125

Basolateral amygdalar D2 receptor activation is required for the companions-exerted suppressive effect on the cocaine conditioning.

PubMed

Tzeng, Wen-Yu; Cherng, Chian-Fang G; Yu, Lung; Wang, Ching-Yi

2017-01-01

The presence of companions renders decreases in cocaine-stimulated dopamine release in the nucleus accumbens and cocaine-induced conditioned place preference (CPP) magnitude. Limbic systems are widely believed to underlie the modulation of accumbal dopamine release and cocaine conditioning. Thus, this study aimed to assess whether intact basolateral nucleus of amygdala (BLA), dorsal hippocampus (DH), and dorsolateral striatum (DLS) is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Three cage mates, serving as companions, were arranged to house with the experimental mice in the cocaine conditioning compartment throughout the cocaine conditioning sessions. Approximately 1week before the conditioning procedure, intracranial ibotenic acid infusions were done in an attempt to cause excitotoxic lesions targeting bilateral BLA, DH and DLS. Albeit their BLA, DH, and DLS lesions, the lesioned mice exhibited comparable cocaine-induced CPP magnitudes compared to the intact and sham lesion controls. Bilateral BLA, but not DH or DLS, lesions abolished the companions-exerted suppressive effect on the cocaine-induced CPP. Intact mice receiving intra-BLA infusion of raclopride, a selective D2 antagonist, 30min prior to the cocaine conditioning did not exhibit the companions-exerted suppressive effect on the cocaine-induced CPP. Intra-BLA infusion of Sch23390, a selective D1 antagonist, did not affect the companions-exerted suppressive effect on the CPP. These results, taken together, prompt us to conclude that the intactness of BLA is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Importantly, activation of D2 receptor in the BLA is required for such suppressive effect on the CPP. Copyright © 2016 Elsevier Inc. All rights reserved.

Main mental disorders in crack-cocaine users treated at Psychosocial Care Centers for Alcohol and Drugs in the city of Recife, Brazil.

PubMed

Castro, Antonio Gomes de; Silva, Diego César Nunes da; Figueiroa, Magda da Silva

2016-01-01

Brazil's Northeast region has the highest crack-cocaine consumption in the country. Crack-cocaine has more intense effects than cocaine powder and can cause greater chemical dependence. Psychosocial Care Centers for Alcohol and Drugs (CAPSad) are public health services that provide treatment for drug dependence. It is common for drug users, and particularly crack-cocaine users, to develop mental disorders. Objective: To evaluate the most common mental disorders in crack-cocaine dependents in treatment at CAPSad in the city of Recife, Brazil. The research database "Between rocks and shots: user profiles, consumption strategies, and social impact of crack cocaine" (CEP/CCS/UFPE no. 206/11) was consulted to establish the areas of crack cocaine consumption in the city of Recife. There were 885 patients in treatment for crack-cocaine use, with a mean age of 29.8±9.4 years. The mean duration of drug use was 6.1±4.6 years. Most of the patients were males (80.3%), had left school at some point between the 1st and 9th grades (45.6%), were unemployed and/or seeking employment (52%) and used drugs daily (56.4%). Cocaine chemical dependence was more significant when correlated with use of crack-cocaine and other drugs such as medications and hallucinogens (p = 0.01). Data from this study showed strong associations between crack-cocaine uses and development of mental disorders, particularly when abuse of multiple substances occurs. Based on these data, there is a clear need for coordination of related public policies for support and social reintegration to provide these people with comprehensive care.

A chimeric human/murine anticocaine monoclonal antibody inhibits the distribution of cocaine to the brain in mice.

PubMed

Norman, Andrew B; Tabet, Michael R; Norman, Mantana K; Buesing, William R; Pesce, Amadeo J; Ball, William J

2007-01-01

The predominantly human sequence, high-affinity anticocaine monoclonal antibody (mAb) 2E2 was cleared slowly from mouse blood by a first-order process with an elimination t(1/2) of 8.1 days. Infused 2E2 also produced a dramatic dose-dependent increase in plasma cocaine concentrations and a concomitant decrease in the brain cocaine concentrations produced by an i.v. injection of cocaine HCl (0.56 mg/kg). At the highest dose of 2E2 tested (3:1, mAb/drug), cocaine was not detectable in the brain. Pharmacokinetic studies showed that the normal disappearance of cocaine from plasma was described by a two-compartment pharmacokinetic model with distribution t(1/2alpha) and terminal elimination t(1/2beta) values of 1.9 and 26.1 min, respectively. In the presence of an equimolar dose of mAb 2E2, there was a 26-fold increase in the area under the plasma cocaine concentration-time curve (AUC) relative to the AUC in the absence of 2E2. Consequently, 2E2 decreased the volume of distribution of cocaine from 6.0 to 0.20 l/kg, which approximated that of 2E2 (0.28 l/kg). However, cocaine was still rapidly cleared from plasma, and its elimination was now described by a single-compartment model with an elimination t(1/2) of 17 min. Importantly, 2E2 also produced a 4.5-fold (78%) decrease in the cocaine AUC in the brain. Therefore, the effect of 2E2 on plasma and brain cocaine concentrations was predominantly caused by a change in the distribution of cocaine with negligible effects on its rate of clearance. These data support the concept of immunotherapy for drug abuse.

Cocaine induces astrocytosis through ER stress-mediated activation of autophagy.

PubMed

Periyasamy, Palsamy; Guo, Ming-Lei; Buch, Shilpa

2016-08-02

Cocaine is known to induce inflammation, thereby contributing in part, to the pathogenesis of neurodegeneration. A recent study from our lab has revealed a link between macroautophagy/autophagy and microglial activation. The current study was aimed at investigating whether cocaine could also mediate activation of astrocytes and, whether this process involved induction of autophagy. Our findings demonstrated that cocaine mediated the activation of astrocytes by altering the levels of autophagy markers, such as BECN1, ATG5, MAP1LC3B-II, and SQSTM1 in both human A172 astrocytoma cells and primary human astrocytes. Furthermore, cocaine treatment resulted in increased formation of endogenous MAP1LC3B puncta in human astrocytes. Additionally, astrocytes transfected with the GFP-MAP1LC3B plasmid also demonstrated cocaine-mediated upregulation of the green fluorescent MAP1LC3B puncta. Cocaine-mediated induction of autophagy involved upstream activation of ER stress proteins such as EIF2AK3, ERN1, ATF6 since blockage of autophagy using either pharmacological or gene-silencing approaches, had no effect on cocaine-mediated induction of ER stress. Using both pharmacological and gene-silencing approaches to block either ER stress or autophagy, our findings demonstrated that cocaine-induced activation of astrocytes (measured by increased levels of GFAP) involved sequential activation of ER stress and autophagy. Cocaine-mediated-increased upregulation of GFAP correlated with increased expression of proinflammatory mediators such as TNF, IL1B, and IL6. In conclusion, these findings reveal an association between ER stress-mediated autophagy and astrogliosis in cocaine-treated astrocytes. Intervention of ER stress and/or autophagy signaling would thus be promising therapeutic targets for abrogating cocaine-mediated neuroinflammation.

Access to a running wheel decreases cocaine-primed and cue-induced reinstatement in male and female rats.

PubMed

Smith, Mark A; Pennock, Michael M; Walker, Katherine L; Lang, Kimberly C

2012-02-01

Relapse to drug use after a period of abstinence is a persistent problem in the treatment of cocaine dependence. Physical activity decreases cocaine self-administration in laboratory animals and is associated with a positive prognosis in human substance-abusing populations. The purpose of this study was to examine the effects of long-term access to a running wheel on drug-primed and cue-induced reinstatement of cocaine-seeking behavior in male and female rats. methods: Long-Evans rats were obtained at weaning and assigned to sedentary (no wheel) and exercising (access to wheel) groups for the duration of the study. After 6 weeks, rats were implanted with intravenous catheters and trained to self-administer cocaine for 14 days. After training, saline was substituted for cocaine and responding was allowed to extinguish, after which cocaine-primed reinstatement was examined in both groups. Following this test, cocaine self-administration was re-established in both groups for a 5-day period. Next, a second period of abstinence occurred in which both cocaine and the cocaine-associated cues were withheld. After 5 days of abstinence, cue-induced reinstatement was examined in both groups. Sedentary and exercising rats exhibited similar levels of cocaine self-administration, but exercising rats responded less than sedentary rats during extinction. In tests of cocaine-primed and cue-induced reinstatement, exercising rats responded less than sedentary rats, and this effect was apparent in both males and females. These data indicate that long-term access to a running wheel decreases drug-primed and cue-induced reinstatement, and that physical activity may be effective at preventing relapse in substance-abusing populations. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Kappa Opioid Receptor-Mediated Dysregulation of GABAergic Transmission in the Central Amygdala in Cocaine Addiction

PubMed Central

Kallupi, Marsida; Wee, Sunmee; Edwards, Scott; Whitfield, Tim W.; Oleata, Christopher S.; Luu, George; Schmeichel, Brooke E.; Koob, George F.; Roberto, Marisa

2013-01-01

Background Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA). Methods We identified KOR-related physiological changes in the CeA following escalation of cocaine self-administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1h (short access, ShA) or 6h (long access, LgA) sessions induced plasticity at CeA GABAergic synapses, or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (nor-BNI). We then determined the functional effects of CeA KOR blockade in cocaine-related behaviors. Results Baseline evoked GABAergic transmission was enhanced in the CeA from ShA and LgA rats compared to cocaine-naïve rats. Acute cocaine (1 uM) application significantly decreased GABA release in all groups (naïve, ShA, and LgA rats). Application of U50488 (1 uM) significantly decreased GABAergic transmission in the CeA from naïve rats, but increased it in LgA rats. Conversely, nor-BNI (200 nM) significantly increased GABAergic transmission in the CeA from naïve rats, but decreased it in LgA rats. Nor-BNI did not alter the acute cocaine-induced inhibition of GABAergic responses. Finally, CeA microinfusion of nor-BNI blocked cocaine-induced locomotor sensitization and attenuated the heightened anxiety-like behavior observed during withdrawal from chronic cocaine exposure in the defensive burying paradigm. Conclusion Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction. PMID:23751206

Induction and blockade of adolescent cocaine-induced habits

PubMed Central

DePoy, Lauren M.; Zimmermann, Kelsey S.; Marvar, Paul J.; Gourley, Shannon L.

2017-01-01

Background Cocaine use during adolescence increases vulnerability to drug dependence and decreases the likelihood that individuals will seek treatment as adults. Understanding how early-life cocaine exposure influences decision-making processes in adulthood is thus critically important. Methods Adolescent or adult mice were exposed to subchronic cocaine, then behavioral sensitivity to changes in the predictive relationship between actions and their consequences was tested. Dendritic spines on the principal pyramidal neurons of the orbitofrontal prefrontal cortex (oPFC) were also imaged and enumerated. To determine whether cytoskeletal regulatory systems in the oPFC influenced decision-making strategies, we then inhibited the activity of Abl-family and Rho kinases, as well as NR2B-containing NMDA receptors. We also attempted to block the reinstatement of cocaine seeking in cocaine self-administering mice. Results Adult mice with a history of subchronic cocaine exposure in adolescence engaged habit-based response strategies at the expense of goal-directed decision-making strategies and had fewer dendritic spines in the oPFC. Inhibition of the cytoskeletal regulatory Abl-family kinases in the oPFC recapitulated these neurobehavioral deficiencies, while Rho-kinase inhibition corrected response strategies. Additionally, the NR2B-selective NMDA receptor antagonists ifenprodil and CP-101,606 blocked cocaine-induced habits, and this was dependent on Abl-family signaling in the oPFC. Ifenprodil also mitigated cue-induced reinstatement of cocaine seeking in mice self-administering cocaine. Conclusions We suggest that adolescent cocaine exposure confers a bias towards habit-based behavior in adulthood via long-term cellular structural modifications in the oPFC. Treatments aimed at mitigating the durable consequences of early-life cocaine may benefit from targeting cytoskeletal regulatory systems. PMID:27871669

Manipulating a "cocaine engram" in mice.

PubMed

Hsiang, Hwa-Lin Liz; Epp, Jonathan R; van den Oever, Michel C; Yan, Chen; Rashid, Asim J; Insel, Nathan; Ye, Li; Niibori, Yosuke; Deisseroth, Karl; Frankland, Paul W; Josselyn, Sheena A

2014-10-15

Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the "cocaine memory trace" or "cocaine engram"). We found that a small population of neurons (∼10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine-conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsáki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. Copyright © 2014 the authors 0270-6474/14/3414115-13$15.00/0.

Liquid chromatography/tandem mass spectrometry method for simultaneous determination of cocaine and its metabolite (-)ecgonine methyl ester in human acidified stabilized plasma samples.

PubMed

Liu, Yongzhen; Zheng, Bo; Strafford, Stephanie; Orugunty, Ravi; Sullivan, Michael; Gus, Jeffrey; Heidbreder, Christian; Fudala, Paul J; Nasser, Azmi

2014-06-15

Two simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) methods (low range and high range) were developed and validated for the quantification of cocaine and its metabolite (-)ecgonine methyl ester (EME) in human acidified stabilized plasma samples. In the low range assay, cocaine and the internal standard, cocaine-D3, were extracted using a single step liquid-liquid extraction from human acidified stabilized plasma. For the high range assay, human acidified stabilized plasma containing cocaine, EME, and the internal standards, cocaine-D3 and EME-D3, was mixed with acetonitrile, and the protein precipitate was separated by centrifugation. Both cocaine and EME extracted from both assays were separated on a HILIC column and detected in positive ion mode using multiple reaction monitoring (MRM). Both methods were validated and the specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries and stability were determined. The linear range for the low range assay was 0.01-5ng/mL for cocaine; in the high range assay values were 5-1000ng/mL for cocaine and 1-200ng/mL for EME. The correlation coefficient (R(2)) values for both assays were 0.993 or greater. The precision and accuracy for intra-day and inter-day were better than 13.0%. The recovery was above 85% and matrix effects were low with the matrix factor ranging from 0.817 to 1.10 for both analytes in both assays. The validated methods were successfully used to quantify the plasma concentrations of cocaine and EME in clinical pharmacokinetic and pharmacodynamic studies. Copyright © 2014 Elsevier B.V. All rights reserved.

β-Endorphin via the Delta Opioid Receptor is a Major Factor in the Incubation of Cocaine Craving

PubMed Central

Dikshtein, Yahav; Barnea, Royi; Kronfeld, Noam; Lax, Elad; Roth-Deri, Ilana; Friedman, Alexander; Gispan, Iris; Elharrar, Einat; Levy, Sarit; Ben-Tzion, Moshe; Yadid, Gal

2013-01-01

Cue-induced cocaine craving intensifies, or ‘incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid β-endorphin. In the present study, we examined the possible involvement of β-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in β-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while β-endorphin levels remained unchanged. Intra-NAc infusion of an anti-β-endorphin antibody (4 μg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic β-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the δ opioid receptor antagonist naltrindole (1 μg) on day 1 and naltrindole together with β-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the μ opioid receptor antagonist CTAP (30 ng and 3 μg) had no behavioral effect. Altogether, these results demonstrate a novel role for β-endorphin and the δ opioid receptor in the development of the incubation of cocaine craving. PMID:23800967

The Role of Security Assistance in the Andean Initiative

DTIC Science & Technology

1992-01-01

acid is added to the kerosene mixture, forming cocaine sulfate. The kerosene is removed, more alkaline is added and cocaine paste forms in the pit...Kerosene is added to the paste, forming cocaine crystals. The crystals are washed in alcohol and dissolved in acid , filtered, and dried. The dried...substance is cocaine base, which is further refined, with either, acetone, and acid , into cocaine hydrochloride.$ These operations are conducted in the

Cocaine evokes a profile of oxidative stress and impacts innate antiviral response pathways in astrocytes.

PubMed

Cisneros, Irma E; Erdenizmenli, Mert; Cunningham, Kathryn A; Paessler, Slobodan; Dineley, Kelly T

2018-06-01

HIV-1 and Zika virus (ZIKV) represent RNA viruses with neurotropic characteristics. Infected individuals suffer neurocognitive disorders aggravated by environmental toxins, including drugs of abuse such as cocaine, exacerbating HIV-associated neurocognitive disorders through a combination of astrogliosis, oxidative stress and innate immune signaling; however, little is known about how cocaine impacts the progression of ZIKV neural perturbations. Impaired innate immune signaling is characterized by weakened antiviral activation of interferon signaling and alterations in inflammatory signaling, factors contributing to cognitive sequela associated with cocaine in HIV-1/ZIKV infection. We employed cellular/molecular biology techniques to test if cocaine suppresses the efficacy of astrocytes to initiate a Type 1 interferon response to HIV-1/ZIKV, in vitro. We found cocaine activated antiviral signaling pathways and type I interferon in the absence of inflammation. Cocaine pre-exposure suppressed antiviral responses to HIV-1/ZIKV, triggering antiviral signaling and phosphorylation of interferon regulatory transcription factor 3 to stimulate type I interferon gene transcription. Our data indicate that oxidative stress is a major driver of cocaine-mediated astrocyte antiviral immune responses. Although astrocyte antiviral signaling is activated following detection of foreign pathogenic material, oxidative stress and increased cytosolic double-stranded DNA (dsDNA) can drive antiviral signaling via stimulation of pattern recognition receptors. Pretreatment with the glial modulators propentofylline (PPF) or pioglitazone (PIO) reversed cocaine-mediated attenuation of astrocyte responses to HIV-1/ZIKV. Both PPF/PIO protected against cocaine-mediated generation of reactive oxygen species (ROS), increased dsDNA, antiviral signaling pathways and increased type I interferon, indicating that cocaine induces astrocyte type I interferon signaling in the absence of virus and oxidative stress is a major driver of cocaine-mediated astrocyte antiviral immunity. Lastly, PPF and PIO have therapeutic potential to ameliorate cocaine-mediated dysregulation of astrocyte antiviral immunity possibly via a myriad of protective actions including decreases in reactive phenotype and damaging immune factors. Published by Elsevier Ltd.

Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys.

PubMed

Brutcher, Robert E; Nader, Susan H; Nader, Michael A

2016-02-01

There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations.

PubMed

Hong, Weimin C; Kopajtic, Theresa A; Xu, Lifen; Lomenzo, Stacey A; Jean, Bernandie; Madura, Jeffry D; Surratt, Christopher K; Trudell, Mark L; Katz, Jonathan L

2016-03-01

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3β-aryltropanes with 2β-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2α-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2β-Ph2COCH2-3β-4-Cl-Ph analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2β compounds increased locomotion, only the 2β-(4-ClPh)PhCOCH2-3β-4-Cl-Ph analog had cocaine-like efficacy. None of the 2α-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)- compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2β- and 2α-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine. U.S. Government work not protected by U.S. copyright.

Effects of Serotonin 2C Receptor Agonists on the Behavioral and Neurochemical Effects of Cocaine in Squirrel Monkeys

PubMed Central

Manvich, Daniel F.; Kimmel, Heather L.

2012-01-01

Accumulating evidence indicates that the serotonin system modulates the behavioral and neurochemical effects of cocaine, but the receptor subtypes mediating these effects remain unknown. Recent studies have demonstrated that pharmacological activation of the serotonin 2C receptor (5-HT2CR) attenuates the behavioral and neurochemical effects of cocaine in rodents, but such compounds have not been systematically evaluated in nonhuman primates. The present experiments sought to determine the impact of pretreatment with the preferential 5-HT2CR agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT2CR agonist Ro 60-0175 [(α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press according to a 300-s fixed-interval schedule of stimulus termination, pretreatment with either 5-HT2CR agonist dose-dependently and insurmountably attenuated the behavioral stimulant effects of cocaine. In subjects trained to self-administer cocaine, both compounds dose-dependently and insurmountably attenuated cocaine-induced reinstatement of previously extinguished responding in an antagonist-reversible manner, and the selective agonist Ro 60-0175 also attenuated the reinforcing effects of cocaine during ongoing cocaine self-administration. It is noteworthy that the selective agonist Ro 60-0175 exhibited behavioral specificity because it did not significantly alter nondrug-maintained responding. Finally, in vivo microdialysis studies revealed that pretreatment with Ro 60-0175 caused a reduction of cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus. These results suggest that 5-HT2CR agonists functionally antagonize the behavioral effects of cocaine in nonhuman primates, possibly via a selective modulation of cocaine-induced dopamine increases within the mesolimbic dopamine system and may therefore represent a novel class of pharmacotherapeutics for the treatment of cocaine abuse. PMID:22328576

Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation.

PubMed

Gauthier, Jamie M; Lin, Amy; Nic Dhonnchadha, Bríd Á; Spealman, Roger D; Man, Heng-Ye; Kantak, Kathleen M

2017-01-01

This study investigated the combination of environmental enrichment (EE) with cocaine-cue extinction training on reacquisition of cocaine self-administration. Rats were trained under a second-order schedule for which responses were maintained by cocaine injections and cocaine-paired stimuli. During three weekly extinction sessions, saline was substituted for cocaine but cocaine-paired stimuli were presented. Rats received 4-h periods of EE at strategic time points during extinction training, or received NoEE. Additional control rats received EE or NoEE without extinction training. One week later, reacquisition of cocaine self-administration was evaluated for 15 sessions, and then GluA1 expression, a cellular substrate for learning and memory, was measured in selected brain regions. EE provided both 24 h before and immediately after extinction training facilitated extinction learning and deterred reacquisition of cocaine self-administration for up to 13 sessions. Each intervention by itself (EE alone or extinction alone) was ineffective, as was EE scheduled at individual time points (EE 4 h or 24 h before, or EE immediately or 6 h after, each extinction training session). Under these conditions, rats rapidly reacquired baseline rates of cocaine self-administration. Cocaine self-administration alone decreased total GluA1 and/or pSer845GluA1 expression in basolateral amygdala and nucleus accumbens. Extinction training, with or without EE, opposed these changes and also increased total GluA1 in ventromedial prefrontal cortex and dorsal hippocampus. EE alone increased pSer845GluA1 and EE combined with extinction training decreased pSer845GluA1 in ventromedial prefrontal cortex. EE might be a useful adjunct to extinction therapy by enabling neuroplasticity that deters relapse to cocaine self-administration. © 2015 Society for the Study of Addiction.

Glutamatergic Biomarkers for Cocaine Addiction: A Longitudinal Study Using MR Spectroscopy and mGluR5 PET in Self-Administering Rats.

PubMed

de Laat, Bart; Weerasekera, Akila; Leurquin-Sterk, Gil; Bormans, Guy; Himmelreich, Uwe; Casteels, Cindy; Van Laere, Koen

2018-06-01

Cocaine addiction is a disorder that still lacks diagnostic biomarkers or effective pharmacotherapy. We present findings on a rat model of cocaine self-administration that was followed up longitudinally using the metabotropic glutamate receptor type 5 (mGluR5) tracer 18 F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ( 18 F-FPEB) PET, proton MR spectroscopy ( 1 H-MRS), and behavioral tests. Methods: Forty-two Wistar rats were scanned with 18 F-FPEB PET and 1 H-MRS before and after sucrose or intravenous cocaine self-administration, during withdrawal, and during relapse. All animals performed a rodent Iowa Gambling Task (rIGT) at baseline to evaluate decision making. Baseline values were used in a mixed model to assess associations with later cocaine use, and follow-up measurements were compared with the values before drug exposure. Results: Preexposure rIGT scores were significantly related to both cocaine and sucrose use during the drug-exposure phase. However, only cocaine self-administration induced a decrease in 18 F-FPEB binding. This decrease was most pronounced bilaterally in the hippocampus, where mGluR5 availability correlated with the amount of cocaine used during relapse. Compared with the sucrose group, a larger decrease was observed in the hippocampo-prefrontal cortex pathway. Preexposure glutamate and glycine concentrations in the prefrontal cortex were significantly associated with cocaine use during the drug-exposure phase. Moreover, prefrontal glutamate exhibited a distinct, reversible decrease when animals had access to cocaine but not sucrose. Conclusion: Baseline values of prefrontal glutamate and glycine are associated with future cocaine use. Furthermore, baseline rIGT scores are associated with both sucrose and cocaine. Finally, both glutamate concentration and mGluR5 availability decrease during exposure to cocaine. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.; Volkow, N.D.

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and {sup 18}FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo andmore » once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.« less

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Telang, Frank; Fowler, Joanna S.; Pradhan, Kith; Jayne, Millard; Logan, Jean; Goldstein, Rita Z.; Alia-Klein, Nelly; Wong, Christopher

2010-01-01

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction. PMID:20634975

The Fate of Bacterial Cocaine Esterase (CocE): An In Vivo Study of CocE-Mediated Cocaine Hydrolysis, CocE Pharmacokinetics, and CocE EliminationS⃞

PubMed Central

Brim, Remy L.; Noon, Kathleen R.; Collins, Gregory T.; Stein, Aron; Nichols, Joseph; Narasimhan, Diwa; Ko, Mei-Chuan; Woods, James H.

2012-01-01

Cocaine abuse and toxicity remain widespread problems in the United States. Currently cocaine toxicity is treated only symptomatically, because there is no Food and Drug Administration-approved pharmacotherapy for this indication. To address the unmet need, a stabilized mutant of bacterial cocaine esterase [T172R/G173Q-CocE (DM-CocE)], which hydrolyzes cocaine into inactive metabolites and has low immunogenic potential, has been developed and previously tested in animal models of cocaine toxicity. Here, we document the rapid cocaine hydrolysis by low doses of DM-CocE in vitro and in vivo, as well as the pharmacokinetics and distribution of the DM-CocE protein in rats. DM-CocE at 50.5 μg/kg effectively eliminated 4 mg/kg cocaine within 2 min in both male and female rats as measured by mass spectrometry. We expanded on these findings by using a pharmacologically relevant dose of DM-CocE (0.32 mg/kg) in rats and monkeys to hydrolyze convulsant doses of cocaine. DM-CocE reduced cocaine to below detection limits rapidly after injection; however, elimination of DM-CocE resulted in peripheral cocaine redistribution by 30 to 60 min. Elimination of DM-CocE was quantified by using [35S] labeling of the enzyme and was found to have a half-life of 2.1 h in rats. Minor urinary output of DM-CocE was also observed. Immunohistochemistry, Western blotting, and radiography all were used to elucidate the mechanism of DM-CocE elimination, rapid proteolysis, and recycling of amino acids into all tissues. This rapid elimination of DM-CocE is a desirable property of a therapeutic for cocaine toxicity and should reduce the likelihood of immunogenic or adverse reactions as DM-CocE moves toward clinical use. PMID:21990608

Cocaine Modulates Mammalian Circadian Clock Timing by Decreasing Serotonin Transport in the SCN

PubMed Central

Prosser, Rebecca A.; Stowie, Adam; Amicarelli, Mario; Nackenoff, Alex G.; Blakely, Randy D.; Glass, J. David

2014-01-01

Cocaine abuse disrupts reward and homeostatic processes through diverse processes, including those involved in circadian clock regulation. Recently we showed that cocaine administration to mice disrupts nocturnal photic phase resetting of the suprachiasmatic (SCN) circadian clock, whereas administration during the day induces non-photic phase shifts. Importantly, the same effects are seen when cocaine is applied to the SCN in vitro, where it blocks photic-like (glutamate-induced) phase shifts at night and induces phase advances during the day. Furthermore, our previous data suggest that cocaine acts in the SCN by enhancing serotonin (5-HT) signaling. For example, the in vitro actions of cocaine mimic those of 5-HT and are blocked by the 5-HT antagonist, metergoline, but not the dopamine receptor antagonist, fluphenazine. Although our data are consistent with cocaine acting through enhance 5-HT signaling, the nonselective actions of cocaine as an antagonist of monoamine transporters raises the question of whether inhibition of the 5-HT transporter (SERT) is key to its circadian effects. Here we investigate this issue using transgenic mice expressing a SERT that exhibits normal 5-HT recognition and transport but significantly reduced cocaine potency (SERT Met172). Circadian patterns of SCN behavioral and neuronal activity did not differ between WT and SERT Met172 mice, nor did they differ in the ability of the 5-HT1A,2,7 receptor agonist, 8-OH-DPAT to reset SCN clock phase, consistent with the normal SERT expression and activity in the transgenic mice. However, 1) cocaine administration does not induce phase advances when administered in vivo or in vitro in SERT Met172 mice; 2) cocaine does not block photic or glutamate-induced (phase shifts in SERT Met172 mice; and 3) cocaine does not induce long-term changes in free-running period in SERT Met172 mice. We conclude that SERT antagonism is required for the phase shifting of the SCN circadian clock induced by cocaine. PMID:24950119

A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking.

PubMed

Luo, Yi-xiao; Xue, Yan-xue; Liu, Jian-feng; Shi, Hai-shui; Jian, Min; Han, Ying; Zhu, Wei-li; Bao, Yan-ping; Wu, Ping; Ding, Zeng-bo; Shen, Hao-wei; Shi, Jie; Shaham, Yavin; Lu, Lin

2015-07-14

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.

The effects of prenatal cocaine use on infant development.

PubMed

Richardson, Gale A; Goldschmidt, Lidush; Willford, Jennifer

2008-01-01

This study examined the effect of prenatal cocaine use on infant physical, cognitive, and motor development, and temperamental characteristics, controlling for other factors that affect infant development. Women were, on average, 26.8 years old, had 12 years of education, and 46% were African American. During the first trimester, 18% were frequent users of cocaine (> or =1 line/day). The infants were, on average, 14.6 months old at this follow-up phase. Women who used cocaine during pregnancy rated their infants as more fussy/difficult and unadaptable than did women who did not use cocaine. Cocaine use in the second trimester was associated with significantly lower motor scores on the Bayley Scales of Infant Development (BSID) [N. Bayley, Manual for the Bayley Scales of Infant Development, Psychological Corporation, New York, 1969.]. There was no effect of prenatal cocaine use on BSID mental performance or on growth. These findings are consistent with other reports in the literature and with the hypothesis that prenatal cocaine exposure affects development through changes in neurotransmitter systems.

A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking

PubMed Central

Luo, Yi-xiao; Xue, Yan-xue; Liu, Jian-feng; Shi, Hai-shui; Jian, Min; Han, Ying; Zhu, Wei-li; Bao, Yan-ping; Wu, Ping; Ding, Zeng-bo; Shen, Hao-wei; Shi, Jie; Shaham, Yavin; Lu, Lin

2015-01-01

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts. PMID:26169171

Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction

PubMed Central

Narasimhan, Diwahar; Woods, James H; Sunahara, Roger K

2012-01-01

Cocaine is highly addictive and there are no pharmacotherapeutic drugs available to treat acute cocaine toxicity or chronic abuse. Antagonizing an inhibitor such as cocaine using a small molecule has proven difficult. The alternative approach is to modify cocaine’s pharmacokinetic properties by sequestering or hydrolyzing it in serum and limiting access to its sites of action. We took advantage of a bacterial esterase (CocE) that has evolved to hydrolyze cocaine and have developed it as a therapeutic that rapidly and specifically clears cocaine from the subject. Native enzyme was unstable at 37°C, thus limiting CocE’s potential. Innovative computational methods based on the protein’s structure helped elucidate its mechanism of destabilization. Novel protein engineering methodologies were applied to substantially improve its stability in vitro and in vivo. These improvements rendered CocE as a powerful and efficacious therapeutic to treat cocaine intoxication and lead the way towards developing a therapy for addiction. PMID:22300094

Orexin/hypocretin is necessary for context-driven cocaine-seeking

PubMed Central

Smith, Rachel J.; Tahsili-Fahadan, Pouya; Aston-Jones, Gary

2009-01-01

Summary Orexin/hypocretin signaling at the orexin 1 receptor (OX1R) has recently been implicated in addiction and relapse. We examined the role of the orexin system in cocaine-seeking elicited by a drug-associated context following abstinence or extinction from chronic cocaine self-administration. Male Sprague-Dawley rats self-administered cocaine in 2-hour sessions for 10 days, followed by extinction training or extended abstinence in the home cage. The OX1R antagonist SB-334867 (SB; 10, 20, or 30 mg/kg, i.p.) was administered prior to re-exposure to the cocaine self-administration environment. We found that pretreatment with SB significantly attenuated cocaine-seeking when rats were placed back into the self-administration environment following either 1 day or 2 weeks of abstinence (no extinction), or following extinction of cocaine-seeking in an alternative environment (distinct from the training environment). These results indicate that orexin signaling at OX1R is critical for conditioned cocaine-seeking elicited by a drug-associated context, following either extinction or abstinence. PMID:19591850

Evidence for opponent-process actions of intravenous cocaine.

PubMed

Ettenberg, A; Raven, M A; Danluck, D A; Necessary, B D

1999-11-01

The present experiment was devised to test a prediction of the Opponent-Process Theory of drug action. This theory presumes that the initial affective experience of a subject treated with cocaine would be diametrically different immediately after administration compared to some point later in time when the positive impact of the drug had subsided. A conditioned place-preference procedure was employed in which a novel environment was paired with the effects of cocaine either immediately after, 5 min after, or 15 min after an intravenous injection of 0.75 mg/kg cocaine. It was hypothesized that animals would come to prefer environments associated with the immediate positive effects of cocaine and avoid environments associated with the drug's subsequent negative effects. The results confirmed this hypothesis. While the 0-min delay and 5-min delay groups exhibited conditioned preferences for the cocaine-paired environment, the 15-min delay group came to avoid the side of the preference apparatus paired with cocaine. These data, therefore, serve as additional support for an Opponent-Process account of cocaine's actions.

Screening for cocaine on Euro banknotes by a highly sensitive enzyme immunoassay.

PubMed

Abdelshafi, Nahla A; Panne, Ulrich; Schneider, Rudolf J

2017-04-01

This study focused on quantitative detection of cocaine on Euro banknotes in Germany. A sensitive direct competitive immunoassay was developed and optimized with a limit of detection (LOD) of 5.6ng/L. Exhaustive cocaine extraction by solvent was tested using different methanol concentrations and buffered solutions. Cross-reactivity studies were performed to determine the degree of interference of cocaine metabolites with the immunoassay. Sixty-five Euro banknotes obtained from different districts in Berlin were evaluated. A 100% contamination frequency with cocaine was detected. A comparison between the amount of cocaine extracted by cotton swabbing of one square centimeter of the banknote showed a good correlation for lower contamination levels. This assay showed high sensitivity of detecting pg of cocaine per 1cm 2 of one banknote by swabbing 1cm 2 : 0, 14, and 21pg/cm 2 . Moreover, three notes of different denominations revealed high cocaine concentration; 1.1mg/note, and twice 55µg/note. Copyright © 2017 Elsevier B.V. All rights reserved.

Baclofen has opposite effects on escalation of cocaine self-administration: increased intake in rats selectively bred for high (HiS) saccharin intake and decreased intake in those selected for low (LoS) saccharin intake

PubMed Central

Holtz, Nathan A.; Carroll, Marilyn E.

2011-01-01

Rats selectively bred for high saccharin intake (HiS) self-administer more cocaine, escalate their cocaine intake during long access, and reinstate cocaine seeking at higher levels than those bred for low saccharin intake (LoS). The present study was conducted to determine if baclofen, an agonist at the GABAb receptor, has differential effects on the escalation of i.v. cocaine intake and reinstatement of cocaine-seeking in HiS and LoS rats. HiS and LoS rats self-administered cocaine during a 2-h daily short-access (ShA) phase for 3 days and then long-access (LgA) sessions for 21 days followed by a second ShA phase. One group of HiS and LoS rats received i.p. injections of 2.5 mg/kg baclofen (HiS+B and LoS+B, respectively), and other groups of HiS and LoS rats received saline (HiS+Sal and LoS+Sal) before each daily session. In a second experiment, HiS and LoS rats self-administered i.v. cocaine during 2-h sessions for 14 days followed by a 21-day extinction period. Baclofen (2.5 mg/kg, i.p.) or saline was administered before saline- or cocaine-primed reinstatement sessions. The HiS+B group escalated their cocaine self-administration and had increased cocaine infusions in the post-LgA ShA phase. The LoS+B group self-administered less cocaine throughout the entire LgA period compared to the LoS+Sal or HiS groups. Baclofen attenuated reinstatement of cocaine seeking in both the HiS and LoS rats with no phenotype differences. Baclofen had opposite effects on cocaine intake in HiS and LoS rats during escalation; HiS increased and LoS decreased intake. These results suggest that treatment effects might vary with individual differences (HiS vs. LoS) and the phase of drug-motivated behavior that is modeled. PMID:21924281

Dopamine transporter occupancy by RTI-55 determined using labeled cocaine, and displacement of RTI-55 with unlabeled cocaine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gatley, S.J.; Volkow, N.D.; Fowler, J.S.

We have previously visualized dopamine transporters (DAT) in human and baboon striatum using PET and C-11 cocaine. Cocaine analogs such as 3{beta}-(4-iodophenyl) tropane-2{beta}-carboxylic acid methyl ester (RTI-55 or {beta}CIT) with a higher affinity for the DAT may be potentially useful in interfering with cocaine`s actions in brain. We evaluated the time course of the effects of RTI-55 on C-11 cocaine binding in baboon brain prior to and 90 minutes, 24 hours, 4-5 days and 11-13 days after RTI-55(0.3 mg/kg iv). RTI-55 significantly inhibited C-11 cocaine binding at 90 minutes and 24 hours after administration. The half life for the clearancemore » of RTI-55 from the DAT was estimated to be 2 to 3 days in the baboon brain. Parallel studies with H-3 cocaine and RTI-55 (0.5 mg/kg iv or 2 mg/kg ip) were performed in mice, where RTI-55 significantly inhibited 5 minute striatum-to-cerebellium ratios (S/C) at 60 and 180 minutes after administration, and recovery was obtained at 12 hours. However, unlabeled cocaine (20 mg/Kg, i/p) given 60 minutes after RTI-55 led to a greater recovery of H-3 cocaine uptake measured at 180 minutes (S/C = 1.23 {plus_minus} 0.07, n= 5), than in control animals given saline after RTI-55 (S/C = 9.5{plus_minus}0.08). Animals given saline instead of RTI-55 had S/C = 1.45{plus_minus}0.04. These results document long lasting inhibition of cocaine binding by RTI-55 and corroborate the assumption that the binding kinetics of RTI-55 in striatum observed in SPECT imaging studies with I-123 RTI-55 represents binding to DAT`s. However, a pharmacological dose of cocaine is able to displace a fraction of the previously bound RTI-55 from the DAT. These findings have implications for drug development strategies for cocaine abuse.« less

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

PubMed Central

Sun, Wei-Lun; Eisenstein, Sarah A.; Zelek-Molik, Agnieszka

2015-01-01

Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. PMID:25522393

Adenosine A2A receptors in the nucleus accumbens bi-directionally alter cocaine seeking in rats.

PubMed

O'Neill, Casey E; LeTendre, McKenzie L; Bachtell, Ryan K

2012-04-01

Repeated cocaine administration enhances dopamine D(2) receptor sensitivity in the mesolimbic dopamine system, which contributes to drug relapse. Adenosine A(2A) receptors are colocalized with D(2) receptors on nucleus accumbens (NAc) medium spiny neurons where they antagonize D(2) receptor activity. Thus, A(2A) receptors represent a target for reducing enhanced D(2) receptor sensitivity that contributes to cocaine relapse. The aim of these studies were to determine the effects of adenosine A(2A) receptor modulation in the NAc on cocaine seeking in rats that were trained to lever press for cocaine. Following at least 15 daily self-administration sessions and 1 week of abstinence, lever pressing was extinguished in daily extinction sessions. We subsequently assessed the effects of intra-NAc core microinjections of the A(2A) receptor agonist, CGS 21680 (4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride), and the A(2A) receptor antagonist, MSX-3 (3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate), in modulating cocaine- and quinpirole-induced reinstatement to cocaine seeking. Intra-NAc pretreatment of CGS 21680 reduced both cocaine- and quinpirole-induced reinstatement. These effects were specific to cocaine reinstatement as intra-NAc CGS 21680 had no effect on sucrose seeking in rats trained to self-administer sucrose pellets. Intra-NAc treatment with MSX-3 modestly reinstated cocaine seeking when given alone, and exacerbated both cocaine- and quinpirole-induced reinstatement. Interestingly, the exacerbation of cocaine seeking produced by MSX-3 was only observed at sub-threshold doses of cocaine and quinpirole, suggesting that removing tonic A(2A) receptor activity enables behaviors mediated by dopamine receptors. Taken together, these findings suggest that A(2A) receptor stimulation reduces, while A(2A) blockade amplifies, D(2) receptor signaling in the NAc that mediates cocaine relapse.

Adenosine A2A Receptors in the Nucleus Accumbens Bi-Directionally Alter Cocaine Seeking in Rats

PubMed Central

O'Neill, Casey E; LeTendre, Mckenzie L; Bachtell, Ryan K

2012-01-01

Repeated cocaine administration enhances dopamine D2 receptor sensitivity in the mesolimbic dopamine system, which contributes to drug relapse. Adenosine A2A receptors are colocalized with D2 receptors on nucleus accumbens (NAc) medium spiny neurons where they antagonize D2 receptor activity. Thus, A2A receptors represent a target for reducing enhanced D2 receptor sensitivity that contributes to cocaine relapse. The aim of these studies were to determine the effects of adenosine A2A receptor modulation in the NAc on cocaine seeking in rats that were trained to lever press for cocaine. Following at least 15 daily self-administration sessions and 1 week of abstinence, lever pressing was extinguished in daily extinction sessions. We subsequently assessed the effects of intra-NAc core microinjections of the A2A receptor agonist, CGS 21680 (4-[2-[[6-amino-9-(N-ethyl-b--ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride), and the A2A receptor antagonist, MSX-3 (3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate), in modulating cocaine- and quinpirole-induced reinstatement to cocaine seeking. Intra-NAc pretreatment of CGS 21680 reduced both cocaine- and quinpirole-induced reinstatement. These effects were specific to cocaine reinstatement as intra-NAc CGS 21680 had no effect on sucrose seeking in rats trained to self-administer sucrose pellets. Intra-NAc treatment with MSX-3 modestly reinstated cocaine seeking when given alone, and exacerbated both cocaine- and quinpirole-induced reinstatement. Interestingly, the exacerbation of cocaine seeking produced by MSX-3 was only observed at sub-threshold doses of cocaine and quinpirole, suggesting that removing tonic A2A receptor activity enables behaviors mediated by dopamine receptors. Taken together, these findings suggest that A2A receptor stimulation reduces, while A2A blockade amplifies, D2 receptor signaling in the NAc that mediates cocaine relapse. PMID:22169945

In vitro model to study cocaine and its contaminants.

PubMed

Steinmetz, Aline; Steffens, Luiza; Morás, Ana Moira; Prezzi, Flávia; Braganhol, Elizandra; Saffi, Jenifer; Ortiz, Rafael Scorsatto; Barros, Helena M T; Moura, Dinara Jaqueline

2018-04-01

Cocaine is one of the most popular illicit drug worldwide. Due its great addictive potential, which leads to euphoria and hyperactivity, it is considered a public health concern. At the central nervous system, the drug acts inhibiting catecholamine re-uptake. It is now known that in addition to the toxicity of the drug itself, the contaminants present in the street drug have raised concern about the harmful effects on health. Toxicological in vivo and in vitro studies have demonstrated the toxic effects of cocaine correlated with the generation of reactive oxygen species (ROS), which in turn lead to oxidative damage to the cells. Therefore the aim of this work was to propose an in vitro model that reunites the main parameters of toxicity of the cocaine already observed in the literature so far, and we tested this model using cocaine and seizure cocaine sample (SCS), kindly provided by Federal Police of Brazil. For that, we used a C6 glioblastoma cells and evaluated cell death, oxygen reactive species induction, oxidation of macromolecules as membrane lipids and DNA and loss of mitochondrial membrane potential after cocaine exposure. The results showed that cocaine can decrease cellular viability in a dose-dependent way in the C6 cell immortalized and astrocytes primary culture. Cocaine also induced cellular death by apoptosis. However, in the seizure cocaine sample (SCS), the predominant cell death was due to necrosis. Using dichlorofluorescein (DCF) assay, we confirmed ROS production after cocaine exposition. In agreement with these findings, occurred an increasing in MDA production, as well as increased superoxide dismutase (SOD) and catalase (CAT) activity. The induction of DNA damage was observed after cocaine. Our results demonstrate the occurrence of mitochondrial dysfunction by depolarization of mitochondrial membrane as a consequence of cocaine treatment. In summary, these results demonstrated that cocaine can induce reactive oxygen species formation, leading to oxidative stress. As a consequence of this unbalance, DNA damage, lipidic peroxidation and loss of mitochondrial membrane occurred, which could be an answer to cell death observed. Copyright © 2018 Elsevier B.V. All rights reserved.

The epidemiology of cocaine use in Spain.

PubMed

Barrio Anta, G; Vicente Orta, J; Bravo Portela, M J; de la Fuente de Hoz, L

1993-12-01

Trends and patterns of cocaine use in Spain are described with the aid of different information sources such as population surveys, the State Information System on Drug Abuse, and anthropological studies. In recent years the magnitude of cocaine supply indicators has increased greatly. High levels of last-month prevalence of cocaine use have been detected among the general population--consistently higher than those for heroin-- and cocaine consumption among heroin users has increased. Although the frequency of some health problems related to cocaine use--treatment admissions, hospital emergency admissions--has increased, it is still 30 times less than for heroin. Various hypotheses to explain these discrepancies are discussed.

Drug smuggling using clothing impregnated with cocaine.

PubMed

McDermott, Seán D; Power, John D

2005-11-01

A case study is presented where a woman travelling from South America to the Republic of Ireland was detained at Dublin Airport and articles of clothing she had in her luggage were found to be impregnated with cocaine. The study shows that the amount of powder recovered from the garments was approximately 14% of the total weight of the garments. The cocaine was in the form of cocaine hydrochloride and the purity was approximately 80%. An examination of the garments under filtered light highlighted the areas exposed to cocaine and indicated that the method of impregnation was by pouring liquid containing cocaine onto the clothing.

Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage.

PubMed

Gao, Yang; Geng, Liyi; Orson, Frank; Kinsey, Berma; Kosten, Thomas R; Shen, Xiaoyun; Brimijoin, Stephen

2013-03-25

In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100-120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ~400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat.

PubMed

de Guglielmo, Giordano; Cippitelli, Andrea; Somaini, Lorenzo; Gerra, Gilberto; Li, Hongwu; Stopponi, Serena; Ubaldi, Massimo; Kallupi, Marsida; Ciccocioppo, Roberto

2013-07-01

Pregabalin (Lyrica™) is a structural analog of γ-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users.

PubMed

Wesley, Michael J; Lohrenz, Terry; Koffarnus, Mikhail N; McClure, Samuel M; De La Garza, Richard; Salas, Ramiro; Thompson-Lake, Daisy G Y; Newton, Thomas F; Bickel, Warren K; Montague, P Read

2014-01-01

Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC.

Children's cognitive ability from 4 to 9 years old as a function of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence.

PubMed

Bennett, David S; Bendersky, Margaret; Lewis, Michael

2008-07-01

This study examined the effects of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence on children's cognitive ability. Gender and age were examined as moderators of potential cocaine exposure effects. The Stanford-Binet IV intelligence test was administered to 231 children (91 cocaine exposed, 140 unexposed) at ages 4, 6, and 9 years. Neonatal medical risk and other prenatal exposures (alcohol, cigarettes, and marijuana) were also examined for their unique effects on child IQ. Mixed models analysis indicated that prenatal cocaine exposure interacted with gender, as cocaine-exposed boys had lower composite IQ scores. Age at assessment did not moderate this relation, indicating that cocaine-exposed boys had lower IQs across this age period. A stimulating home environment and high maternal verbal IQ also predicted higher composite IQ scores. Cocaine-exposed boys had lower scores on the Abstract/Visual Reasoning subscale, with trends for lower scores on the Short-Term Memory and Verbal Reasoning subscales, as exposure effects were observed across domains. The findings indicate that cocaine exposure continues to place children at risk for mild cognitive deficits into preadolescence. Possible mechanisms for the Exposure x Gender interaction are discussed.

Cocaine and thrombosis: a narrative systematic review of clinical and in-vivo studies

PubMed Central

Wright, Nat MJ; Martin, Matthew; Goff, Tom; Morgan, John; Elworthy, Rebecca; Ghoneim, Shariffe

2007-01-01

Purpose To systematically review the literature pertaining to the link between cocaine and either arterial or venous thrombosis. Procedures Narrative systematic review of Medline, CINAHL, Embase, Psycinfo and Cochrane databases supplemented by hand trawling of relevant journals and reference lists up to April 2007. In-vivo studies and those with clinical endpoints were included in the review. Results A total of 2458 abstracts led to 186 full-text papers being retrieved. 15 met the criteria for inclusion in the review. The weight of evidence would support cocaine as a pro-thrombotic agent. There is evidence of it activating thrombotic pathways. The effect of cocaine upon clinical endpoints has not been quantified though there is evidence of an association between cocaine and myocardial infarction particularly amongst young adults. Cocaine may also be a causal agent in cerebrovascular accident though studies lacked sufficient power to determine a statistically significant effect. There is a gap in the evidence pertaining to the issue of cocaine and venous thrombosis. Conclusion Clinicians should consider questioning for cocaine use particularly amongst young adults who present with cardiac symptoms. More epidemiological work is required to quantify the effect of cocaine upon both arterial and venous clotting mechanisms. PMID:17880705

The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation

PubMed Central

Anderson, Rachel M.; Cosme, Caitlin V.; Glanz, Ryan M.; Miller, Mary C.; Romig-Martin, Sara A.; LaLumiere, Ryan T.

2015-01-01

The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic cocaine self-administration in rats leads to decrements in medial prefrontal structural and functional plasticity. Notably, these impairments were largely accounted for in rats that self-administered cocaine compared with yoked counterparts. Moreover, we verified previous reports showing that adrenocortical output is augmented by cocaine administration and is more protracted in rats that were permitted to receive the drug contingently instead of passively. These studies suggest that increased adrenocortical activity resulting from cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. PMID:26311772

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

PubMed Central

Grundt, Peter; Cao, Jianjing; Platt, Donna M.; Newman, Amy Hauck; Spealman, Roger D.

2010-01-01

Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin- 1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl]methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H- imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaine's discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine- and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine. PMID:20494958

Sex Differences in Psychiatric Comorbidity and Plasma Biomarkers for Cocaine Addiction in Abstinent Cocaine-Addicted Subjects in Outpatient Settings

PubMed Central

Pedraz, María; Araos, Pedro; García-Marchena, Nuria; Serrano, Antonia; Romero-Sanchiz, Pablo; Suárez, Juan; Castilla-Ortega, Estela; Mayoral-Cleries, Fermín; Ruiz, Juan Jesús; Pastor, Antoni; Barrios, Vicente; Chowen, Julie A.; Argente, Jesús; Torrens, Marta; de la Torre, Rafael; Rodríguez De Fonseca, Fernando; Pavón, Francisco Javier

2015-01-01

There are sex differences in the progression of drug addiction, relapse, and response to therapies. Because biological factors participate in these differences, they should be considered when using biomarkers for addiction. In the current study, we evaluated the sex differences in psychiatric comorbidity and the concentrations of plasma mediators that have been reported to be affected by cocaine. Fifty-five abstinent cocaine-addicted subjects diagnosed with lifetime cocaine use disorders (40 men and 15 women) and 73 healthy controls (48 men and 25 women) were clinically assessed with the diagnostic interview “Psychiatric Research Interview for Substance and Mental Disorders.” Plasma concentrations of chemokines, cytokines, N-acyl-ethanolamines, and 2-acyl-glycerols were analyzed according to history of cocaine addiction and sex, controlling for covariates age and body mass index (BMI). Relationships between these concentrations and variables related to cocaine addiction were also analyzed in addicted subjects. The results showed that the concentrations of chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 (CCL2/MCP-1) and chemokine (C-X-C motif) ligand 12/stromal cell-derived factor-1 (CXCL12/SDF-1) were only affected by history of cocaine addiction. The plasma concentrations of interleukin 1-beta (IL-1β), IL-6, IL-10, and tumor necrosis factor-alpha (TNFα) were affected by history of cocaine addiction and sex. In fact, whereas cytokine concentrations were higher in control women relative to men, these concentrations were reduced in cocaine-addicted women without changes in addicted men. Regarding fatty acid derivatives, history of cocaine addiction had a main effect on the concentration of each acyl derivative, whereas N-acyl-ethanolamines were increased overall in the cocaine group, 2-acyl-glycerols were decreased. Interestingly, N-palmitoleoyl-ethanolamine (POEA) was only increased in cocaine-addicted women. The covariate BMI had a significant effect on POEA and N-arachidonoyl-ethanolamine concentrations. Regarding psychiatric comorbidity in the cocaine group, women had lower incidence rates of comorbid substance use disorders than did men. For example, alcohol use disorders were found in 80% of men and 40% of women. In contrast, the addicted women had increased prevalences of comorbid psychiatric disorders (i.e., mood, anxiety, and psychosis disorders). Additionally, cocaine-addicted subjects showed a relationship between the concentrations of N-stearoyl-ethanolamine and 2-linoleoyl-glycerol and diagnosis of psychiatric comorbidity. These results demonstrate the existence of a sex influence on plasma biomarkers for cocaine addiction and on the presence of comorbid psychopathologies for clinical purposes. PMID:25762940

Cocaine-Induced Behavioral Sensitization Is Associated With Changes in the Expression of Endocannabinoid and Glutamatergic Signaling Systems in the Mouse Prefrontal Cortex

PubMed Central

Blanco, Eduardo; Pavón, Francisco J.; Palomino, Ana; Luque-Rojas, María Jesús; Serrano, Antonia; Rivera, Patricia; Bilbao, Ainhoa; Alen, Francisco; Vida, Margarita; Suárez, Juan

2015-01-01

Background: Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. Methods: We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. Results: Although acute cocaine (10mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3. Conclusions: These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas. PMID:25539508

Facile and enantiospecific syntheses of (6S,7R)-6-chloro-7-benzyloxy-, (7S)-halo-, and (7S)-hydroxy-cocaine and natural (-)-cocaine from D-(-)-ribose.

PubMed

Shing, Tony K M; So, King H

2011-06-03

First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D-(-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.

Effects of escitalopram and imipramine on cocaine reinforcement and drug-seeking behaviors in a rat model of depression.

PubMed

Jastrzębska, Joanna; Frankowska, Małgorzata; Suder, Agata; Wydra, Karolina; Nowak, Ewa; Filip, Małgorzata; Przegaliński, Edmund

2017-10-15

Depression and substance cocaine abuse are disorders with a high frequency of comorbidity. In the present study, we combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with intravenous cocaine self-administration and extinction/reinstatement in rats to investigate the effects of two antidepressant drugs, escitalopram (ESC) and imipramine (IMI), with the goal of determining whether these drugs altered cocaine-induced reinforcement and seeking behaviors. Acute administration of IMI (2.5-30mg/kg) reduced the cocaine reinforcement in OBX and SHAM rats. Moreover, IMI effectively reduced the cocaine-seeking behavior after the drug acute or repeated administration during extinction training in OBX rats and SHAM-operated controls. By contrast, acutely administered ESC (2.5-20mg/kg) did not alter cocaine reinforcement in OBX rats or SHAM-operated controls. The lack of ESC effects was also demonstrated during reinstatement tests to study drug-seeking behavior after ESC repeated daily treatment during extinction trials. However, acute treatment with ESC dose-dependently decreased the cocaine-seeking behavior and relapse triggered by cocaine priming or drug-associated conditioned cues in both OBX and SHAM rats. These results indicate the cocaine anti-reinforcement and anti-seeking efficacy of the two antidepressant drugs studied here. However, the mechanisms for the IMI and ESC activity should be clarified in further studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Glutamatergic and neurometabolic alterations in chronic cocaine users measured with (1) H-magnetic resonance spectroscopy.

PubMed

Hulka, Lea M; Scheidegger, Milan; Vonmoos, Matthias; Preller, Katrin H; Baumgartner, Markus R; Herdener, Marcus; Seifritz, Erich; Henning, Anke; Quednow, Boris B

2016-01-01

Cocaine addiction is a chronically relapsing disorder that is associated with harmful consequences. Relapses occur frequently and effective pharmacotherapies are currently sparse. Preclinical studies suggest that altered glutamatergic signaling is crucial for the maintenance of cocaine self-administration. However, the translational validity of these models is currently unknown. Therefore, we investigated potential differences of glutamate, glutamine and further metabolite levels in the pregenual anterior cingulate cortex (pgACC) and the right dorsolateral prefrontal cortex (rDLPFC) of chronic cocaine users and controls using the PRior knOwledge FITting 2.0 tool in combination with two-dimensional J-resolved single-voxel (1) H-magnetic resonance spectroscopy at 3T and voxel tissue composition and relaxation correction. Glutamate and glutamine levels did not differ between cocaine users and controls, but higher weekly cocaine use and higher cocaine hair concentrations were associated with lower glutamine/creatine ratios in the pgACC. Interestingly, cocaine users exhibited higher glucose/total creatine ratios than controls in the pgACC and higher choline/creatine ratios in the pgACC and rDLPFC. These results imply that cocaine use is associated with altered cortical glucose metabolism and membrane turnover. Finally, cocaine use over the past 6 months appears to decrease cortical glutamine levels indicating changes in glutamate cycling. © 2014 Society for the Study of Addiction.

An Antidote for Acute Cocaine Toxicity

PubMed Central

Treweek, Jennifer B.; Janda, Kim D.

2012-01-01

Not only has immunopharmacotherapy grown into a field that addresses the abuse of numerous illicit substances, but also the treatment methodologies within immunopharmacotherapy have expanded from traditional active vaccination to passive immunization with anti-drug monoclonal antibodies, optimized mAb formats, and catalytic drug-degrading antibodies. Many laboratories have focused on transitioning distinct immunopharmacotherapeutics to clinical evaluation, but with respect to the indication of cocaine abuse, only the active vaccine TA-CD, which is modeled after our original cocaine hapten GNC1, has been carried through to human clinical trials.2 The successful application of murine mAb GNC92H2 to the reversal of cocaine overdose in a mouse model prompted investigations of human immunoglobulins with the clinical potential to serve as cocaine antidotes. We now report the therapeutic utility of a superior clone, human mAb GNCgzk (Kd = 0.18 nM), which offers a 10-fold improvement in cocaine binding affinity. The GNCgzk manifold was engineered for rapid cocaine clearance, and administration of the F(ab′)2 and Fab formats even after the appearance of acute behavioral signs of cocaine toxicity granted nearly complete prevention of lethality. Thus, contrary to the immunopharmacotherapeutic treatment of drug self-administration, minimal antibody doses were shown to counteract the lethality of a molar excess of circulating cocaine. Passive vaccination with drug-specific antibodies represents a viable treatment strategy for the human condition of cocaine overdose. PMID:22380623

Direct fluorescence anisotropy assay for cocaine using tetramethylrhodamine-labeled aptamer.

PubMed

Liu, Yingxiong; Zhao, Qiang

2017-06-01

Development of simple, sensitive, and rapid method for cocaine detection is important in medicine and drug abuse monitoring. Taking advantage of fluorescence anisotropy and aptamer, this study reports a direct fluorescence anisotropy (FA) assay for cocaine by employing an aptamer probe with tetramethylrhodamine (TMR) labeled on a specific position. The binding of cocaine and the aptamer causes a structure change of the TMR-labeled aptamer, leading to changes of the interaction between labeled TMR and adjacent G bases in aptamer sequence, so FA of TMR varies with increasing of cocaine. After screening different labeling positions of the aptamer, including thymine (T) bases and terminals of the aptamer, we obtained a favorable aptamer probe with TMR labeled on the 25th base T in the sequence, which exhibited sensitive and significant FA-decreasing responses upon cocaine. Under optimized assay conditions, this TMR-labeled aptamer allowed for direct FA detection of cocaine as low as 5 μM. The maximum FA change reached about 0.086. This FA method also enabled the detection of cocaine spiked in diluted serum and urine samples, showing potential for applications. Graphical Abstract The binding of cocaine to the TMR-labeled aptamer causes conformation change and alteration of the intramolecular interaction between TMR and bases of aptamer, leading to variance of fluorescence anisotropy (FA) of TMR, so direct FA analyis of cocaine is achieved.

Lack of cocaine-like discriminative-stimulus effects of σ-receptor agonists in rats.

PubMed

Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2011-09-01

Previous studies demonstrated the effectiveness of selective σ-receptor (σR) agonists [1,3-di-o-tolylguanidine (DTG), PRE-084] as reinforcers in rats trained to self-administer cocaine. Similar to cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine seemed to be mediated by σRs. In addition, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus, pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. This study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG), produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects.

Lack of Cocaine-Like Discriminative-Stimulus Effects of σ Receptor Agonists in Rats

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi; Katz, Jonathan L.

2013-01-01

Previous studies demonstrated effectiveness of selective sigma-receptor (σR) agonists (DTG, PRE-084) as reinforcers in rats trained to self-administer cocaine. Like cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine appeared to be mediated by σRs. Additionally, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. The present study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG) produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (i.p., s.c. or i.v.) or pretreatment time (5- or 30-min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects. PMID:21808192

Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats.

PubMed

Navailles, Sylvia; Guillem, Karine; Vouillac-Mendoza, Caroline; Ahmed, Serge H

2015-09-01

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effects of GABA(B) receptor agents on cocaine priming, discrete contextual cue and food induced relapses.

PubMed

Filip, Małgorzata; Frankowska, Małgorzata

2007-10-01

In the present study we investigated the effects of the GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phosphinic acid (SKF 97541), and the allosteric positive modulator 3,5-bis(1,1-dimethylethyl)-4-hydroxy-beta,beta-dimethylbenzenepropanol (CGP 7930) on cocaine seeking behavior. The effects of the above drugs on the reinstatement of responding induced by natural reinforcer (food) were also studied. Male Wistar rats were trained to self-administer either cocaine (0.5 mg/kg/infusion) or food (sweet milk) and responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine, i.p.), a discrete contextual cue, or a contingent presentation of food. SCH 50911 (3-10 mg/kg) dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned cue reinstatement. At the same time, it failed to alter reinstatement of food-seeking behavior. Baclofen (1.25-5 mg/kg) and SKF 97541 (0.03-0.3 mg/kg) attenuated cocaine- or food-seeking behavior; the effect of the drug appeared more effective for cocaine-seeking than food-seeking. CGP 7930 (10-30 mg/kg) reduced cocaine seeking without affecting food-induced reinstatement on reward seeking. Our results indicate that tonic activation of GABA(B) receptors is required for cocaine seeking behavior in rats. Moreover, the GABA(B) receptor antagonist SCH 50911 was effective in reducing relapse to cocaine at doses that failed to alter reinstatement of food-seeking behavior (present study), basal locomotor activity, cocaine and food self-administration (Filip et al., submitted for publication), suggesting its selective effects on motivated drug-seeking behavior. The potent inhibitory responses on cocaine seeking behavior were also seen following the GABA(B) receptor agonists or the allosteric positive modulator, however, doses of baclofen and SKF 97541 that inhibited cocaine-seeking were only threefold lower of those that inhibited food-seeking. In addition, the direct GABA(B) receptor agonists and the allosteric positive modulator cause decreases in cocaine or food self-administration (Filip et al., submitted for publication), indicating their nonspecific effects on relapse to drug-seeking and drug-taking behavior. In conclusion, the GABA(B) receptor antagonist SCH 50911 seems to be viable treatment for reducing cocaine craving and preventing relapse, while the GABA(B) receptor allosteric positive modulator CGP 7930 may hold the highest promise for attenuating cue-evoked relapses to cocaine as well as the direct rewarding properties of cocaine.

Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice

PubMed Central

Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, JA; Colado, MI; O'Shea, E

2010-01-01

Background and purpose: 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Experimental approach: Mice received a course of cocaine (20 mg·kg−1, ×2 for 3 days) followed by MDMA (20 mg·kg−1, ×2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Key results: Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Conclusions and implications: Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA. PMID:20015297

Eating high fat chow enhances the locomotor-stimulating effects of cocaine in adolescent and adult female rats.

PubMed

Baladi, Michelle G; Koek, Wouter; Aumann, Megan; Velasco, Fortino; France, Charles P

2012-08-01

Dopamine systems vary through development in a manner that can impact drugs acting on those systems. Dietary factors can also impact the effects of drugs acting on dopamine systems. This study examined whether eating high fat chow alters locomotor effects of cocaine (1-56 mg/kg) in adolescent and adult female rats. Cocaine was studied in rats (n = 6/group) with free access to standard (5.7% fat) or high fat (34.3%) chow or restricted access to high fat chow (body weight matched to rats eating standard chow). After 1 week of eating high fat chow (free or restricted access), sensitivity to cocaine was significantly increased in adolescent and adult rats, compared with rats eating standard chow. Sensitivity to cocaine was also increased in adolescent rats with restricted, but not free, access to high fat chow for 4 weeks. When adolescent and adult rats that previously ate high fat chow ate standard chow, sensitivity to cocaine returned to normal. In adolescent and adult female rats eating high fat chow, but not those eating standard chow, sensitivity to cocaine increased progressively over once weekly tests with cocaine (i.e., sensitization) in a manner that was not statistically different between adolescents and adults. These results show that eating high fat chow alters sensitivity of female rats to acutely administered cocaine and also facilitates the development of sensitization to cocaine. That the type of food consumed can increase drug effects might have relevance to vulnerability to abuse cocaine in the female population.

Intake-dependent effects of cocaine self-administration on impulsive choice in a delay discounting task

PubMed Central

Mitchell, Marci R.; Weiss, Virginia G.; Ouimet, Dominique J.; Fuchs, Rita A.; Morgan, Drake; Setlow, Barry

2014-01-01

Cocaine use is associated with high levels of impulsive choice (greater discounting of delayed rewards) in humans, but the cause/effect relationships between cocaine use and impulsive choice are not fully understood. In previous work, we found that both experimenter- and self-administration of fixed quantities of cocaine caused lasting increases in impulsive choice in rats. The present study extended these findings by taking into account baseline impulsive choice prior to self-administration, and by allowing rats free access to cocaine. Male Long-Evans rats were trained in a delay discounting task in which they made discrete-trial choices between small immediate and large delayed food rewards. Half of the rats were then implanted with intravenous catheters and, following recovery, allowed to self-administer cocaine HCl (1.0 mg/kg/infusion) in 6 hour sessions over 14 days. Control rats orally self-administered a sucrose solution under similar conditions. Upon completion of self-administration training, rats remained abstinent for 3 weeks before retesting in the delay discounting task. Cocaine and control groups did not differ prior to self-administration, but afterward, the cocaine group showed greater impulsive choice (fewer choices of large, delayed rewards) than controls. Additional analyses revealed that the effects of cocaine on impulsive choice were intake-dependent; rats classified as “low intake” did not differ from controls, whereas rats classified as “high intake” were significantly more impulsive than both controls and their pre-cocaine baseline. These findings are consistent with the idea that cocaine-induced, pharmacologically based neural adaptations promote the development of impulsive decision making. PMID:24841739

The motivation to self-administer is increased after a history of spiking brain levels of cocaine.

PubMed

Zimmer, Benjamin A; Oleson, Erik B; Roberts, David Cs

2012-07-01

Recent attempts to model the addiction process in rodents have focused on cocaine self-administration procedures that provide extended daily access. Such procedures produce a characteristic loading phase during which blood levels rapidly rise and then are maintained within an elevated range for the duration of the session. The present experiments tested the hypothesis that multiple fast-rising spikes in cocaine levels contribute to the addiction process more robustly than constant, maintained drug levels. Here, we compared the effects of various cocaine self-administration procedures that produced very different patterns of drug intake and drug dynamics on Pmax, a behavioral economic measure of the motivation to self-administer drug. Two groups received intermittent access (IntA) to cocaine during daily 6-h sessions. Access was limited to twelve 5-min trials that alternated with 25-min timeout periods, using either a hold-down procedure or a fixed ratio 1 (FR1). Cocaine levels could not be maintained with this procedure; instead the animals experienced 12 fast-rising spikes in cocaine levels each day. The IntA groups were compared with groups given 6-h FR1 long access and 2-h short access sessions and two other control groups. Here, we report that cocaine self-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase the motivation to self-administer cocaine.

Palmitoylethanolamide attenuates cocaine-induced behavioral sensitization and conditioned place preference in mice.

PubMed

Zambrana-Infantes, Emma; Rosell Del Valle, Cristina; Ladrón de Guevara-Miranda, David; Galeano, Pablo; Castilla-Ortega, Estela; Rodríguez De Fonseca, Fernando; Blanco, Eduardo; Santín, Luis Javier

2018-03-01

Cocaine addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking behaviors. Previous studies have demonstrated that cocaine, as well as other drugs of abuse, alters the levels of lipid-based signaling molecules, such as N-acylethanolamines (NAEs). Moreover, brain levels of NAEs have shown sensitivity to cocaine self-administration and extinction training in rodents. Given this background, the aim of this study was to investigate the effects of repeated or acute administration of palmitoylethanolamide (PEA), an endogenous NAE, on psychomotor sensitization and cocaine-induced contextual conditioning. To this end, the potential ability of repeated PEA administration (1 or 10 mg/kg, i.p.) to modulate the acquisition of cocaine-induced behavioral sensitization (BS) and conditioned place preference (CPP) was assessed in male C57BL/6J mice. In addition, the expression of cocaine-induced BS and CPP following acute PEA administration were also studied. Results showed that repeated administration of both doses of PEA were able to block the acquisition of cocaine-induced BS. Furthermore, acute administration of both doses of PEA was able to abolish the expression of BS, while the highest dose also abolished the expression of cocaine-induced CPP. Taken together, these results indicate that exogenous administration of PEA attenuated psychomotor sensitization, while the effect of PEA in cocaine-induced CPP depended on whether PEA was administered repeatedly or acutely. These findings could be relevant to understand the role that NAEs play in processes underlying the development and maintenance of cocaine addiction. Copyright © 2018 Elsevier Inc. All rights reserved.

Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex.

PubMed

McCarthy, Deirdre M; Bhide, Pradeep G

2012-01-01

Cocaine abuse during pregnancy produces harmful effects not only on the mother but also on the unborn child. The neurotransmitters dopamine and serotonin are known as the principal targets of the action of cocaine in the fetal and postnatal brain. However, recent evidence suggests that cocaine can impair cerebral cortical GABA neuron development and function. We sought to analyze the effects of prenatal cocaine exposure on the number and distribution of GABA and projection neurons (inhibitory interneurons and excitatory output neurons, respectively) in the mouse cerebral cortex. We found that the prenatal cocaine exposure decreased GABA neuron numbers and GABA-to-projection neuron ratio in the medial prefrontal cortex of 60-day-old mice. The neighboring prefrontal cortex did not show significant changes in either of these measures. However, there was a significant increase in projection neuron numbers in the prefrontal cortex but not in the medial prefrontal cortex. Thus, the effects of cocaine on GABA and projection neurons appear to be cortical region specific. The population of parvalbumin-immunoreactive GABA neurons was decreased in the medial prefrontal cortex following the prenatal cocaine exposure. The cocaine exposure also delayed the developmental decline in the volume of the medial prefrontal cortex. Thus, prenatal cocaine exposure produced persisting and region-specific effects on cortical cytoarchitecture and impaired the physiological balance between excitatory and inhibitory neurotransmission. These structural changes may underlie the electrophysiological and behavioral effects of prenatal cocaine exposure observed in animal models and human subjects. Copyright © 2012 S. Karger AG, Basel.

Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dewey, S.L.; Straughter-Moore, R.; Chen, R.

We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series ofmore » PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.« less

The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

PubMed Central

Yoo, Ji Hoon; Kitchen, Ian; Bailey, Alexis

2012-01-01

Cocaine addiction has become a major concern in the UK as Britain tops the European ‘league table’ for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse. PMID:22428846

Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

PubMed Central

Scofield, Michael D.; Rice, Kenner C.; Cheng, Kejun; Roques, Bernard P.

2014-01-01

The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse. PMID:24431463

A Subpopulation of Neurochemically-Identified Ventral Tegmental Area Dopamine Neurons Is Excited by Intravenous Cocaine

PubMed Central

Mejias-Aponte, Carlos A.; Ye, Changquan; Bonci, Antonello; Kiyatkin, Eugene A.

2015-01-01

Systemic administration of cocaine is thought to decrease the firing rates of ventral tegmental area (VTA) dopamine (DA) neurons. However, this view is based on categorizations of recorded neurons as DA neurons using preselected electrophysiological characteristics lacking neurochemical confirmation. Without applying cellular preselection, we recorded the impulse activity of VTA neurons in response to cocaine administration in anesthetized adult rats. The phenotype of recorded neurons was determined by their juxtacellular labeling and immunohistochemical detection of tyrosine hydroxylase (TH), a DA marker. We found that intravenous cocaine altered firing rates in the majority of recorded VTA neurons. Within the cocaine-responsive neurons, half of the population was excited and the other half was inhibited. Both populations had similar discharge rates and firing regularities, and most neurons did not exhibit changes in burst firing. Inhibited neurons were more abundant in the posterior VTA, whereas excited neurons were distributed evenly throughout the VTA. Cocaine-excited neurons were more likely to be excited by footshock. Within the subpopulation of TH-positive neurons, 36% were excited by cocaine and 64% were inhibited. Within the subpopulation of TH-negative neurons, 44% were excited and 28% were inhibited. Contrary to the prevailing view that all DA neurons are inhibited by cocaine, we found a subset of confirmed VTA DA neurons that is excited by systemic administration of cocaine. We provide evidence indicating that DA neurons are heterogeneous in their response to cocaine and that VTA non-DA neurons play an active role in processing systemic cocaine. PMID:25653355

Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats.

PubMed

Zakharova, E; Miller, J; Unterwald, E; Wade, D; Izenwasser, S

2009-10-20

This study was done to determine whether social and environmental factors alter cocaine reward and proteins implicated in mediating drug reward in rats during early adolescence. On postnatal day (PND) 23, rats were housed under conditions where both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone impoverished with no toys (II) or enriched with toys (IE). Social rats were housed two rats/cage with no toys (SI2) or with toys (SE2), or three/cage with (SE3) or without (SI3) toys. On PND 43, cocaine conditioned place preference (CPP) sessions began with the post-test done on PND 47. Cocaine CPP was established in response to 5 or 10 mg/kg cocaine in II rats, and CPP was decreased with the addition of cage mates or toys. No CPP was seen to any dose in SI3 or SE3 rats. Enriched housing (SE3) increased dopamine transporter (DAT) protein in the nucleus accumbens compared to II. There also were differential effects of cocaine on tyrosine hydroxylase and DAT depending on housing, with both increased by cocaine in II but not SE3 rats. DARPP-32 was unchanged by housing or cocaine, while phospho-Thr(34)-DARPP-32 was increased by cocaine treatment across conditions. Thus, both social and environmental enrichment decrease cocaine CPP during adolescence and different housing alters proteins that regulate dopaminergic neurotransmission in a manner that may account for the observed differences in cocaine-induced reward.

Differentiation of South American crack and domestic (US) crack cocaine via headspace-gas chromatography/mass spectrometry.

PubMed

Colley, Valerie L; Casale, John F

2015-03-01

South American 'crack' cocaine, produced directly from coca leaf, can be distinguished from US domestically produced crack on the basis of occluded solvent profiles. In addition, analysis of domestically produced crack indicates the solvents that were used for cocaine hydrochloride (HCl) processing in South America. Samples of cocaine base (N=3) from South America and cocaine from the USA (N=157 base, N=88 HCl) were analyzed by headspace-gas chromatography-mass spectrometry (HS-GC-MS) to determine their solvent profiles. Each cocaine HCl sample was then converted to crack cocaine using the traditional crack production method and re-examined by HS-GC-MS. The resulting occluded solvent profiles were then compared to their original HCl solvent profiles. Analysis of the corresponding crack samples confirmed the same primary processing solvents found in the original HCl samples, but at reduced levels. Domestically seized crack samples also contained reduced levels of base-to-HCl conversion solvents. In contrast, analysis of South American crack samples confirmed the presence of low to high boiling hydrocarbons and no base-to-HCl conversion solvents. The presented study showed analysis of crack cocaine samples provides data on which processing solvents were originally utilized in the production of cocaine HCl in South America, prior to conversion to crack cocaine. Determination of processing solvents provides valuable information to the counter-drug intelligence community and assists the law enforcement community in determining cocaine distribution and trafficking routes throughout the world. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.

PubMed

Murthy, Vishakantha; Geng, Liyi; Gao, Yang; Zhang, Bin; Miller, Jordan D; Reyes, Santiago; Brimijoin, Stephen

2015-08-01

Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.

Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death.

PubMed

Cao, Lu; Walker, Mary P; Vaidya, Naveen K; Fu, Mingui; Kumar, Santosh; Kumar, Anil

2016-09-01

Cocaine, a commonly used drug of abuse, has been shown to cause neuropathological dysfunction and damage in the human brain. However, the role of autophagy in this process is not defined. Autophagy, generally protective in nature, can also be destructive leading to autophagic cell death. This study was designed to investigate whether cocaine induces autophagy in the cells of CNS origin. We employed astrocyte, the most abundant cell in the CNS, to define the effects of cocaine on autophagy. We measured levels of the autophagic marker protein LC3II in SVGA astrocytes after exposure with cocaine. The results showed that cocaine caused an increase in LC3II level in a dose- and time-dependent manner, with the peak observed at 1 mM cocaine after 6-h exposure. This result was also confirmed by detecting LC3II in SVGA astrocytes using confocal microscopy and transmission electron microscopy. Next, we sought to explore the mechanism by which cocaine induces the autophagic response. We found that cocaine-induced autophagy was mediated by sigma 1 receptor, and autophagy signaling proteins p-mTOR, Atg5, Atg7, and p-Bcl-2/Beclin-1 were also involved, and this was confirmed by using selective inhibitors and small interfering RNAs (siRNAs). In addition, we found that chronic treatment with cocaine resulted in cell death, which is caspase-3 independent and can be ameliorated by autophagy inhibitor. Therefore, this study demonstrated that cocaine induces autophagy in astrocytes and is associated with autophagic cell death.

Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys.

PubMed

Schwienteck, Kathryn L; Negus, S Stevens; Poklis, Justin L; Banks, Matthew L

2015-10-01

One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in rhesus monkeys (Macaca mulatta). For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine versus food choice during continuous saline and nicotine treatment. Rhesus monkeys (N = 3) responded under a concurrent schedule of food pellet (1 g) and intravenous cocaine (0-0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1-1.0 mg/kg/hr, intravenous) were continuously infused for 7-day treatment periods and separated by 24-hr saline treatment periods. Acute effects of mecamylamine (0.32-1.8 mg/kg, intramuscular, 15 min pretreatment) were determined during continuous saline and 0.32-mg/kg/hr nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine versus food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 hr following termination of 0.32-mg/kg/hr nicotine treatment, despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/hr, does not enhance cocaine choice and does not produce nicotine dependence, as demonstrated by the lack of abstinence signs. (c) 2015 APA, all rights reserved).

Quantitative electroencephalographic studies of cue-induced cocaine craving.

PubMed

Reid, Malcolm S; Prichep, Leslie S; Ciplet, Debra; O'Leary, Siobhan; Tom, MeeLee; Howard, Bryant; Rotrosen, John; John, E Roy

2003-07-01

Quantitative electroencephalographic (qEEG) profiles were studied in cocaine dependent patients in response to cocaine cue exposure. Using neurometric analytical methods, the spectral power of each primary bandwidth was computed and topographically mapped. Additional measures of cue-reactivity included cocaine craving, anxiety and related subjective ratings, and physiological measures of skin conductance, skin temperature, heart rate, and plasma cortisol and HVA levels. Twenty-four crack cocaine-dependent subjects were tested for their response to tactile, visual and audio cues related to crack cocaine or neutral items. All measures were analyzed for significant difference by comparing cocaine versus neutral cue conditions. An increase in cocaine craving, anxiety and related subjective ratings, elevated plasma cortisol levels, and a decrease in skin temperature, were induced by cocaine cue exposure. Distinct qEEG profiles were found during the paraphernalia handling and video viewing (eyes-open), and guided imagery (eyes-closed), phases of cocaine cue exposure. During paraphernalia handling and video viewing, there was an increase in beta activity accompanied by a drop in delta power in the frontal cortex, and an increase in beta mean frequency in the occipital cortex. In contrast, during guided imagery there was an increase in theta and delta power in the frontal cortex, and an increase in beta power in the occipital cortex. Correlation analyses revealed that cue-induced anxiety during paraphernalia handling and video viewing was associated with reduced high frequency and enhanced low frequency EEG activity. These findings demonstrated that EEG activation during cue-induced cocaine craving may be topographically mapped and subsequently analyzed for functional relevance.

A Randomized, Double-Blind, Placebo-Controlled Trial of Citicoline for Cocaine Dependence in Bipolar I Disorder.

PubMed

Brown, E Sherwood; Todd, Jackie Peterson; Hu, Lisa T; Schmitz, Joy M; Carmody, Thomas J; Nakamura, Alyson; Sunderajan, Prabha; Rush, A John; Adinoff, Bryon; Bret, Mary Ellen; Holmes, Traci; Lo, Alexander

2015-10-01

Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use. A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale. In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed. Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.

Mesolimbic leptin signaling negatively regulates cocaine-conditioned reward.

PubMed

Shen, M; Jiang, C; Liu, P; Wang, F; Ma, L

2016-12-06

The regulatory mechanisms underlying the response to addictive drugs are complex, and increasing evidence indicates that there is a role for appetite-regulating pathways in substance abuse. Leptin, an important adipose hormone that regulates energy balance and appetite, exerts its physiological functions via leptin receptors. However, the role of leptin signaling in regulating the response to cocaine remains unclear. Here we examined the potential role of leptin signaling in cocaine reward using a conditioned place preference (CPP) procedure. Our results showed that inhibition of leptin signaling by intracerebroventricular infusion of the leptin receptor (LepR) antagonist SMLA during cocaine conditioning increased the cocaine-CPP and upregulated the level of dopamine and its metabolites in the nucleus accumbens (NAc). We then selectively knocked down the LepR in the mesolimbic ventral tegmental area (VTA), NAc core and central amygdala (CeA) by injecting AAV-Cre into Lepr flox/flox mice. LepR deletion in the VTA increased the dopamine levels in the NAc and enhanced the cocaine-conditioned reward. LepR deletion in the NAc core enhanced the cocaine-conditioned reward and impaired the effect of the D2-dopamine receptor on cocaine-CPP, whereas LepR deletion in the CeA had no effect on cocaine-CPP but increased the anxiety level of mice. In addition, prior exposure to saccharin increased LepR mRNA and STAT3 phosphorylation in the NAc and VTA and impaired cocaine-CPP. These results indicate that leptin signaling is critically involved in cocaine-conditioned reward and the regulation of drug reward by a natural reward and that these effects are dependent on mesolimbic LepR.

Snow Control - An RCT protocol for a web-based self-help therapy to reduce cocaine consumption in problematic cocaine users

PubMed Central

2011-01-01

Background Cocaine use has increased in most European countries, including Switzerland, and many states worldwide. The international literature has described treatment models that target the general population. In addition to supplying informative measures at the level of primary and secondary prevention, the literature also offers web-based self-help tools for problematic substance users, which is in line with tertiary prevention. Such programs, however, have been primarily tested on individuals with problematic alcohol and cannabis consumption, but not on cocaine-dependent individuals. Methods/Design This paper presents the protocol of a randomised clinical trial to test the effectiveness of a web-based self-help therapy to reduce cocaine use in problematic cocaine users. The primary outcome is severity of cocaine dependence. Secondary outcome measures include cocaine craving, consumption of cocaine and other substances of abuse in the past month, and changes in depression characteristics. The therapy group will receive a 6-week self-help therapy to reduce cocaine consumption based on methods of Cognitive Behavioural Therapy, principles of Motivational Interviewing and self-control practices. The control group will be presented weekly psycho-educative information with a quiz. The predictive validity of participant characteristics on treatment retention and outcome will be explored. Discussion To the best of our knowledge, this will be the first randomised clinical trial to test the effectiveness of online self-help therapy to reduce or abstain from cocaine use. It will also investigate predictors of outcome and retention. This trial is registered at Current Controlled Trials and is traceable as NTR-ISRCTN93702927. PMID:21943294

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats.

PubMed

Buffalari, Deanne M; Feltenstein, Matthew W; See, Ronald E

2013-11-01

Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success. The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration. Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction. Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test. Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.

Association between oral mucosal lesions and crack and cocaine addiction in men: a cross-sectional study.

PubMed

Cury, Patricia Ramos; Araujo, Nara Santos; das Graças Alonso Oliveira, Maria; Dos Santos, Jean Nunes

2018-05-08

The aim of this cross-sectional study was to evaluate the prevalence of oral mucosal lesions (OMLs) and their association with crack/cocaine addiction in men. Clinical oral examination was performed in 161 adult male patients at the School of Dentistry of the Federal University of Bahia, Brazil. Crack/cocaine addiction was determined from the medical records, and all drug-addicted individuals used both crack and cocaine. All participants (40 crack/cocaine-addicted men and 121 non-addicted men) underwent a systematic evaluation of the lips, labial mucosa, commissures, buccal mucosa and sulcus, gingiva and alveolar ridge, tongue, floor of the mouth, and soft and hard palate by a single examiner. Bivariate and regression analyses were conducted to assess for the presence of OMLs and the association of OMLs with crack/cocaine addiction. OMLs were found in 22 participants with a significantly greater prevalence in the crack/cocaine-addicted group (25 vs. 9.9%; p = 0.01). The most prevalent types of lesions in the addicted group were traumatic ulcer and actinic cheilitis (7.5% for each) followed by fistulae associated with a retained dental root (5%). After adjusting for covariates, crack/cocaine addiction was significantly associated with OMLs (OR = 2.87; 95% CI = 1.08-7.67; p = 0.03). The prevalence of OMLs was higher in crack/cocaine-addicted individuals, and crack/cocaine addiction was significantly associated with OMLs. A public health program aimed at the early diagnosis and treatment of OMLs is vital to improving the oral health status of individuals addicted to crack/cocaine.

Side effects of cocaine abuse: multiorgan toxicity and pathological consequences.

PubMed

Riezzo, I; Fiore, C; De Carlo, D; Pascale, N; Neri, M; Turillazzi, E; Fineschi, V

2012-01-01

Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

Neuroticism associated with cocaine-induced psychosis in cocaine-dependent patients: a cross-sectional observational study.

PubMed

Roncero, Carlos; Daigre, Constanza; Barral, Carmen; Ros-Cucurull, Elena; Grau-López, Lara; Rodríguez-Cintas, Laia; Tarifa, Nuria; Casas, Miguel; Valero, Sergi

2014-01-01

Cocaine consumption can induce transient psychotic symptoms, which has been correlated with more severe addiction and aggressive behavior. However, little is known about the nature of the relationship between personality traits and psychotic symptoms in cocaine-dependent patients. This study examined the relationship between neuroticism and cocaine-induced psychosis. A total of 231 cocaine-dependent patients seeking treatment were recruited to the study. Personality was evaluated by the Zuckerman-Kuhlman Personality Questionnaire. Cocaine-induced psychosis questionnaire, SCID-I, and SCID-II were used to evaluate comorbidity and clinical characteristics. Data analysis was performed in three steps: descriptive, bivariate, and multivariate analyses. Cocaine-induced psychosis was reported in 65.4% of the patients and some personality disorder in 46.8%. Two personality dimensions (Neuroticism-Anxiety and Aggression-Hostility) presented a significant effect on the risk of experiencing psychotic symptoms (t(229) = 2.69, p = 0.008; t(229) = 2.06, p = 0.004), and patients with psychotic symptoms showed higher scores in both variables. On the multivariate analysis, only Neuroticism remained as a significant personality factor independently associated with psychotic symptoms (Wald = 7.44, p<0.05, OR = 1.08, CI 95% 1.02-1.16) after controlling for age, gender and number of consumption substances. An association between high neuroticism scores and presence of psychotic symptoms induced by cocaine has been found, independently of other consumption variables. Personality dimensions should be evaluated in cocaine-dependent patients in order to detect high scores of neuroticism and warn patients about the risk of developing cocaine-induced psychotic symptoms.

Cocaine-mediated autophagy in astrocytes involves sigma 1 receptor, PI3K, m-TOR, Atg5/7, Beclin-1 and induces Type II programed cell death

PubMed Central

Cao, Lu; Walker, Mary P; Vaidya, Naveen K; Fu, Mingui; Kumar, Santosh; Kumar, Anil

2015-01-01

Cocaine, a commonly used drug of abuse, has been shown to cause neuropathological dysfunction and damage in the human brain. However, the role of autophagy in this process is not defined. Autophagy generally protective in nature, can also be destructive leading to autophagic cell death. This study was designed to investigate whether cocaine induces autophagy in the cells of CNS origin. We employed astrocyte, the most abundant cell in the CNS, to define the effects of cocaine on autophagy. We measured levels of the autophagic marker protein LC3II in SVGA astrocytes after exposure with cocaine. The results showed that cocaine caused an increase in LC3II level in a dose- and time-dependent manner, with the peak observed at 1 mM cocaine after 6 hours exposure. This result was also confirmed by detecting LC3II in SVGA astrocytes using confocal microscopy and transmission electron microscopy. Next, we sought to explore the mechanism by which cocaine induces the autophagic response. We found that cocaine-induced autophagy was mediated by sigma 1 receptor, and autophagy signaling proteins p-mTOR, Atg5, Atg7 and p-Bcl-2/Beclin-1 were also involved and this was confirmed by using selective inhibitors and siRNAs. In addition, we found that chronic treatment with cocaine resulted in cell death, which is caspase-3 independent, and can be ameliorated by autophagy inhibitor. Therefore, this study demonstrated that cocaine induces autophagy in astrocytes and is associated with autophagic cell death. PMID:26243186

Effects of continuous nicotine treatment and subsequent termination on cocaine vs. food choice in male rhesus monkeys

PubMed Central

Schwienteck, Kathryn L.; Negus, S. Stevens; Poklis, Justin L.; Banks, Matthew L.

2015-01-01

One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine vs. food choice in rhesus monkeys. For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine vs. food choice during continuous saline and nicotine treatment. Rhesus monkeys (n=3) responded under a concurrent schedule of food pellet (1g) and intravenous cocaine (0 – 0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1 – 1.0 mg/kg/h, IV) were continuously infused for 7-day treatment periods and separated by 24 h saline treatment periods. Acute effects of mecamylamine (0.32 – 1.8 mg/kg, IM, 15 min pretreatment) were determined during continuous saline and 0.32 mg/kg/h nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine vs. food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 h following termination of 0.32 mg/kg/h nicotine treatment despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/h, does not enhance cocaine choice and does not produce nicotine dependence as demonstrated by the lack of abstinence signs. PMID:26098473

Prenatal Cocaine Exposure and Infant Cortisol Reactivity

ERIC Educational Resources Information Center

Eiden, Rina D.; Veira, Yvette; Granger, Douglas A.

2009-01-01

This study examined the effects of prenatal cocaine exposure on infant hypothalamic-pituitary-adrenal axis activity and reactivity at 7 months of infant age. Participants were 168 caregiver-infant dyads (87 cocaine exposed, 81 not cocaine exposed; 47% boys). Maternal behavior, caregiving instability, and infant growth and behavior were assessed,…

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

A Southern Command Military Campaign against Drug Operations

DTIC Science & Technology

1989-05-01

Peruvian and Bolivian cocaine is refined in Columbia and transported to the US. Although, some of the cocaine is also transported through Brazil and...effects of cocaine are unpredictable. There have been cases of a single use bringing death. In 1986 cocaine poisoning took the life of football star Don

Molecular approaches to treatments for cocaine abuse

NASA Astrophysics Data System (ADS)

Flippen-Anderson, Judith L.; George, Clifford; Deschamps, Jeffrey R.

2003-02-01

Cocaine is a potent stimulant of the central nervous system with severe addiction potential. Its abuse is a major problem worldwide. The exact mechanism of action of cocaine is still uncertain but it is known that its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). This paper discusses efforts that are underway to identify ligands for possible use in the treatment of cocaine abuse. Much of this effort has been focussed on understanding cocaine interactions at DAT receptor sites.

Cargo contraband screening

NASA Astrophysics Data System (ADS)

Kim, L. H.; Danylewich-May, Lucy L.; Jadamec, Joseph R.; Su, Chih-Wu; Rigdon, Stephen W.; Norwood, LaVan J.; Hoglund, David E.

1994-10-01

The IONSCANTM operating parameters for detection of benzoic acid and acetic acid have been optimized. Various materials and chromatographic coatings were investigated for the vapor preconcentration of benzoic acid, acetic acid and cocaine. Limited field trials indicated a possibility of detecting benzoic acid from seized cocaine shipment. From the laboratory investigation and some field tests it has been shown that cocaine free base is present in cocaine hydrochloride in sufficiently high concentration to provide constant supply of cocaine vapors in the headspace for a long period of time.

Self-Efficacy for Cocaine Abstinence: Pretreatment Correlates and Relationship to Outcomes

PubMed Central

Dolan, Sara L.; Martin, Rosemarie A.; Rohsenow, Damaris J.

2009-01-01

Little research has been conducted on the relationship of self-efficacy at treatment entry to individual differences or to treatment outcome for patients with cocaine dependence. Those relationships were examined in 163 cocaine dependent patients in a residential treatment program using two measures of self-efficacy administered in the first week of treatment: beliefs about success in quitting in general and confidence about not using in 11 cocaine-specific high-risk situations. The most robust correlates of self-efficacy were greater desire to stop using and lower urge to use in high-risk situations. Age, depressive symptoms, cognitive functioning, recent substance use, and past success with quitting also correlated with self-efficacy. Both measures of self-efficacy predicted quantity and frequency of cocaine use and abstinence at 3 but not 6 months after treatment after controlling pretreatment cocaine use. Results suggest that treatments should target self-efficacy in cocaine-dependent patients. PMID:18191329

Vaccines for cocaine abuse.

PubMed

Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Kosten, Thomas R

2009-04-01

Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.

Dancing on coke: smuggling cocaine dispersed in polyvinyl alcohol.

PubMed

van Nuijs, Alexander L N; Maudens, Kristof E; Lambert, Willy E; Van Calenbergh, Serge; Risseeuw, Martijn D P; Van hee, Paul; Covaci, Adrian; Neels, Hugo

2012-01-01

Recent trends suggest that cocaine smugglers have become more and more inventive to avoid seizures of large amounts of cocaine transported between countries. We report a case of a mail parcel containing a dance pad which was seized at the Customs Department of Brussels Airport, Belgium. After investigation, the inside of the dance pad was found to contain a thick polymer, which tested positive for cocaine. Analysis was performed using a routine colorimetric swipe test, gas chromatography coupled with mass spectrometry and nuclear magnetic resonance spectroscopy. The polymer was identified as polyvinyl alcohol (PVA) and contained 18% cocaine, corresponding to a street value of € 20,000. Laboratory experiments showed that cocaine could be easily extracted from the PVA matrix. This case report reveals a new smuggling technique for the transportation of large amounts of cocaine from one country to another. © 2011 American Academy of Forensic Sciences.

Neurobehavioral Syndromes in Cocaine-Exposed Newborn Infants.

ERIC Educational Resources Information Center

Lester, Barry M.; And Others

1991-01-01

The effects of fetal cocaine exposure on newborn cry characteristics were studied in 80 cocaine-exposed and 80 control infants. Findings were consistent with the notion that two neurobehavioral syndromes, excitable and depressed, can be described in cocaine-exposed infants and that these two syndromes are a result of direct neurotoxic effects and…

Lifestyle Differences between Young Adult Cocaine Users and Their Nonuser Peers.

ERIC Educational Resources Information Center

Castro, Felipe G.; And Others

1987-01-01

Examined health-related behaviors in 25 young adult cocaine users and 25 matched nonusers. Found cocaine users consumed more coffee and alcohol, and fewer balanced meals, than did nonusers. Users reported less relaxation and daily organization than did nonusers. Suggests that cocaine use is embedded in complex of interrelated unhealthy behaviors;…

Cocaine Directly Impairs Memory Extinction and Alters Brain DNA Methylation Dynamics in Honey Bees.

PubMed

Søvik, Eirik; Berthier, Pauline; Klare, William P; Helliwell, Paul; Buckle, Edwina L S; Plath, Jenny A; Barron, Andrew B; Maleszka, Ryszard

2018-01-01

Drug addiction is a chronic relapsing behavioral disorder. The high relapse rate has often been attributed to the perseverance of drug-associated memories due to high incentive salience of stimuli learnt under the influence of drugs. Drug addiction has also been interpreted as a memory disorder since drug associated memories are unusually enduring and some drugs, such as cocaine, interfere with neuroepigenetic machinery known to be involved in memory processing. Here we used the honey bee (an established invertebrate model for epigenomics and behavioral studies) to examine whether or not cocaine affects memory processing independently of its effect on incentive salience. Using the proboscis extension reflex training paradigm we found that cocaine strongly impairs consolidation of extinction memory. Based on correlation between the observed effect of cocaine on learning and expression of epigenetic processes, we propose that cocaine interferes with memory processing independently of incentive salience by directly altering DNA methylation dynamics. Our findings emphasize the impact of cocaine on memory systems, with relevance for understanding how cocaine can have such an enduring impact on behavior.

Cocaine Directly Impairs Memory Extinction and Alters Brain DNA Methylation Dynamics in Honey Bees

PubMed Central

Søvik, Eirik; Berthier, Pauline; Klare, William P.; Helliwell, Paul; Buckle, Edwina L. S.; Plath, Jenny A.; Barron, Andrew B.; Maleszka, Ryszard

2018-01-01

Drug addiction is a chronic relapsing behavioral disorder. The high relapse rate has often been attributed to the perseverance of drug-associated memories due to high incentive salience of stimuli learnt under the influence of drugs. Drug addiction has also been interpreted as a memory disorder since drug associated memories are unusually enduring and some drugs, such as cocaine, interfere with neuroepigenetic machinery known to be involved in memory processing. Here we used the honey bee (an established invertebrate model for epigenomics and behavioral studies) to examine whether or not cocaine affects memory processing independently of its effect on incentive salience. Using the proboscis extension reflex training paradigm we found that cocaine strongly impairs consolidation of extinction memory. Based on correlation between the observed effect of cocaine on learning and expression of epigenetic processes, we propose that cocaine interferes with memory processing independently of incentive salience by directly altering DNA methylation dynamics. Our findings emphasize the impact of cocaine on memory systems, with relevance for understanding how cocaine can have such an enduring impact on behavior. PMID:29487536

Maternal Cocaine Use: Estimated Effects on Mother-Child Play Interactions in the Preschool Period

PubMed Central

Johnson, Arnise L.; Morrow, Connie E.; Accornero, Veronica H.; Xue, Lihua; Anthony, James C.; Bandstra, Emmalee S.

2009-01-01

The study objective was to evaluate the quality of parent-child interactions in preschool-aged children exposed prenatally to cocaine. African-American mothers and their full-term newborns (n = 343) were enrolled prospectively at birth and classified as either prenatally cocaine-exposed (n = 157) or non–cocaine-exposed (n = 186) on the basis of maternal self-report and bioassays. Follow-up evaluations at 3 years of age (mean age, 40 mo) included a videotaped dyadic play session and maternal interviews to assess ongoing drug use and maternal psychological distress. Play interactions were coded using a modified version of Egeland et al’s Teaching Task coding scheme. Regression analyses indicated cocaine-associated deficits in mother-child interaction, even with statistical adjustment for multiple suspected influences on interaction dynamics. Mother-child interactions were most impaired in cocaine-exposed dyads when the mother continued to report cocaine use at the 3-year follow-up. Multivariate profile analysis of the Egeland interaction subscales indicated greater maternal intrusiveness and hostility, poorer quality of instruction, lower maternal confidence, and diminished child persistence in the cocaine-exposed dyads. PMID:12177564

A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis.

PubMed

Castilla-Ortega, Estela; Serrano, Antonia; Blanco, Eduardo; Araos, Pedro; Suárez, Juan; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Santín, Luis J

2016-07-01

Cocaine addiction is a chronic brain disease in which the drug seeking habits and profound cognitive, emotional and motivational alterations emerge from drug-induced neuroadaptations on a vulnerable brain. Therefore, a 'cocaine addiction brain circuit' has been described to explain this disorder. Studies in both cocaine patients and rodents reveal the hippocampus as a main node in the cocaine addiction circuit. The contribution of the hippocampus to cocaine craving and the associated memories is essential to understand the chronic relapsing nature of addiction, which is the main obstacle for the recovery. Interestingly, the hippocampus holds a particular form of plasticity that is rare in the adult brain: the ability to generate new functional neurons. There is an active scientific debate on the contributions of these new neurons to the addicted brain. This review focuses on the potential role(s) of adult hippocampal neurogenesis (AHN) in cocaine addiction. Although the current evidence primarily originates from animal research, these preclinical studies support AHN as a relevant component for the hippocampal effects of cocaine. Copyright © 2016 Elsevier Ltd. All rights reserved.

Salivary buffer capacity, pH, and stimulated flow rate of crack cocaine users.

PubMed

Woyceichoski, Iverson Ernani Cogo; Costa, Carlos Henrique; de Araújo, Cristiano Miranda; Brancher, João Armando; Resende, Luciane Grochocki; Vieira, Iran; de Lima, Antonio Adilson Soares

2013-08-01

Crack cocaine is the freebase form of cocaine that can be smoked. The use of this drug has been considered a public health problem in many countries. The aim of this study was to assess the stimulated salivary flow rate (SSFR), pH, and the buffer capacity of saliva in crack cocaine users. Stimulated whole saliva was collected from 54 selected crack cocaine users and 40 non-users. All samples were analyzed for SSFR, pH, and buffer capacity. SSFR was analyzed by gravimetric method. The buffer capacity and pH were determined using a digital pH meter. The crack cocaine users demonstrated higher buffer capacity than the control group (P > 0.05). Salivary pH was lower in crack cocaine users (P < 0.05). Mean values of the SSFR for the experimental and control groups were 1.1 and 1.3 mL/min, respectively (P > 0.05). Crack cocaine users might exhibit a significant decrease in salivary pH, but not in salivary flow rate or buffer capacity. © 2012 Blackwell Publishing Asia Pty Ltd.

Biphasic alterations in serotonin-1B (5-HT1B) receptor function during abstinence from extended cocaine self-administration.

PubMed

O'Dell, Laura E; Manzardo, Ann M; Polis, Ilham; Stouffer, David G; Parsons, Loren H

2006-12-01

Alterations in 5-HT1B receptor function during cocaine abstinence were evaluated in rats given either limited- or extended access (LA and EA, respectively) to cocaine self-administration. The locomotor response to the 5-HT1B/1A agonist RU24969 was significantly reduced in cocaine-experienced animals relative to cocaine-naïve controls following 6 h of abstinence but became sensitized over the subsequent 14 days of abstinence. Both the early phase subsensitivity and later phase supersensivity to RU 24969-induced activity were greater in EA versus LA animals. Intra-nucleus accumbens administration of the 5-HT1B agonist CP 93, 129 produced significantly greater increases in dialysate dopamine levels in EA versus control animals following 14 days of abstinence. However, there was no difference between EA and cocaine-naïve control animals in the augmentation of cocaine-induced increases in nucleus accumbens DA produced by intra-VTA CP 93, 129. Collectively these findings demonstrate that 5-HT1B receptor function is persistently altered by cocaine self-administration.

Prevalence and correlates of crack-cocaine injection among young injection drug users in the United States, 1997-1999.

PubMed

Santibanez, Scott S; Garfein, Richard S; Swartzendruber, Andrea; Kerndt, Peter R; Morse, Edward; Ompad, Danielle; Strathdee, Steffanie; Williams, Ian T; Friedman, Samuel R; Ouellet, Lawrence J

2005-03-07

We estimated prevalence and identified correlates of crack-cocaine injection among young injection drug users in the United States. We analyzed data from the second Collaborative Injection Drug Users Study (CIDUS II), a 1997-1999 cohort study of 18-30-year-old, street-recruited injection drug users from six US cities. Crack-cocaine injection was reported by 329 (15%) of 2198 participants. Prevalence varied considerably by site (range, 1.5-28.0%). No participants injected only crack-cocaine. At four sites where crack-cocaine injection prevalence was greater than 10%, recent (past 6 months) crack-cocaine injection was correlated with recent daily injection and sharing of syringes, equipment, and drug solution. Lifetime crack-cocaine injection was correlated with using shooting galleries, initiating others into drug injection, and having serologic evidence of hepatitis B virus and hepatitis C virus infection. Crack-cocaine injection may be a marker for high-risk behaviors that can be used to direct efforts to prevent HIV and other blood-borne viral infections.

Acute morphine and cocaine related death after trimethoprim-adultered cocaine abuse.

PubMed

Fucci, Nadia; Pascali, Vincenzo L

2014-01-01

Over the last few decades, cocaine and morphine (heroin) have been among the primary causes of deaths related to drug abuse. Cocaine is frequently altered by dilution, substitution, contamination, and adulteration. Trimethoprim has never been identified in the powders of cocaine, making this the first post-mortem case report in which the presence of this compound is described. The case reported here is that of a 46-year-old woman with a history of cocaine and morphine abuse who was found dead inside her bathroom. The police found the corpse next to a syringe, with a telephone card containing trace of cocaine on the sink. Toxicological analysis was performed, and drug levels were measured by means of gas chromatography/mass spectrometry. In addition to the presence of cocaine and smaller alkaloids, trimethoprim was also detected on the syringe and telephone card and in the woman's nasal mucosa. Trimethoprim analysis is very quick and easy and can be added to the routine analysis of drugs of abuse seized on the illicit market to obtain more information. © 2014 by the Association of Clinical Scientists, Inc.

Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users

PubMed Central

Wesley, Michael J.; Lohrenz, Terry; Koffarnus, Mikhail N.; McClure, Samuel M.; De La Garza, Richard; Salas, Ramiro; Thompson-Lake, Daisy G. Y.; Newton, Thomas F.; Bickel, Warren K.; Montague, P. Read

2014-01-01

Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC. PMID:25197609

Acute effects of cocaine and cannabis on reversal learning as a function of COMT and DRD2 genotype.

PubMed

Spronk, Desirée B; Van der Schaaf, Marieke E; Cools, Roshan; De Bruijn, Ellen R A; Franke, Barbara; van Wel, Janelle H P; Ramaekers, Johannes G; Verkes, Robbert J

2016-01-01

Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known. In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype. A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning. Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning. These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene.

Among long-term crack smokers, who avoids and who succumbs to cocaine addiction?

PubMed

Falck, Russel S; Wang, Jichuan; Carlson, Robert G

2008-11-01

Crack cocaine is a highly addictive drug. To learn more about crack addiction, long-term crack smokers who had never met the DSM-IV criteria for lifetime cocaine dependence were compared with those who had. The study sample consisted of crack users (n=172) from the Dayton, Ohio, area who were interviewed periodically over 8 years. Data were collected on a range of variables including age of crack initiation, frequency of recent use, and lifetime cocaine dependence. Cocaine dependence was common with 62.8% of the sample having experienced it. There were no statistically significant differences between dependent and non-dependent users for age of crack initiation or frequency of crack use. In terms of sociodemographics, only race/ethnicity was significant, with proportionally fewer African-Americans than whites meeting the criteria for cocaine dependence. Controlling for sociodemographics, partial correlation analysis showed positive, statistically significant relationships between lifetime cocaine dependence and anti-social personality disorder, attention deficit/hyperactivity disorder, and lifetime dependence on alcohol, cannabis, amphetamine, sedative-hypnotics, and opioids. These results highlight the importance addressing race/ethnicity and comorbid disorders when developing, implementing, and evaluating interventions targeting people who use crack cocaine. Additional research is needed to better understand the role of race/ethnicity in the development of cocaine dependence resulting from crack use.

Effects of inhibitory GABA-active neurosteroids on cocaine seeking and cocaine taking in rats.

PubMed

Schmoutz, Christopher D; Runyon, Scott P; Goeders, Nicholas E

2014-09-01

Several compounds that potentiate GABA-induced inhibitory currents also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds that reduce stress-induced responses might be efficacious in treating addiction. Since endogenous neurosteroids such as allopregnanolone may function in a manner similar to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli, we hypothesized that exogenously applied neurosteroids would reduce cocaine reinforcement in two animal models. Male Wistar rats were trained to self-administer cocaine and food under a concurrent alternating operant schedule of reinforcement. Two separate groups of rats were trained to self-administer cocaine or food pellets and were then exposed to similar cue-induced reinstatement paradigms. Both groups of rats were pretreated with various doses of neurosteroids. Allopregnanolone and 3α-hydroxy-3β-methyl-17β-nitro-5α-androstane (R6305-7, a synthetic neurosteroid) were ineffective in selectively decreasing cocaine relative to food self-administration. On the other hand, both allopregnanolone and R6305-7 significantly decreased the cue-induced reinstatement of extinguished cocaine seeking, confirmed by one-way ANOVA. These results suggest that neurosteroids may be effective in reducing the relapse to cocaine use without affecting ongoing cocaine self-administration.

Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse.

PubMed

Feltenstein, Matthew W; Altar, C Anthony; See, Ronald E

2007-03-01

Aripiprazole (Abilify) is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D2 receptors and low side effects. Based on pharmacologic properties that include a stabilization of mesocorticolimbic DA activity, a pathway implicated in addiction, aripiprazole was tested for its ability to prevent relapse to cocaine seeking in rats. We assessed the dose-dependent effects of aripiprazole on conditioned cue-induced and cocaine-primed reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. Aripiprazole potently and dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned-cued reinstatement. Aripiprazole was effective at doses that failed to alter cocaine self-administration, food self-administration, reinstatement of food-seeking behavior, or basal locomotor activity, suggesting selective effects of aripiprazole on motivated drug-seeking behavior. These results in a relapse model show that aripiprazole can block cocaine seeking without affecting other behaviors. The D2 partial agonist properties of aripiprazole likely account for the blockade of reinstatement of cocaine-seeking behavior. Given its established efficacy and tolerability as a treatment for psychosis, aripiprazole may be an excellent therapeutic choice for reducing craving and preventing relapse in people with cocaine dependency.

Magnetic dispersive solid-phase extraction based on modified magnetic nanoparticles for the detection of cocaine and cocaine metabolites in human urine by high-performance liquid chromatography-mass spectrometry.

PubMed

Yang, Feiyu; Zou, Yun; Ni, Chunfang; Wang, Rong; Wu, Min; Liang, Chen; Zhang, Jiabin; Yuan, Xiaoliang; Liu, Wenbin

2017-11-01

An easy-to-handle magnetic dispersive solid-phase extraction procedure was developed for preconcentration and extraction of cocaine and cocaine metabolites in human urine. Divinyl benzene and vinyl pyrrolidone functionalized silanized Fe 3 O 4 nanoparticles were synthesized and used as adsorbents in this procedure. Scanning electron microscopy, vibrating sample magnetometry, and infrared spectroscopy were employed to characterize the modified adsorbents. A high-performance liquid chromatography with mass spectrometry method for determination of cocaine and its metabolites in human urine sample has been developed with pretreatment of the samples by magnetic dispersive solid-phase extraction. The obtained results demonstrated the higher extraction capacity of the prepared nanoparticles with recoveries between 75.1 to 105.7% and correlation coefficients higher than 0.9971. The limits of detection for the cocaine and cocaine metabolites were 0.09-1.10 ng/mL. The proposed magnetic dispersive solid-phase extraction method provided a rapid, environmentally friendly and magnetic stuff recyclable approach and it was confirmed that the prepared adsorbents material was a kind of highly effective extraction materials for the trace cocaine and cocaine metabolites analyses in human urine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Norepinephrine signaling through β-adrenergic receptors is critical for expression of cocaine-induced anxiety

PubMed Central

Schank, Jesse R.; Liles, L. Cameron; Weinshenker, David

2008-01-01

Background Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine’s rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. Methods In this study we evaluated the performance of dopamine β-hydroxylase knockout (Dbh −/−) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. Results We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/−) mice, as measured by a decrease in open arm exploration. Dbh −/− mice had normal baseline performance in the EPM, but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/− mice following administration of disulfiram, a DBH inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the β-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/− and wild-type C57BL6/J mice, while the α1 antagonist prazosin and the α2 antagonist yohimbine had no effect. Conclusions These results indicate that noradrenergic signaling via β-adrenergic receptors is required for cocaine-induced anxiety in mice. PMID:18083142

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine.

PubMed

Brodnik, Zachary D; Black, Emily M; Clark, Meagan J; Kornsey, Kristen N; Snyder, Nathaniel W; España, Rodrigo A

2017-10-01

Patients with post-traumatic stress disorder have a heightened vulnerability to developing substance use disorders; however, the biological underpinnings of this vulnerability remain unresolved. We used the predator odor stress model of post-traumatic stress disorder with segregation of subjects as susceptible or resilient based on elevated plus maze behavior and context avoidance. We then determined behavioral and neurochemical differences across susceptible, resilient, and control populations using a panel of behavioral and neurochemical assays. Susceptible subjects showed a significant increase in the motoric and dopaminergic effects of cocaine, and this corresponded with heightened motivation to self-administer cocaine. Resilient subjects did not show differences in the motoric effects of cocaine, in dopamine signaling in vivo, or in any measure of cocaine self-administration. Nonetheless, we found that these animals displayed elevations in both the dopamine release-promoting effects of cocaine and dopamine autoreceptor sensitivity ex vivo. Our results suggest that the experience of traumatic stress may produce alterations in dopamine systems that drive elevations in cocaine self-administration behavior in susceptible subjects, but may also produce both active and passive forms of resilience that function to prevent gross changes in cocaine's reinforcing efficacy in resilient subjects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Concurrent crack and powder cocaine users from Sao Paulo: Do they represent a different group?

PubMed Central

Guindalini, Camila; Vallada, Homero; Breen, Gerome; Laranjeira, Ronaldo

2006-01-01

Background Cocaine abuse is a serious and socially damaging illegal drug problem. Different routes of administration are associated with a specific progression of use, different degrees of abuse liability, propensity for dependence and treatment response. There have been relatively few studies comparing different cocaine users groups and no studies into the characterization of the group of individuals reporting concurrent use of powder cocaine and crack cocaine. Methods Six hundred and ninety-nine cocaine users were assessed during the period August 1997 to October 1998 in one outpatient and six inpatient clinics located in the São Paulo, Brazil. Patients were interviewed using a structured questionnaire schedule in Portuguese, designed specifically for the Brazilian population. The statistical analyses were performed using either ANOVA or a chi-squared test and focusing on their preferred form of use/route of administration and other variables. Results For 83% of the variables tested in this study, the Dual Users subgroup (using both powder and crack cocaine) demonstrated statistical differences from the single drug user subgroups. Those differences include the initiation of cocaine, the abuse of other illicit drugs, and rates of criminal history. Conclusion These data suggest cocaine-dependent individuals who report use of both powder and crack cocaine are an at least partially, distinct subgroup. However, further studies will be necessary to confirm this and to determine if they also show a different treatment response. PMID:16426451

Influence of acute bupropion pre-treatment on the effects of intranasal cocaine.

PubMed

Stoops, William W; Lile, Joshua A; Glaser, Paul E A; Hays, Lon R; Rush, Craig R

2012-06-01

The aim of this experiment was to determine the influence of acute bupropion pre-treatment on subject-rated effects and choice of intranasal cocaine versus money. A randomized, within-subject, placebo-controlled, double-blind experiment. An out-patient research unit. Eight cocaine-using adults. Subjects completed nine experimental sessions in which they were pre-treated with 0, 100 or 200 mg oral immediate release bupropion. Ninety minutes later they sampled an intranasal cocaine dose [4 (placebo), 15 or 45 mg] and made six choices between that dose and an alternative reinforcer (US$0.25), available on independent, concurrent progressive ratio schedules. Subjects also completed a battery of subject-rated, performance and physiological measures following the sample doses of cocaine. After 0 mg bupropion, the high dose of cocaine (45 mg) was chosen five of six times on average compared to 2.25 of six choices for placebo cocaine (4 mg) (P < 0.05). Active bupropion reduced choice of 45 mg cocaine to 3.13 (100 mg) or 4.00 (200 mg) out of six drug choices on average. Bupropion also consistently enhanced positive subject-rated effects of cocaine (e.g. good effects; willing to take again) while having no effects of its own. The atypical antidepressant, bupropion, acutely appears to reduce preference for intranasal cocaine versus a small amount of money but to increase reported positive experiences of the drug. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

PubMed

Montagud-Romero, S; Aguilar, M A; Maldonado, C; Manzanedo, C; Miñarro, J; Rodríguez-Arias, M

2015-08-01

Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine-induced CPP with the subthreshold dose of cocaine, and they needed a higher number of extinction sessions for the 25mg/kg cocaine-induced CPP to be extinguished. In adolescent mice, on the other hand, ASD reduced the conditioned reinforcing effects of cocaine, since CPP was not produced with the lower dose of cocaine and was extinguished faster when they were conditioned with 25mg/kg. Adult mice exposed to social defeat displayed higher levels of corticosterone than their controls and adolescent mice. Our results confirm that the effect of social defeat stress on the acquisition and reinstatement of the CPP induced by cocaine varies depending on the age at which this stress is experienced. Copyright © 2015 Elsevier Inc. All rights reserved.

Relationship between cocaine-induced subjective effects and dopamine transporter occupancy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Fischman, M.; Wang, G.J.

The ability of cocaine to occupy the dopamine transporter has been linked to its reinforcing properties. However, such a relationship has not been demonstrated in humans. Methods: Positron Emission Tomography and [C-11]cocaine were used to estimate dopamine transporter occupancies after different doses of cocaine in 18 active cocaine abusers. The ratio of the distribution volume of [C-11]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1 and is insensitive to changes in cerebral blood flow, was our measure of dopamine transporter availability. In parallel subjective effects were measured to assess the relationship between dopamine transporter occupancy and cocainesmore » behavioral effects. Intravenous cocaine produced a significant dose,-dependent blockade of dopamine transporters: 73 % for 0.6 mg/kg; 601/6 for 0.3 mg/kg; 48 % for 0.1 mg/kg iv and 40 % for 0.05 mg/kg. In addition, dopamine transporter occupancies were significantly correlated with cocaine plasma concentration (r = 0.55 p < 0.001). Cocaine also produced dose-dependent increases in self-reported ratings of {open_quotes}high{close_quotes} which were significantly correlated with the levels of dopamine transporter blockade. Discussion: These results provide the first documentation in humans that dopamine transporter occupancy is associated with cocaine induced subjective effects. They also suggest that dopamine transporter occupancies equal to or greater than 60% are required to produce significant effects on ratings of {open_quotes}high{close_quotes}.« less

Long-lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: Effects on zif 268 and homer 1a

PubMed Central

Unal, Cagri T.; Beverley, Joel A.; Willuhn, Ingo; Steiner, Heinz

2009-01-01

Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers (zif 268, homer 1a) that offer a high anatomical resolution to map cocaine-induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21-day, but not 1-day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a, changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long-lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction. PMID:19419424

Disrupted social development enhances the motivation for cocaine in rats.

PubMed

Baarendse, Petra J J; Limpens, Jules H W; Vanderschuren, Louk J M J

2014-04-01

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction. The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats. Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration. Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose-response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation. Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.

Determinants of cocaine self-administration by laboratory animals.

PubMed

Woolverton, W L

1992-01-01

The reinforcing effect of a drug is that effect that increases the probability that the drug will be self-administered again. Like other drug effects, a reinforcing effect is the result of an interaction between organism, drug and environment. Laboratory research using animal subjects has helped elucidate the contribution of each of these factors to the self-administration of cocaine. A substantial amount of research indicates that increased dopamine neurotransmission in the brain, particularly in mesolimbic and mesocortical regions, plays a major role in cocaine self-administration. Both indirect and direct dopamine agonists can function as positive reinforcers in animals, whereas noradrenergic and serotonergic (5-HT, 5-hydroxytryptamine) agonists have not been found to do so. In addition, evidence suggests that dopamine but not noradrenaline (norepinephrine) or serotonin antagonists can attenuate the reinforcing effect of cocaine. Environmental factors have also been shown to be critical determinants of the reinforcing effect of cocaine. The schedule of reinforcement essentially determines the rate and pattern of drug-maintained behaviour. In addition, punishing self-administration, increasing the value of alternative reinforcers that are available, and increasing the cost of cocaine have all been shown to decrease the reinforcing effect of cocaine. With regard to organismic factors, recent research has suggested that there are significant genetic determinants of cocaine consumption. Taken together these research findings in animals imply that certain individuals may be more sensitive to the reinforcing effect of cocaine but that cocaine abuse can be decreased by pharmacological or behavioural means or by a combination of the two.

Simultaneous Liquid Chromatography–Mass Spectrometry Quantification of Urinary Opiates, Cocaine, and Metabolites in Opiate-Dependent Pregnant Women in Methadone-Maintenance Treatment

PubMed Central

Shakleya, Diaa M.; Dams, Riet; Choo, Robin E.; Jones, Hendree; Huestis, Marilyn A.

2011-01-01

Opiates, cocaine, and metabolites were quantified by liquid chromatography–mass spectrometry (LC–MS) in 284 urine specimens, collected thrice weekly, to monitor possible drug relapse in 15 pregnant heroin-dependent women. Opiates were detected in 149 urine specimens (52%) with limits of quantification (LOQ) of 10–50 μg/L. Morphine, morphine-3-glucuronide, and/or morphine-6-glucuronide were positive in 121 specimens; 6-acetylmorphine, a biomarker of heroin ingestion, was quantifiable in only 7. No heroin, 6-acetylcodeine, papaverine, or noscapine were detected. One hundred and sixty-five urine specimens (58%) from all 15 participants were positive for one or more cocaine analytes (LOQ 10–100 μg/L). Ecgonine methylester (EME) and/or benzoylecgonine were the major cocaine biomarkers in 142. Anhydroecgonine methylester, a biomarker of smoked cocaine, was positive in six; cocaethylene and/or ecgonine ethylester, biomarkers of cocaine and ethanol co-ingestion, were found in 25. At the current Substance Abuse Mental Health Services Administration cutoffs for total morphine (2000 μg/L), codeine (2000 μg/L), 6-acetylmorphine (10 μg/L), and benzoylecgonine (100 μg/L), 16 opiate- and 29 cocaine-positive specimens were identified. Considering 100 μg/L EME as an additional urinary cocaine biomarker would identify 51 more positive cocaine specimens. Of interest is the differential pattern of opiate and cocaine biomarkers observed after LC–MS as compared to gas chromatography–mass spectrometry analysis. PMID:20109298

The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory.

PubMed

Monsey, Melissa S; Sanchez, Hayde; Taylor, Jane R

2017-02-01

Sustained abstinence from cocaine use is frequently compromised by exposure to environmental stimuli that have previously been strongly associated with drug taking. Such cues trigger memories of the effects of the drug, leading to craving and potential relapse. Our work has demonstrated that manipulating cocaine-cue memories by destabilizing them through interfering with the reconsolidation process is one potential therapeutic tool by which to prolong abstinence. Here, we examine the use of the naturally occurring amnestic agent garcinol to manipulate an established cocaine-cue memory. Rats underwent 12 days of cocaine self-administration training during which time active lever presses resulted in an i.v. infusion of cocaine that was paired with a light/tone cue. Next rats underwent lever extinction for 8 days followed by light/tone reactivation and a test of cue-induced cocaine-seeking behavior. Systemic injection of garcinol 30 min after reactivation significantly impaired the reconsolidation of the cocaine-associated cue memory. Further testing revealed that garcinol had no effect on drug-induced cocaine-seeking, but was capable of blocking the initial conditioned reinforcing properties of the cue and prevents the acquisition of a new response. Additional experiments showed that the effects of garcinol are specific to reactivated memories only, temporally constrained, cue-specific, long-lasting, and persist following extended cocaine access. These data provide strong evidence that the naturally occurring compound, garcinol, may be a potentially useful tool to sustain abstinence from drug abuse.

The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory

PubMed Central

Monsey, Melissa S; Sanchez, Hayde; Taylor, Jane R

2017-01-01

Sustained abstinence from cocaine use is frequently compromised by exposure to environmental stimuli that have previously been strongly associated with drug taking. Such cues trigger memories of the effects of the drug, leading to craving and potential relapse. Our work has demonstrated that manipulating cocaine-cue memories by destabilizing them through interfering with the reconsolidation process is one potential therapeutic tool by which to prolong abstinence. Here, we examine the use of the naturally occurring amnestic agent garcinol to manipulate an established cocaine-cue memory. Rats underwent 12 days of cocaine self-administration training during which time active lever presses resulted in an i.v. infusion of cocaine that was paired with a light/tone cue. Next rats underwent lever extinction for 8 days followed by light/tone reactivation and a test of cue-induced cocaine-seeking behavior. Systemic injection of garcinol 30 min after reactivation significantly impaired the reconsolidation of the cocaine-associated cue memory. Further testing revealed that garcinol had no effect on drug-induced cocaine-seeking, but was capable of blocking the initial conditioned reinforcing properties of the cue and prevents the acquisition of a new response. Additional experiments showed that the effects of garcinol are specific to reactivated memories only, temporally constrained, cue-specific, long-lasting, and persist following extended cocaine access. These data provide strong evidence that the naturally occurring compound, garcinol, may be a potentially useful tool to sustain abstinence from drug abuse. PMID:27380937

Beliefs and attitudes regarding drug treatment: application of the theory of planned behavior in African-American cocaine users.

PubMed

Booth, Brenda M; Stewart, Katharine E; Curran, Geoffrey M; Cheney, Ann M; Borders, Tyrone F

2014-10-01

The Theory of Planned Behavior (TPB) can provide insights into perceived need for cocaine treatment among African American cocaine users. A cross-sectional community sample of 400 (50% rural) not-in-treatment African-American cocaine users was identified through respondent-driven sampling in one urban and two rural counties in Arkansas. Measures included self-reports of attitudes and beliefs about cocaine treatment, perceived need and perceived effectiveness of treatment, and positive and negative cocaine expectancies. Normative beliefs were measured by perceived stigma and consequences of stigma regarding drug use and drug treatment. Perceived control was measured by readiness for treatment, prior drug treatment, and perceived ability to cut down on cocaine use without treatment. Multiple regression analysis found that older age (standardized regression coefficient β=0.15, P<0.001), rural residence (β=-0.09, P=0.025), effectiveness of treatment (β=0.39, P<0.001), negative cocaine expectancies (β=0.138, P=0.003), experiences of rejection (β=0.18, P<0.001), need for secrecy (β=0.12, P=0.002), and readiness for treatment (β=0.15, P<0.001) were independently associated with perceived need for cocaine treatment. TPB is a relevant model for understanding perceived need for treatment among African-American cocaine users. Research has shown perceived need to be a major correlate of treatment participation. Study results should be applicable for designing interventions to encourage treatment participation. Copyright © 2014. Published by Elsevier Ltd.

Loss of Feedback Inhibition via D2 Autoreceptors Enhances Acquisition of Cocaine Taking and Reactivity to Drug-Paired Cues

PubMed Central

Holroyd, Kathryn B; Adrover, Martin F; Fuino, Robert L; Bock, Roland; Kaplan, Alanna R; Gremel, Christina M; Rubinstein, Marcelo; Alvarez, Veronica A

2015-01-01

A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self-administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse. PMID:25547712

Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats.

PubMed

Baladi, Michelle G; Newman, Amy H; France, Charles P

2014-02-01

The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects. This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine. Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine. Apomorphine, quinpirole, and lisuride occasioned >90 % responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90 % responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D2/D3 receptor antagonist raclopride and the D3 receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D2 receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats. These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures.

Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats

PubMed Central

Baladi, Michelle G; Newman, Amy H; France, Charles P

2013-01-01

Rationale The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects. Objective This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine. Method Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine. Result Apomorphine, quinpirole, and lisuride occasioned >90% responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90% responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D2/D3 receptor antagonist raclopride and the D3 receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D2 receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats. Conclusion These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures. PMID:24030470

Caffeine's Attenuation of Cocaine-Induced Dopamine Release by Inhibition of Adenosine.

PubMed

Malave, Lauren B; Broderick, Patricia A

2014-06-01

Background: It is well known that the reinforcing properties of cocaine addiction are caused by the sharp increase of dopamine (DA) in the reward areas of the brain. However, other mechanisms have been speculated to contribute to the increase. Adenosine is one system that is associated with the sleep-wake cycle and is most important in regulating neuronal activity. Thus, more and more evidence is pointing to its involvement in regulating DA release. The current study set out to examine the role of adenosine in cocaine-induced DA release. Methods: Increasing doses of cocaine, caffeine, and their combination, as well as, 8-cyclopentyltheophylline (CPT), an adenosine A1 antagonist (alone and in combination with cocaine) were used to denote a response curve. A novel biosensor, the BRODERICK PROBE ® was implanted in the nucleus accumbens to image the drug-induced surge of DA release in vivo , in the freely moving animal in real time. Results: Combinations of cocaine and caffeine were observed to block the increased release of DA moderately after administration of the low dose (2.5 mg/kg cocaine and 12.5 mg/kg caffeine) and dramatically after administration of the high dose (10 mg/kg cocaine and 50 mg/kg caffeine), suggesting neuroprotection. Similarly, CPT and cocaine showed a decreased DA surge when administered in combination. Thus, the low and high dose of a nonselective adenosine antagonist, caffeine, and a moderate dose of a selective adenosine antagonist, CPT, protected against the cocaine-induced DA release. Conclusions: These results show a significant interaction between adenosine and DA release and suggest therapeutic options for cocaine addiction and disorders associated with DA dysfunction.

Caffeine's Attenuation of Cocaine-Induced Dopamine Release by Inhibition of Adenosine

PubMed Central

Malave, Lauren B.

2014-01-01

Background: It is well known that the reinforcing properties of cocaine addiction are caused by the sharp increase of dopamine (DA) in the reward areas of the brain. However, other mechanisms have been speculated to contribute to the increase. Adenosine is one system that is associated with the sleep-wake cycle and is most important in regulating neuronal activity. Thus, more and more evidence is pointing to its involvement in regulating DA release. The current study set out to examine the role of adenosine in cocaine-induced DA release. Methods: Increasing doses of cocaine, caffeine, and their combination, as well as, 8-cyclopentyltheophylline (CPT), an adenosine A1 antagonist (alone and in combination with cocaine) were used to denote a response curve. A novel biosensor, the BRODERICK PROBE® was implanted in the nucleus accumbens to image the drug-induced surge of DA release in vivo, in the freely moving animal in real time. Results: Combinations of cocaine and caffeine were observed to block the increased release of DA moderately after administration of the low dose (2.5 mg/kg cocaine and 12.5 mg/kg caffeine) and dramatically after administration of the high dose (10 mg/kg cocaine and 50 mg/kg caffeine), suggesting neuroprotection. Similarly, CPT and cocaine showed a decreased DA surge when administered in combination. Thus, the low and high dose of a nonselective adenosine antagonist, caffeine, and a moderate dose of a selective adenosine antagonist, CPT, protected against the cocaine-induced DA release. Conclusions: These results show a significant interaction between adenosine and DA release and suggest therapeutic options for cocaine addiction and disorders associated with DA dysfunction. PMID:25054079

Cocaine and sigma-1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model.

PubMed

Roth, Michael D; Whittaker, Katherine M; Choi, Ruth; Tashkin, Donald P; Baldwin, Gayle Cocita

2005-12-01

Cocaine is associated with an increased risk for, and progression of, clinical disease associated with human immunodeficiency virus (HIV) infection. A human xenograft model, in which human peripheral blood mononuclear cells were implanted into severe combined immunodeficiency mice (huPBL-SCID) and infected with a HIV reporter virus, was used to investigate the biological interactions between cocaine and HIV infection. Systemic administration of cocaine (5 mg/kg/d) significantly increased the percentage of HIV-infected PBL (two- to threefold) and viral load (100- to 300-fold) in huPBL-SCID mice. Despite the capacity for cocaine to increase corticosterone and adrenocorticotropic hormone levels in control mice, the hypothalamic-pituitary-adrenal axis was suppressed in HIV-infected animals, and corticosterone levels were further decreased when animals were exposed to HIV and cocaine. Activating huPBL in vitro in the presence of 10(-8) M cocaine increased expression of CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptors. Expression of CCR5 was also increased at early time-points in the huPBL-SCID model following systemic exposure to cocaine (54.1+/-9.4% increase over control, P<0.01). This effect preceded the boost in viral infection and waned as HIV infection progressed. Cocaine has been shown to mediate immunosuppressive effects by activating sigma-1 receptors in immune cells in vitro and in vivo. Consistent with these reports, a selective sigma-1 antagonist, BD1047, blocked the effects of cocaine on HIV replication in the huPBL-SCID mouse. Our results suggest that systemic exposure to cocaine can enhance HIV infection in vivo by activating sigma-1 receptors and by modulating the expression of HIV coreceptors.

Weakening of negative relative to positive associations with cocaine-paired cues contributes to cue-induced responding after drug removal.

PubMed

Su, Zu-In; Kichaev, Gleb; Wenzel, Jennifer; Ben-Shahar, Osnat; Ettenberg, Aaron

2012-01-01

Cocaine has been shown to have initial positive (euphoric) and delayed negative (anxiogenic) effects in both humans and animals. Cocaine-paired cues are consequently imbued with mixed positive and negative associations. The current study examines the relative roles of these dual associations in the enhanced drug-seeking observed upon presentation of cocaine-paired cues. Rats ran a straight alley once/day for a single i.v. injection of cocaine (1.0 mg/kg/inj) in the presence of a distinctive olfactory cue (scented cotton swabs placed under the apparatus). An alternate scent was presented in a separate cage 2-h prior to runway testing. After 15 trials/days, the scents and cocaine reinforcer were removed and a series of extinction trials (lasting for 1 or 3 weeks) was initiated. Immediately following extinction, runway responding was tested during a single trial in the presence of the cocaine-paired or non-paired cue. As previously reported, while subjects initiated responding faster over trials (reduced latencies to leave the start box), they exhibited a progressive increase in approach-avoidance conflict behavior ("retreats") regarding goal-box entry, reflecting cocaine's dual positive+negative effects. Once established, retreat behaviors persisted over the course of 1 or 3 weeks days of extinction. However, both run times and retreats decreased in response to presentation of the cocaine-paired but not the non-paired scent. These data suggest that, after reinforcer removal, cue-induced cocaine-seeking stems in part from a reduction in approach-avoidance conflict; i.e., a greater weakening of the negative relative to the positive associations that animals form with cocaine-paired stimuli. Copyright © 2011 Elsevier Inc. All rights reserved.

ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine.

PubMed

Berezniuk, Iryna; Rodriguiz, Ramona M; Zee, Michael L; Marcus, David J; Pintar, John; Morgan, Daniel J; Wetsel, William C; Fricker, Lloyd D

2017-11-01

To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10 mg/kg cocaine or saline for 7 days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS. © 2017 International Society for Neurochemistry.

Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

PubMed Central

Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J.; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J.

2017-01-01

ABSTRACT Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal. PMID:28138095

Reduced Metabolsim in Brain 'Control Networks' Following Cocaine-Cues Exposure in Female Cocaine Abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.; Volkow, N.D.

Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved. To test this we compared brain metabolism (using PET and {sup 18}FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video. Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreasedmore » metabolism (-8.6% {+-} 10) whereas males tended to increase it (+5.5% {+-} 18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus). Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from 'control networks' (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.« less

[Cocaine - Characteristics and addiction].

PubMed

Girczys-Połedniok, Katarzyna; Pudlo, Robert; Jarząb, Magdalena; Szymlak, Agnieszka

Cocaine use leads to health, social and legal problems. The aim of this paper is to discuss cocaine action, addicts characteristics, use patterns and consequences, as well as addiction treatment methods. A literature review was based on the Medline, PubMed, Polish Medical Bibliography databases and the Silesian Library resources. The Police and Central Statistical Office statistics, as well as the World Health Organization, the European Monitoring Centre for Drugs and Drug Addiction and the National Office for Combating Drug Addiction reports were used. Cocaine leads to mood improvement, appetite decrease, physical and intellectual activity enhancement, euphoria, inflated self-esteem, social networking ease and increased sexual desire. Cocaine hydrochloride is mainly used intranasaly, but also as intravenous and subcutaneous injections. Cocaine use and first addiction treatment fall in later age compared to other psychoactive substances. There is a high men to women ratio among addicts. There is a relationship between cocaine addiction, the presence of other disorders and genetic predisposition to addiction development. Polish reports indicate higher popularity of cocaine among people with a high economic and social status. Although Poland is a country with the low percentage of cocaine use, its popularity is growing. The consequences of cocaine use concern somatic and mental health problems, socioeconomic and legal conditions. The drug plays a role in crimes and traffic accidents. Because of the risks associated with cocaine use, it has been listed in a register of drugs attached to the Act on Counteracting Drug Addiction. Addiction treatment includes psychological, pharmacological and harm reduction strategies. Med Pr 2016;67(4):537-544. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Effects of social reorganization on dopamine D2/D3 receptor availability and cocaine self-administration in male cynomolgus monkeys.

PubMed

Czoty, P W; Gould, R W; Gage, H D; Nader, M A

2017-09-01

Studies have demonstrated that brain dopamine D2/D3 receptors (D2/D3R) and the reinforcing effects of cocaine can be influenced by a monkey's position in the social dominance hierarchy. In this study, we manipulated the social ranks of monkeys by reorganizing social groups and assessed effects on D2/D3R availability and cocaine self-administration. Male cynomolgus monkeys (N = 12) had been trained to self-administer cocaine under a concurrent cocaine-food reinforcement schedule. Previously, PET measures of D2/D3R availability in the caudate nucleus and putamen had been obtained with [ 18 F]fluoroclebopride during cocaine abstinence, while monkeys lived in stable social groups of four monkeys/pen. For this study, monkeys were reorganized into groups that consisted of (1) four previously dominant, (2) four previously subordinate, and (3) a mix of previously dominant and subordinate monkeys. After 3 months, D2/D3R availability was redetermined and cocaine self-administration was reexamined. D2/D3R availability significantly increased after reorganization in monkeys who were formerly subordinate, with the greatest increases observed in those that became dominant. No consistent changes in D2/D3R availability were observed in formerly dominant monkeys. Cocaine self-administration did not vary according to rank after reorganization of social groups. However, when compared to their previous cocaine self-administration data, the potency of cocaine as a reinforcer decreased in 9 of 11 monkeys. These results indicate that changing the social conditions can alter D2/D3R availability in subordinate monkeys in a manner suggestive of environmental enrichment. In most monkeys, social reorganization shifted the cocaine dose-response curve to the right, also consistent with environmental enrichment.

Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

PubMed Central

Grotewold, Susan K.; Wall, Vanessa L.; Goodell, Dayton J.; Hayter, Cassandra

2015-01-01

Rationale Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation. Objectives The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT). Methods Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters. Results ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT. Conclusions Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates. PMID:24553577

Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition.

PubMed

Shi, Xiangdang; Miller, Jonathan S; Harper, Lauren J; Poole, Rachel L; Gould, Thomas J; Unterwald, Ellen M

2014-08-01

Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction. The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory. Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine. Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories. These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.

Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats.

PubMed

Xu, Haiyang; Das, Sasmita; Sturgill, Marc; Hodgkinson, Colin; Yuan, Qiaoping; Goldman, David; Grasing, Kenneth

2017-08-01

The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding. The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats. Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats. HS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors. Diminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity.

Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking.

PubMed

Augur, Isabel F; Wyckoff, Andrew R; Aston-Jones, Gary; Kalivas, Peter W; Peters, Jamie

2016-09-28

The ventromedial prefrontal cortex (vmPFC) has been shown to negatively regulate cocaine-seeking behavior, but the precise conditions by which vmPFC activity can be exploited to reduce cocaine relapse are currently unknown. We used viral-mediated gene transfer of designer receptors (DREADDs) to activate vmPFC neurons and examine the consequences on cocaine seeking in a rat self-administration model of relapse. Activation of vmPFC neurons with the Gq-DREADD reduced reinstatement of cocaine seeking elicited by cocaine-associated cues, but not by cocaine itself. We used a retro-DREADD approach to confine the Gq-DREADD to vmPFC neurons that project to the medial nucleus accumbens shell, confirming that these neurons are responsible for the decreased cue-induced reinstatement of cocaine seeking. The effects of vmPFC activation on cue-induced reinstatement depended on prior extinction training, consistent with the reported role of this structure in extinction memory. These data help define the conditions under which chemogenetic activation of extinction neural circuits can be exploited to reduce relapse triggered by reminder cues. The ventromedial prefrontal cortex (vmPFC) projection to the nucleus accumbens shell is important for extinction of cocaine seeking, but its anatomical proximity to the relapse-promoting projection from the dorsomedial prefrontal cortex to the nucleus accumbens core makes it difficult to selectively enhance neuronal activity in one pathway or the other using traditional pharmacotherapy (e.g., systemically administered drugs). Viral-mediated gene delivery of an activating Gq-DREADD to vmPFC and/or vmPFC projections to the nucleus accumbens shell allows the chemogenetic exploitation of this extinction neural circuit to reduce cocaine seeking and was particularly effective against relapse triggered by cocaine reminder cues. Copyright © 2016 the authors 0270-6474/16/3610174-07$15.00/0.