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Sample records for active cocaine abusers

  1. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: Association to striatal D2/D3 receptors

    SciTech Connect

    Tomasi, Dardo; Wang, Gene -Jack; Wang, Ruiliang; Caparelli, Elisabeth C.; Logan, Jean; Volkow, Nora D.

    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 default 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.

  2. 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 default modemore » 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

  3. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors

    PubMed Central

    Tomasi, Dardo; Wang, Gene-Jack; Wang, Ruiliang; Caparelli, Elisabeth C.; Logan, Jean; Volkow, Nora D.

    2014-01-01

    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 default 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. 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. PMID:25142207

  4. Response to cocaine, alone and in combination with methylphenidate, in cocaine abusers with ADHD.

    PubMed

    Collins, Stephanie L; Levin, Frances R; Foltin, Richard W; Kleber, Herbert D; Evans, Suzette M

    2006-04-28

    Attention deficit hyperactivity disorder (ADHD) is prevalent in adult cocaine abusers. Yet, it remains to be determined how the response to cocaine differs in cocaine abusers with ADHD compared to cocaine abusers without ADHD. Further, since ADHD is commonly treated with stimulants, such as methylphenidate (MPH), it is important to examine whether MPH maintenance alters the response to cocaine in cocaine abusers with ADHD. Thus, the first phase of this study compared the response to cocaine in adult cocaine abusers with ADHD to those without ADHD. The second phase assessed the effects of oral sustained-release methylphenidate (MPH-SR) maintenance (40 and 60 mg) on the response to cocaine only in those with ADHD. Cocaine abusers with ADHD (N=7) and without ADHD (N=7) who were not seeking treatment remained inpatient initially for 1 week, when the effects of cocaine alone were tested (Phase 1). Cocaine abusers with ADHD remained inpatient for an additional 3 weeks, during which the effects of cocaine during oral MPH-SR maintenance were tested (Phase 2). During cocaine fixed dosing sessions, participants received four injections of i.v. cocaine (0, 16 or 48 mg/70 kg), spaced 14 min apart. During cocaine choice sessions, participants had a choice between receiving i.v. cocaine (16 or 48 mg/70 kg) or two tokens, each exchangeable for 2 US dollars. Subjective effects related to ADHD symptoms (e.g. ratings of "Able to Concentrate") were significantly lower in cocaine abusers with ADHD compared to those without ADHD when placebo cocaine was administered. Active cocaine produced similar increases in cardiovascular and positive subjective effects in both groups and there was no difference in cocaine choice between the two groups. These data suggest that the response to cocaine is not different between cocaine abusers with ADHD compared to those without ADHD. When the cocaine abusers with ADHD were maintained on MPH-SR, cardiovascular effects were increased, however, this did

  5. Multiple mononeuropathy following cocaine abuse

    PubMed Central

    Beniczky, Sándor; Tfelt-Hansen, Peer; Fabricius, Martin; Andersen, Kjeld V

    2009-01-01

    A 31-year-old man with acute-onset of left-sided weakness following the sniffing of cocaine was admitted with rhabdomyolysis. Neurophysiological studies showed axonal degeneration in 4/10 sensory and 3/8 motor nerves, and conduction block outside the typical compression-sites in 3/8 motor nerves. The findings are consistent with a diagnosis of multiple mononeuropathy. Ischaemia due to vasoconstriction is currently believed to be the cause of muscle necrosis following cocaine abuse and we hypothesise that it also explains the neuropathy in this case. PMID:21686808

  6. Enhanced regional brain metabolic responses to benzodiazepines in cocaine abusers

    SciTech Connect

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

    1997-05-01

    While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in cocaine addiction is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors (which arc predominantly located on GABA cells) in cocaine abusers. This finding coupled to GABA`s role as an effector for DA led us to investigate if there were GABAergic abnormalities in cocaine abusers. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission). Methods: The experimental subjects consisted of 12 active cocaine abusers and 32 age matched controls. Each subject underwent two PET FDG scans obtained within 1 week of each other. The first FDG scan was obtained after administration of placebo (3 cc of saline solution) given 40-50 minutes prior to FDG; and the second after administration of lorazepam (30 {mu}g/kg) given 40-50 minutes prior to FDG. The subjects were blind to the drugs received. Results: Lorazepam-induced sleepiness was significantly greater in abusers than in controls (p<0.001). Lorazepam-induced decreases in brain glucose metabolism were significantly larger in cocaine abusers than in controls. Whereas in controls whole brain metabolism decreased 13{+-}7 %, in cocaine abusers it decreased 21{+-}13 % (p < 0.05). Lorazepam-induced decrements in regional metabolism were significantly larger in striatum (p < 0.0 1), thalamus (p < 0.01) and cerebellum (p < 0.005) of cocaine abusers than of controls (ANOVA diagnosis by condition (placebo versus lorazepam) interaction effect). The only brain region for which the absolute metabolic changes-induced by lorazepam in cocaine abusers were equivalent to those in controls was the orbitofrontal cortex. These results document an accentuated sensitivity to benzodiazepines in cocaine abusers which is compatible with disrupted GABAergic function in these patients.

  7. Cerebral vasculitis associated with cocaine abuse

    SciTech Connect

    Kaye, B.R.; Fainstat, M.

    1987-10-16

    A case of cerebral vasculitis in a previously healthy 22-year-old man with a history of cocaine abuse is described. Cerebral angiograms showed evidence of vasculitis. A search for possible causes other than cocaine produced no results. The authors include cocaine with methamphetamines, heroin, and ephedrine as illicit drugs that can cause cerebral vasculitis.

  8. Aminorex poisoning in cocaine abusers.

    PubMed

    Karch, Steven B; Mari, Francesco; Bartolini, Viola; Bertol, Elisabetta

    2012-07-26

    Levamisole is found in more than 80% of illicit cocaine seized within United States borders. Percentages are somewhat lower in Europe. In 2009, controlled in vivo studies demonstrated that horses metabolize levamisole to aminorex. Earlier this year our laboratory demonstrated that the same conversion occurs in man. Levamisole itself causes aplastic anemia and numerous reports have begun to appear in the literature, but the conversion of levamisole to aminorex is of much more concern. Aminorex ingestion was responsible for a five-year epidemic (1967-1972) of idiopathic pulmonary hypertension (IPH) confined to Switzerland, Austria, and Germany, the only countries where aminorex had been marketed as an anorectic. The incidence of IPH reverted to normal levels as soon as aminorex was withdrawn. In most cases onset of symptoms in IPH began after six to nine months of aminorex use, with average dosage ranges of 10 to 40 mg per day. The outcome was almost uniformly fatal. The conversion rate of levamisole to aminorex has not been established, but given the high daily intake of cocaine by many abusers, it seems likely that many of them will have ingested enough contaminated cocaine to ultimately cause IPH. Until the disease is well established, the symptoms of IHP are vague, and existing drug registries specifically exclude drug abusers, making it difficult to track these cases. This review is intended to draw attention to what may be a slowly emerging new epidemic.

  9. 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.

  10. Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers

    SciTech Connect

    Tomasi, D.; Tomasi, D.; Volkow, N.D.; Wang, R.; Carrillo, J.; Maloney, T.; Alia-Klein, N.; Woicik, P.A.; Telang, F.; Goldstein, R.Z.

    2010-06-01

    Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

  11. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

    SciTech Connect

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Telang, F.; Fowler, J.S.; Pradhan, K.; Jayne, M.; Logan, J.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2010-07-01

    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 {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 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

  12. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

    PubMed

    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

    2010-07-09

    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 (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 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

  13. Sigma receptors and cocaine abuse.

    PubMed

    Narayanan, Sanju; Mesangeau, Christophe; Poupaert, Jacques H; McCurdy, Christopher R

    2011-01-01

    Sigma receptors have been well documented as a protein target for cocaine and have been shown to be involved in the toxic and stimulant actions of cocaine. Strategies to reduce the access of cocaine to sigma receptors have included antisense oligonucleotides to the sigma-1 receptor protein as well as small molecule ligand with affinity for sigma receptor sites. These results have been encouraging as novel protein targets that can attenuate the actions of cocaine are desperately needed as there are currently no medications approved for treatment of cocaine toxicity or addiction. Many years of research in this area have yet to produce an effective treatment and much focus was on dopamine systems. A flurry of research has been carried out to elucidate the role of sigma receptors in the blockade of cocaine effects but this research has yet to yield a clinical agent. This review summarizes the work to date on the linkage of sigma receptors and the actions of cocaine and the progress that has been made with regard to small molecules. Although there is still a lack of an agent in clinical trials with a sigma receptor mechanism of action, work is progressing and the ligands are becoming more selective for sigma systems and the potential remains high.

  14. Agents in development for the management of cocaine abuse.

    PubMed

    Gorelick, David A; Gardner, Eliot L; Xi, Zheng-Xiong

    2004-01-01

    Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-beta-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes

  15. 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)

  16. Effects of chronic cocaine abuse on postsynaptic dopamine receptors

    SciTech Connect

    Volkow, N.D.; Fowler, J.S.; Wolf, A.P.; Schlyer, D.; Shiue, C.Y.; Alpert, R.; Dewey, S.L.; Logan, J.; Bendriem, B.; Christman, D. )

    1990-06-01

    To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated ({sup 18}F)N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of ({sup 18}F)N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.

  17. Reduced Metabolsim in Brain 'Control Networks' Following Cocaine-Cues Exposure in Female Cocaine Abusers

    SciTech Connect

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Telang, F.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2011-03-01

    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 decreased 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.

  18. Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers

    PubMed Central

    Wiers, C E; Shumay, E; Cabrera, E; Shokri-Kojori, E; Gladwin, T E; Skarda, E; Cunningham, S I; Kim, S W; Wong, T C; Tomasi, D; Wang, G-J; Volkow, N D

    2016-01-01

    Neuroimaging studies have documented reduced striatal dopamine D2/D3 receptor (D2/D3R) availability in cocaine abusers, which has been associated with impaired prefrontal activity and vulnerability for relapse. However, the mechanism(s) underlying the decreases in D2/D3R remain poorly understood. Recent studies have shown that sleep deprivation is associated with a downregulation of striatal D2/D3R in healthy volunteers. As cocaine abusers have disrupted sleep patterns, here we investigated whether reduced sleep duration mediates the relationship between cocaine abuse and low striatal D2/D3R availability. We used positron emission tomography with [11C]raclopride to measure striatal D2/D3R availability in 24 active cocaine abusers and 21 matched healthy controls, and interviewed them about their daily sleep patterns. Compared with controls, cocaine abusers had shorter sleep duration, went to bed later and reported longer periods of sleep disturbances. In addition, cocaine abusers had reduced striatal D2/D3R availability. Sleep duration predicted striatal D2/D3R availability and statistically mediated the relationship between cocaine abuse and striatal D2/D3R availability. These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. As sleep impairments are similarly observed in other types of substance abusers (for example, alcohol and methamphetamine), this mechanism may also underlie reductions in D2/D3R availability in these groups. The current findings have clinical implications suggesting that interventions to improve sleep patterns in cocaine abusers undergoing detoxification might be beneficial in improving their clinical outcomes. PMID:26954979

  19. Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling.

    PubMed

    Mash, Deborah C; ffrench-Mullen, Jarlath; Adi, Nikhil; Qin, Yujing; Buck, Andrew; Pablo, John

    2007-11-14

    The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine "rush". Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.

  20. Cocaine Abuse in Humans Is Not Associated with Increased Microglial Activation: An 18-kDa Translocator Protein Positron Emission Tomography Imaging Study with [11C]PBR28

    PubMed Central

    Lopresti, Brian J.; Mason, Neale Scott; Deuitch, Lora; Paris, Jennifer; Himes, Michael L.; Kodavali, Chowdari V.; Nimgaonkar, Vishwajit L.

    2014-01-01

    Basic science investigations have consistently shown that repeated exposure to psychostimulant drugs, such as cocaine, activate the immune response and lead to inflammatory changes in the brain. No previous in vivo studies have confirmed this observation in chronic cocaine-abusing humans. To test this hypothesis, we used positron emission tomography imaging to measure the binding of [11C]PBR28 to the 18 kDa translocator protein (TSPO), a marker for microglial activation in a group of 15 recently abstinent cocaine abusers and 17 matched healthy controls. [11C]PBR28 volumes of distribution expressed relative to total plasma ligand concentration (VT) were measured in subjects with kinetic analysis using the arterial input function. Subjects were also genotyped for the TSPO alanine147 threonine (Ala147Thr, rs6971) polymorphism that has been shown to influence the in vivo binding of PBR28 to TSPO. Consistent with previous reports, the TSPO Ala147Thr genotype predicted the in vivo binding of [11C]PBR28. No significant differences in [11C]PBR28 VT were observed in the cortical and subcortical regions in cocaine abusers compared with healthy controls. The results of this in vivo study do not support increased TSPO expression and, by extension, microglial activation in chronic cocaine-abusing humans. Further research with more direct markers of microglial activation is necessary to conclusively rule out neuroinflammation in cocaine dependence. PMID:25057196

  1. Adolescent cocaine abuse. Addictive potential, behavioral and psychiatric effects.

    PubMed

    Estroff, T W; Schwartz, R H; Hoffmann, N G

    1989-12-01

    Four hundred seventy-nine drug abusing adolescent patients enrolled in seven Straight, Inc. Adolescent Drug-Abuse Treatment Programs in five geographic regions across the United States were studied to determine the severity and patterns of cocaine abuse. Of these, 341 admitted to cocaine use and became part of this survey. Cocaine use was categorized as heavy, intermediate, or light. Areas examined were the addictive spectrum, psychosocial dysfunction, and psychiatric symptoms. Intermediate and heavy users of cocaine abused significantly less marijuana and inhalants than light cocaine abusers. Heavy and intermediate users were more likely to use cocaine intravenously and to use crack. They developed tachyphylaxis more frequently, progressed to weekly use in less than 3 months more frequently, and became preoccupied with obtaining and using cocaine significantly more frequently. They used more sedative hypnotics to calm themselves and engaged in more criminal behavior, such as stealing from parents and stores and passing bad checks. They had more arrests for possession of drugs, stole more cars, sold more drugs, and were more likely to trade sexual favors to obtain the drug. Heavy and intermediate users were significantly more psychiatrically disturbed than light users, becoming more suspicious, nervous, aggressive, and demonstrating increased symptoms of fatigue, sleeplessness, decreased appetite, and increasing cocaine dysphoria. All of these symptoms could be mistaken for psychiatric disorders. This study suggests that cocaine is as addictive in adolescents as in adults; possibly more so. It also causes psychosocial dysfunction and psychiatric symptoms. Further research into cocaine addiction among adolescents is indicated.

  2. Impact of cocaine abuse on HIV pathogenesis

    PubMed Central

    Dash, Sabyasachi; Balasubramaniam, Muthukumar; Villalta, Fernando; Dash, Chandravanu; Pandhare, Jui

    2015-01-01

    Over 1.2 million people in the United States are infected with the human immunodeficiency virus type 1 (HIV-1). Tremendous progress has been made over the past three decades on many fronts in the prevention and treatment of HIV-1 disease. However, HIV-1 infection is incurable and antiretroviral drugs continue to remain the only effective treatment option for HIV infected patients. Unfortunately, only three out of ten HIV-1 infected individuals in the US have the virus under control. Thus, majority of HIV-1 infected individuals in the US are either unaware of their infection status or not connected/retained to care or are non-adherent to antiretroviral therapy (ART). This national public health crisis, as well as the ongoing global HIV/AIDS pandemic, is further exacerbated by substance abuse, which serves as a powerful cofactor at every stage of HIV/AIDS including transmission, diagnosis, pathogenesis, and treatment. Clinical studies indicate that substance abuse may increase viral load, accelerate disease progression and worsen AIDS-related mortality even among ART-adherent patients. However, confirming a direct causal link between substance abuse and HIV/AIDS in human patients remains a highly challenging endeavor. In this review we will discuss the recent and past developments in clinical and basic science research on the effects of cocaine abuse on HIV-1 pathogenesis. PMID:26539167

  3. Cardiac Fas-dependent and mitochondria-dependent apoptosis after chronic cocaine abuse.

    PubMed

    Liou, Cher-Ming; Tsai, Shiow-Chwen; Kuo, Chia-Hua; Ting, Hua; Lee, Shin-Da

    2014-04-09

    To evaluate whether chronic cocaine abuse will increase cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, thirty-two male Wistar rats at 3-4 months of age were randomly divided into a vehicle-treated group (phosphate-buffered saline, PBS, 0.5 mL, SQ per day) and a cocaine-treated group (Cocaine, 10 mg/kg, SQ per day). After 3 months of treatment, the excised left ventricles were measured by H&E staining, Western blotting, DAPI staining and TUNEL assays. More cardiac TUNEL-positive apoptotic cells were observed in the Cocaine group than the PBS group. Protein levels of TNF-alpha, Fas ligand, Fas death receptor, FADD, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts in the Cocaine group were significantly increased, compared to the PBS group. Protein levels of cardiac Bax, cytosolic cytochrome c, t-Bid-to-Bid, Bak-to-Bcl-xL, Bax-to-Bcl-2 ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the Cocaine group, compared to the PBS group. Chronic cocaine exposure appeared to activate the cardiac Fas-dependent and mitochondria-dependent apoptosis, which may indicate a possible mechanism for the development of cardiac abnormalities in humans with chronic cocaine abuse.

  4. Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

    SciTech Connect

    Dewey, S.L.; Straughter-Moore, R.; Chen, R.

    1995-05-01

    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 of 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.

  5. 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 ...

  6. Neuropsychological performance of recently abstinent alcoholics and cocaine abusers.

    PubMed

    Beatty, W W; Katzung, V M; Moreland, V J; Nixon, S J

    1995-03-01

    To examine possible influences of premorbid and comorbid factors on the neuropsychological test performance of recently abstinent (3-5 weeks) drug abusers, we studied 24 alcoholics, 23 cocaine abusers, and 22 healthy controls of comparable age and education. Both alcoholics and cocaine abusers performed significantly more poorly than controls on most measures of learning and memory, problem solving and abstraction and perceptual-motor speed, but the groups did not differ on the measure of sustained attention. Correlational analyses revealed no significant relationships between measures of childhood and residual hyperactivity and neuropsychological performance; scores on the Beck Depression Inventory were related only to performance on the Wisconsin Card Sorting Test. The findings indicate that abuse of cocaine or alcohol is associated with deficits on neuropsychological tests which cannot be attributed to specific premorbid or comorbid factors such as depression or childhood or residual attention deficit disorder.

  7. [acute dystonias in combined abuse of cocaine and neuroleptics].

    PubMed

    Horwitz, E H; van Harten, P N

    1994-11-26

    A 25-year-old mildly retarded black cocaine user was hospitalized 15 times in 10 years for recurrent maniform psychosis. During the last intake he developed severe dystonia following zuclopenthixol 50 mg and droperidol 10 mg i.m. In view of current knowledge regarding the pathophysiology of acute neuroleptic induced dystonias, this suggests that cocaine may be a risk factor for development of acute dystonia. However, only a few studies with small numbers of patients and/or poor design have been reported. Therefore the conclusion cannot be drawn that an anticholinergic should be added to neuroleptics in patients with cocaine abuse.

  8. Internuclear Ophthalmoplegia Secondary to Cocaine Abuse

    PubMed Central

    Wasay, Azeem; Biro, Nicolas; Morcos, Marcelle

    2017-01-01

    Purpose. To report a case of internuclear ophthalmoplegia (INO) caused by cocaine. Method. We report a case of a 54-year-old female who presented with a left INO three days after snorting cocaine, and we review the literature. Results. MRI of the brain demonstrated several small abnormal foci in the pons on FLAIR and diffusion weighted imaging consistent with ischemic infarction. The patient's symptoms remained stable throughout her hospitalization. She was sent to a rehabilitation facility and was lost to follow-up. Conclusion. In cases of extraocular movement abnormalities, it is important to inquire about recreational drug use. PMID:28265477

  9. Sociodemographic representation in published studies of cocaine abuse pharmacotherapy.

    PubMed

    Gorelick, D A; Montoya, I D; Johnson, E O

    1998-01-01

    This study evaluated: (1) the reporting of sociodemographic characteristics of research subjects in published outpatient studies of cocaine abuse pharmacotherapy; (2) the association of study characteristics with such reporting and with the distribution of characteristics; and (3) the comparison of sociodemographic characteristics in the research subjects with those of a community-based sample of cocaine abusers who had sought treatment. Medline search identified 68 articles on cocaine abuse outpatient pharmacotherapy published from 1983 to 1993 in an English language, peer-reviewed journal. Sociodemographic characteristics of research subjects (n = 1802) were compared with those of respondents (weighted n = 135) to the National Comorbidity Survey (1990-1992), who reported at least one cocaine-related problem and had sought substance abuse treatment. Only three (4.4%) articles reported all six of the following sociodemographic characteristics of their subjects: 82.4%, reported mean age; 58.8%, race/ethnicity; 85.3%, sex; 22.1%, employment status; 13.2%, educational status; and 5.9%, socioeconomic status/income. Compared to survey respondents, research subjects were significantly more likely to be African-American and live in the Northeast region of the US and marginally more likely to be male and currently unemployed. These findings indicate that many published articles do not follow currently recommended guidelines for describing sociodemographic characteristics of research subjects and that, aside from race/ethnicity and geographic location, research subjects are fairly comparable in basic sociodemographic characteristics to the larger population of treatment-seeking individuals with cocaine-related problems.

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

    SciTech Connect

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

    1997-05-01

    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 cocaine 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.

  11. 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.

  12. Delusions and hallucinations of cocaine abusers and paranoid schizophrenics: a comparative study.

    PubMed

    Mitchell, J; Vierkant, A D

    1991-05-01

    We compared delusions and hallucinations of 100 cocaine abusers and 100 paranoid schizophrenic subjects admitted to an East Texas state psychiatric hospital. Subjects in both groups feared that individuals or organized groups might harm them in some way, but delusions of the paranoid schizophrenic subjects were more often bizarre than those of the cocaine abuse subjects. "Cocaine bugs" (parasitosis) were more often found in the cocaine abuse subjects. Command hallucinations were found in both groups, but the commands of the schizophrenic group more often related to harming or killing others. Cocaine abusers had a greater frequency of visual hallucinations (47 to 7), distinguished by shadows, flashing lights ("snow lights"), objects moving and bugs crawling on the arm. Finally, the most distinguishing characteristics were identity delusions, possession delusions, grandiose delusions (other than identities and possessions), and delusions that their families were imposters (Capgras Syndrome) reported by paranoid schizophrenics. No such delusions were reported by the cocaine abusers.

  13. Cognitive control of drug craving inhibits brain reward regions in cocaine abusers

    SciTech Connect

    Volkow, N.D.; Fowler, J.; Wang, G.J.; Telang, F.; Logan, J.; Jayne, M.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

    2010-01-01

    Loss of control over drug taking is considered a hallmark of addiction and is critical in relapse. Dysfunction of frontal brain regions involved with inhibitory control may underlie this behavior. We evaluated whether addicted subjects when instructed to purposefully control their craving responses to drug-conditioned stimuli can inhibit limbic brain regions implicated in drug craving. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to measure brain glucose metabolism (marker of brain function) in 24 cocaine abusers who watched a cocaine-cue video and compared brain activation with and without instructions to cognitively inhibit craving. A third scan was obtained at baseline (without video). Statistical parametric mapping was used for analysis and corroborated with regions of interest. The cocaine-cue video increased craving during the no-inhibition condition (pre 3 {+-} 3, post 6 {+-} 3; p < 0.001) but not when subjects were instructed to inhibit craving (pre 3 {+-} 2, post 3 {+-} 3). Comparisons with baseline showed visual activation for both cocaine-cue conditions and limbic inhibition (accumbens, orbitofrontal, insula, cingulate) when subjects purposefully inhibited craving (p < 0.001). Comparison between cocaine-cue conditions showed lower metabolism with cognitive inhibition in right orbitofrontal cortex and right accumbens (p < 0.005), which was associated with right inferior frontal activation (r = -0.62, p < 0.005). Decreases in metabolism in brain regions that process the predictive (nucleus accumbens) and motivational value (orbitofrontal cortex) of drug-conditioned stimuli were elicited by instruction to inhibit cue-induced craving. This suggests that cocaine abusers may retain some ability to inhibit craving and that strengthening fronto-accumbal regulation may be therapeutically beneficial in addiction.

  14. The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic.

    PubMed

    Zhang, Hai-Ying; Bi, Guo-Hua; Yang, Hong-Ju; He, Yi; Xue, Gilbert; Cao, Jian-Jing; Tanda, Gianluigi; Gardner, Eliot L; Newman, Amy Hauck; Xi, Zheng-Xiong

    2017-03-07

    (±)Modafinil ((±)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (±)MOD analogues, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters and enzymes. Although at a concentration of 10 μM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D2-like and sigma1 receptors. R-MOD was more selective, but had much lower affinity at the DAT (Ki=3 μM) than JJC8-016 (Ki=116 nM). In rats, systemic administration of R-MOD alone (10-30 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, while JJC8-016 (10-30 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, while R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens, nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.Neuropsychopharmacology accepted article preview online, 07 March 2017. doi:10.1038/npp.2017.41.

  15. The role of weight control as a motivation for cocaine abuse.

    PubMed

    Cochrane, C; Malcolm, R; Brewerton, T

    1998-01-01

    Heavy use of cocaine and alcohol in female cocaine abusers with eating disorders has been reported, but the prevalence and motivation for concurrent substance use has not been well investigated. This study of 37 female and 40 male cocaine abusers demonstrated that almost half of the women used cocaine and/or alcohol as a weight control measure, and 13% of the males did the same. Thirteen (72%) of 18 females endorsing weight-related use of cocaine had a current diagnosis of an eating disorder. Only two males (5%) had a past history of an eating disorder. Eleven (85%) of those women with a current eating disorder endorsed using alcohol as an appetite suppressant. These findings support the need to evaluate weight control motivation in cocaine users and to provide specific treatment aimed at addressing the interaction between the eating disorder and the substance abuse problem.

  16. Subjective responses and cardiovascular effects of self-administered cocaine in cocaine-abusing men and women.

    PubMed

    Lynch, Wendy J; Kalayasiri, Rasmon; Sughondhabirom, Atapol; Pittman, Brian; Coric, Vladimir; Morgan, Peter T; Malison, Robert T

    2008-09-01

    This study aimed to examine sex differences in cocaine self-administration and cocaine-induced subjective and cardiovascular measures. The research was based on secondary analysis of data collected in our human laboratory in which subjects self-administered cocaine infusions (8, 16 and 32 mg/70 kg) over a 2-hour period under a fixed ratio 1, 5 minute time out schedule in three test sessions. Subjects were 10 women and 21 men with a history of either cocaine abuse or dependence who were not currently seeking treatment. Women and men self-administered similar amounts of cocaine. None of the subjective effects measures showed a significant main effect of sex during the cocaine self-administration session. Significant interactions were observed for subjective ratings of 'high' (sex x time) and 'stimulated' (sex x time x dose), with women reporting lower ratings over time/doses than men. Relative to men, cocaine produced dose- and time-dependent increases in feelings of hunger (i.e., reduced appetite suppression) in women. Systolic and diastolic blood pressures showed different patterns of change in men and women, with women showing less robust cocaine-induced increases than men. Taken together, these findings suggest that women and men may differ in their subjective and cardiovascular responses to self-administered cocaine. Further research that prospectively controls for hormonal influences upon these measures is needed.

  17. Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin

    PubMed Central

    Albertson, Dawn N.; Pruetz, Barb; Schmidt, Carl J.; Kuhn, Donald M.; Kapatos, Gregory; Bannon, Michael J.

    2008-01-01

    Chronic cocaine abuse induces long-term neural adaptations as a consequence of alterations in gene expression. This study was undertaken to identify those transcripts differentially regulated in the nucleus accumbens of human cocaine abusers. Affymetrix microarrays were used to measure transcript abundance in 10 cocaine abusers and 10 control subjects matched for age, race, sex, and brain pH. As expected, gene expression of cocaine- and amphetamine-regulated transcript (CART) was increased in the nucleus accumbens of cocaine abusers. The most robust and consistent finding, however, was a decrease in the expression of a number of myelin-related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP). The differential expression seen by microarray for CART as well as MBP, MOBP, and PLP was verified by RT–PCR. In addition, immunohistochemical experiments revealed a decrease in the number of MBP-immunoreactive oligodendrocytes present in the nucleus accumbens and surrounding white matter of cocaine abusers. These findings suggest a dysregulation of myelin in human cocaine abusers. PMID:15009677

  18. Cocaine

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Cocaine KidsHealth > For Teens > Cocaine A A A What's ... How Can Someone Quit? Avoiding Cocaine What Is Cocaine? Cocaine is a powerful and highly addictive drug ...

  19. Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase.

    PubMed

    Smethells, John R; Swalve, Natashia; Brimijoin, Stephen; Gao, Yang; Parks, Robin J; Greer, Adam; Carroll, Marilyn E

    2016-05-01

    A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

  20. A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse

    SciTech Connect

    Brim, Remy L.; Nance, Mark R.; Youngstrom, Daniel W.; Narasimhan, Diwahar; Zhan, Chang-Guo; Tesmer, John J.G.; Sunahara, Roger K.; Woods, James H.

    2010-09-03

    Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. CocE directly degrades cocaine into inactive products, whereas traditional small-molecule approaches require blockade of the inhibitory action of cocaine on a diverse array of monoamine transporters and ion channels. The usefulness of wild-type (wt) cocaine esterase is hampered by its inactivation at 37 C. Herein, we characterize the most thermostable form of this enzyme to date, CocE-L169K/G173Q. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37 C, which represents a 340-fold improvement over wt and is 15-fold greater than previously reported mutants. Crystallographic analyses of CocE-L169K/G173Q, determined at 1.6-{angstrom} resolution, suggest that stabilization involves enhanced domain-domain interactions involving van der Waals interactions and hydrogen bonding. In vivo rodent studies reveal that intravenous pretreatment with CocE-L169K/G173Q in mice provides protection from cocaine-induced lethality for longer time periods before cocaine administration than wt CocE. Furthermore, intravenous administration (pretreatment) of CocE-L169K/G173Q prevents self-administration of cocaine in a time-dependent manner. Termination of the in vivo effects of CoCE seems to be dependent on, but not proportional to, its clearance from plasma as its half-life is approximately 2.3 h and similar to that of wt CocE (2.2 h). Taken together these data suggest that CocE-L169K/G173Q possesses many of the properties of a biological therapeutic for treating cocaine abuse but requires additional development to improve its serum half-life.

  1. Detection of cocaine induced rat brain activation by photoacoustic tomography

    PubMed Central

    Jo, Janggun; Yang, Xinmai

    2011-01-01

    Photoacoustic tomography (PAT) was used to detect the progressive changes on the cerebral cortex of Sprague Dawley rats after the administration of cocaine hydrochloride. Different concentrations (0, 2.5, and 5.0 mg per kg body) of cocaine hydrochloride in saline solution were injected into Sprague Dawley rats through tail veins. Cerebral cortex images of the animals were continuously acquired by PAT. For continuous observation, PAT system used multi-transducers to reduce the scanning time and maintain a good signal-to-noise ratio (SNR). The obtained photoacoustic images were compared with each other and confirmed that changes in blood volume were induced by cocaine hydrochloride injection. The results demonstrate that PAT may be used to detect the effects of drug abuse-induced brain activation. PMID:21163301

  2. Clinical and forensic signs related to cocaine abuse.

    PubMed

    Dinis-Oliveira, Ricardo Jorge; Carvalho, Félix; Duarte, José Alberto; Proença, Jorge Brandão; Santos, Agostinho; Magalhães, Teresa

    2012-03-01

    Good laboratory practice in toxicological analysis requires pre-analytical steps for collection of detailed information related to the suspected poisoning episodes, including biological and non-biological circumstantial evidences, which should be carefully scrutinized. This procedure provides great help to unveil the suspected cause of poisoning, to select the appropriate and correct samples to be analyzed and can facilitate the decision about the analytical techniques to perform. This implies a good knowledge of the signs related to acute and chronic intoxications by drugs of abuse. In this manuscript we highlight and discuss clinical and forensic imaging related to cocaine abuse, namely the midline destructive lesion, dental health, pseudoscleradermatous triad and crack hands, necrosis and gangrene of extremities and several other skin manifestations, reticular purpura, intracerebral and peripheral hemorrhages, angioneurotic edema, rhabdomyolysis, and crack lung. For this purpose, the state of the art on this topic is discussed, using clinical and forensic cases from our professional database in complement to images and mechanistic data from literature.

  3. Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats

    PubMed Central

    Bonano, Julie S.; Runyon, Scott P.; Hassler, Carla; Glennon, Richard A.; Negus, S. Stevens

    2014-01-01

    Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague-Dawley rats (n=12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0–10 mg/kg) and MDPV (3.2 mg/kg) facilitated ICSS. RTI-118 (3.2––32 mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25–0.5 mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32 mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV. PMID:25220242

  4. Cocaine

    MedlinePlus

    ... DEA 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 ...

  5. Decreased striatal and enhanced thalamic dopaminergic responsivity in detoxified cocaine abusers

    SciTech Connect

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

    1997-05-01

    It has been hypothesized that cocaine addiction could result from decreased brain dopamine (DA) function. However, little is known about changes in (DA) neurotransmission in human cocaine addiction. We used PET and [C-11]raclopride, a DA D2 receptor ligand sensitive to competition with endogenous DA, to measure relative changes in extracellular DA induced by methylphenidate (MP) in 20 cocaine abusers (3-6 weeks after cocaine discontinuation) and 23 controls. MP did not affect the transport of [C-11]raclopride from blood to brain (K1); however it induced a significant reduction in DA D2 receptor availability (Bmax/Kd) in striatum. The magnitude of ND-induced changes in striatal [C-11]raclopride binding were significantly larger in controls (21 + 13% change from baseline) than in cocaine abusers (9 {+-} 13 %) (ANOVA p < 0.005). In cocaine abusers, but not in controls, MP also decreased Bmax/Kd values in thalamus (29 {+-} 35 %) (ANOVA p < 0.005). There were no differences in plasma MP concentration between the groups. In striatum MP-induced changes in Bmax/Kd were significantly correlated with MP-induced changes in self reports of restlessness (r = 0.49, df 42, p < 0.002). In thalamus MP-induced changes in Bmax/Kd were significantly correlated with ND-induced changes in self reports of cocaine craving (r = 0.57, df 42, p < 0.0001). These results are compatible with a decrease in striatal DA brain function in cocaine abusers. They also suggest a participation of thalamic DA pathways in cocaine addiction.

  6. Concurrent Alcohol Dependence Among Methadone-Maintained Cocaine Abusers Is Associated with Greater Abstinence

    PubMed Central

    Byrne, Shannon A.; Petry, Nancy M.

    2011-01-01

    Concurrent alcohol dependence (AD) among polysubstance abusers has been associated with negative consequences, although it may not necessarily lead to poor treatment outcomes. One of the most efficacious treatments for cocaine abuse is contingency management (CM), but little research has explored the impact of AD on abstinence outcomes, particularly among patients in methadone maintenance. Using data from three trials of CM for cocaine use, we compared baseline characteristics and post-treatment and follow-up cocaine outcomes between methadone maintained, cocaine dependent patients (N=193) with and without concurrent AD, randomized to standard care (SC) with or without CM. Patients with and without concurrent AD had similar baseline characteristics, with the exception that AD patients reported more alcohol use. AD patients achieved longer durations of cocaine abstinence and were more likely to submit a cocaine negative sample at follow-up than non-AD patients. Patients randomized to CM achieved better outcomes than those randomized to SC, but there was no interaction between treatment condition and AD status. These findings suggest that cocaine using methadone patients with AD achieve greater cocaine abstinence than their non-AD counterparts and should not be necessarily viewed as more difficult to treat. PMID:21463068

  7. Distinctive Profiles of Gene Expression in the Human Nucleus Accumbens Associated with Cocaine and Heroin Abuse

    PubMed Central

    Albertson, Dawn N; Schmidt, Carl J; Kapatos, Gregory; Bannon, Michael J

    2008-01-01

    Drug abuse is thought to induce long-term cellular and behavioral adaptations as a result of alterations in gene expression. Understanding the molecular consequences of addiction may contribute to the development of better treatment strategies. This study utilized highthroughput Affymetrix microarrays to identify gene expression changes in the post-mortem nucleus accumbens of chronic heroin abusers. These data were analyzed independently and in relation to our previously reported data involving human cocaine abusers, in order to determine which expression changes were drug specific and which may be common to the phenomenon of addiction. A significant decrease in the expression of numerous genes encoding proteins involved in presynaptic release of neurotransmitter was seen in heroin abusers, a finding not seen in the cocaine-abusing cohort. Conversely, the striking decrease in myelin-related genes observed in cocaine abusers was not evident in our cohort of heroin subjects. Overall, little overlap in gene expression profiles was seen between the two drug-abusing cohorts: out of the approximately 39 000 transcripts investigated, the abundance of only 25 was significantly changed in both cocaine and heroin abusers, with nearly one-half of these being altered in opposite directions. These data suggest that the profiles of nucleus accumbens gene expression associated with chronic heroin or cocaine abuse are largely unique, despite what are thought to be common effects of these drugs on dopamine neurotransmission in this brain region. A re-examination of our current assumptions about the commonality of molecular mechanisms associated with substance abuse seems warranted. PMID:16710320

  8. Cocaine

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Cocaine KidsHealth > For Teens > Cocaine Print A A A ... Quit? Avoiding Cocaine en español Cocaína What Is Cocaine? Cocaine is a powerful and highly addictive drug ...

  9. Cocaine Abuse in Later Life: A Case Series and Review of the Literature

    PubMed Central

    2015-01-01

    Objective: To raise awareness about the growing trend of cocaine abuse in later years as an underdiagnosed, undertreated, and comorbid condition in older individuals. Three cases of cocaine use in patients over the age of 50 years in the Malcolm Randall Veterans Medical Center, Gainesville, Florida, within a 10-day span in 2013 are presented. Data Sources: PubMed was searched using combinations of keywords, including cocaine, addiction, elderly, and aging, to find articles published between 1986 and 2013. Study Selection: In total, 37 articles were selected for inclusion on the basis of their relevance to the objective and importance to the representation of cocaine abuse, including international guidelines for addiction. Data Extraction: Each article was reviewed for eligibility. Final decisions were made following full-text review. Results: Cocaine addiction remains a high-morbidity chronic-relapsing illness with few treatment options. A review of the literature shows that late-life cocaine use is sparsely recognized. Of particular interest are the clinical presentations in which a higher index for detection is warranted. The high rate of medical comorbidity associated with cocaine use, especially cerebrovascular deficits, presents special treatment and social challenges. Conclusions: As the number of older individuals admitted for substance use continues to climb, clinicians must adapt to the changing demographics by increasing screening, early detection, and treatment options for older persons. PMID:26445694

  10. Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene–gene–environment interaction

    PubMed Central

    Sullivan, D; Pinsonneault, J K; Papp, A C; Zhu, H; Lemeshow, S; Mash, D C; Sadee, W

    2013-01-01

    Epistatic gene–gene interactions could contribute to the heritability of complex multigenic disorders, but few examples have been reported. Here, we focus on the role of aberrant dopaminergic signaling, involving the dopamine transporter DAT, a cocaine target, and the dopamine D2 receptor, which physically interacts with DAT. Splicing polymorphism rs2283265 of DRD2, encoding D2 receptors, were shown to confer risk of cocaine overdose/death (odds ratio ∼3) in subjects and controls from the Miami Dade County Brain Bank.1 Risk of cocaine-related death attributable to the minor allele of rs2283265 was significantly enhanced to OR=7.5 (P=0.0008) in homozygous carriers of the main 6-repeat allele of DAT rs3836790, a regulatory VNTR in intron8 lacking significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P=0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3′-UTR, occurred in nearly one-third of the cocaine abusers but was absent in African American controls, apparently conferring strong risk. These results demonstrate gene–gene–drug interaction affecting risk of fatal cocaine intoxication. PMID:23340505

  11. Abnormal frontostriatal activity in recently abstinent cocaine users during implicit moral processing

    PubMed Central

    Caldwell, Brendan M.; Harenski, Carla L.; Harenski, Keith A.; Fede, Samantha J.; Steele, Vaughn R.; Koenigs, Michael R.; Kiehl, Kent A.

    2015-01-01

    Investigations into the neurobiology of moral cognition are often done by examining clinical populations characterized by diminished moral emotions and a proclivity toward immoral behavior. Psychopathy is the most common disorder studied for this purpose. Although cocaine abuse is highly co-morbid with psychopathy and cocaine-dependent individuals exhibit many of the same abnormalities in socio-affective processing as psychopaths, this population has received relatively little attention in moral psychology. To address this issue, the authors used functional magnetic resonance imaging (fMRI) to record hemodynamic activity in 306 incarcerated male adults, stratified into regular cocaine users (n = 87) and a matched sample of non-cocaine users (n = 87), while viewing pictures that did or did not depict immoral actions and determining whether each depicted scenario occurred indoors or outdoors. Consistent with expectations, cocaine users showed abnormal neural activity in several frontostriatial regions during implicit moral picture processing compared to their non-cocaine using peers. This included reduced moral/non-moral picture discrimination in the vACC, vmPFC, lOFC, and left vSTR. Additionally, psychopathy was negatively correlated with activity in an overlapping region of the ACC and right lateralized vSTR. These results suggest that regular cocaine abuse may be associated with affective deficits which can impact relatively high-level processes like moral cognition. PMID:26528169

  12. Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients.

    PubMed

    Pandhare, Jui; Addai, Amma B; Mantri, Chinmay K; Hager, Cynthia; Smith, Rita M; Barnett, Louis; Villalta, Fernando; Kalams, Spyros A; Dash, Chandravanu

    2014-04-01

    Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1-associated CD4(+) T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4(+) T cells from HIV-1-negative and HIV-1-positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4(+) T cells with cocaine (up to 100 μmol/L concentrations) did not induce apoptosis, but 200 to 1000 μmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4(+) T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4(+) T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4(+) T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1-infected drug abusers.

  13. Treatment of cocaine abuse during pregnancy: translating research to clinical practice.

    PubMed

    Hull, Lynn; May, James; Farrell-Moore, Dawn; Svikis, Dace S

    2010-10-01

    In the late-1980s and early-1990s, much attention in America was focused on cocaine abuse. In particular, the effects of prenatal cocaine use on mothers and infants were in the news spotlight. Risks of adverse effects prompted funding for novel treatment programs. More recently, media attention has shifted elsewhere, and specialized treatment resources have grown scarce. This redirection of funding is unfortunate, as social stigma and fear of legal consequences continue to encourage cocaine-abusing pregnant women to hide drug use and avoid prenatal care. The purpose of this article is to summarize the most prominent adverse maternal and fetal/infant effects associated with prenatal cocaine use; review treatment options, focusing on comprehensive care programs of the 1990s as well as recent research on evidence-based practices and their applicability to pregnant women; and highlight the population of prenatal cocaine-abusing women uninterested in treatment, with a focus on promising strategies to promote drug abstinence and other positive health behaviors.

  14. 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…

  15. Cognitive impairment, retention and abstinence among cocaine abusers in cognitive-behavioral treatment.

    PubMed

    Aharonovich, Efrat; Nunes, Edward; Hasin, Deborah

    2003-08-20

    Cognitive-behavioral therapy (CBT) depends on adequate cognitive functioning in patients, but prolonged cocaine use may impair cognitive functioning. Therefore, cognitive impairment may impede the ability of cocaine abusers to benefit from CBT. To begin to address this issue, we investigated the relationship between cognitive impairment and two treatment outcomes, therapy completion and abstention. Eighteen carefully screened non-depressed cocaine-dependent patients in a psychopharmacological clinical trial were administered the MicroCog computerized battery to assess cognitive performance at treatment entry. T-tests were used to compare cognitive functioning between completers (patients remaining in treatment at least 12 weeks) and dropouts. The results indicated that treatment completers had demonstrated significantly better cognitive performance at baseline than patients who dropped out of treatment. Cognitive domains that significantly distinguished between treatment completers and dropouts were attention, mental reasoning and spatial processing. This study provides preliminary evidence that cognitive impairments may decrease treatment retention and abstinence in CBT of cocaine dependence.

  16. Contingency Management Improves Abstinence and Quality of Life in Cocaine Abusers

    ERIC Educational Resources Information Center

    Petry, Nancy M.; Alessi, Sheila M.; Hanson, Tressa

    2007-01-01

    Contingency management (CM) treatments enhance drug abstinence. This study evaluated whether CM also improves quality of life and if these effects are mediated by abstinence. Across 3 independent trials, cocaine abusers in intensive outpatient treatment (n = 387) were randomly assigned to 12 weeks of standard treatment as usual or standard…

  17. Extrapyramidal Motor Dysfunction and Resultant Orofacial Dystonia Post-Cocaine Abuse: A Clinical Case Study

    ERIC Educational Resources Information Center

    McMicken, Betty L.; Ostergren, Jennifer A.; Vento-Wilson, Margaret

    2010-01-01

    This case study investigated the consequences of cocaine use and resultant extrapyramidal motor dysfunction. The study focused on a female client, post-long-term drug abuse with concomitant untreated head trauma, experiencing extraneous motor movements of the lips, tongue, jaw, and upper and lower extremities. The goals of this study were to (a)…

  18. Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds.

    PubMed

    Pei, Yue; Mortas, Patrick; Hoener, Marius C; Canales, Juan J

    2015-12-03

    The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioral effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose-response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45, and 1mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose-response curve, indicating that both partial and full TAAR1 activation decrease cocaine, reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self-administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction.

  19. Cocaine-mediated microglial activation involves the ER stress-autophagy axis

    PubMed Central

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases. PMID:26043790

  20. Cocaine-mediated microglial activation involves the ER stress-autophagy axis.

    PubMed

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases.

  1. Daily stressor sensitivity, abuse effects, and cocaine use in cocaine dependence.

    PubMed

    Waldrop, Angela E; Back, Sudie E; Brady, Kathleen T; Upadhyaya, Himanshu P; McRae, Aimee L; Saladin, Michael E

    2007-12-01

    This study highlights respondent sensitivity to daily hassles as it relates to situational cocaine use and perceived long-term effects of adverse events in childhood. Data were drawn from a larger study on stress reactivity in cocaine dependent individuals. Participants (n=104) were cocaine dependent men and women without comorbid posttraumatic stress disorder (PTSD). They completed the Early Trauma Inventory (ETI), the Daily Hassles Scale (DHS), the Inventory of Drug-Taking Situations (IDTS), and the Time-Line Follow-Back (TLFB; for 90 days prior to interview). There were no gender differences in the amount or frequency of cocaine use, although the patterns of use differed between male and female users. Overall, there were some associations in the patterns of cocaine use and sensitivity to daily hassles, particularly the use in response to conflict with others. Early negative life events were positively related to response to daily hassles, but current triggers were more relevant. Reactivity to cocaine cues was related to daily hassle sensitivity among women only. Limitations and implications of the findings are discussed.

  2. Cocaine abuse determination by ion mobility spectrometry using molecular imprinting.

    PubMed

    Sorribes-Soriano, A; Esteve-Turrillas, F A; Armenta, S; de la Guardia, M; Herrero-Martínez, J M

    2017-01-20

    A cocaine-based molecular imprinted polymer (MIP) has been produced by bulk polymerization and employed as selective solid-phase extraction support for the determination of cocaine in saliva samples by ion mobility spectrometry (IMS). The most appropriate conditions for washing and elution of cocaine from MIPs were studied and MIPs were characterized in terms of analyte binding capacity, reusability in water and saliva analysis, imprinting factor and selectivity were established and compared with non-imprinted polymers. The proposed MIP-IMS method provided a LOD of 18μgL(-1) and quantitative recoveries for blank saliva samples spiked from 75 to 500μgL(-1) cocaine. Oral fluid samples were collected from cocaine consumers and analysed by the proposed MIP-IMS methodology. Results, ranging from below the LOD to 51±2mgL(-1), were statistically comparable to those obtained by a confirmatory gas chromatography-mass spectrometry method. Moreover, results were compared to a qualitative lateral flow immunoassay procedure providing similar classification of the samples. Thus, MIP-IMS can be considered an useful alternative that provided fast, selective and sensitive results with a cost affordable instrumentation that does not require skilled operators.

  3. Cocaine: Pharmacology, Effects, and Treatment of Abuse. National Institute on Drug Abuse Research Monograph 50.

    ERIC Educational Resources Information Center

    Grabowski, John, Ed.

    This monograph consists of eight papers which refer in one way or another to the pharmacology of cocaine. The papers are: (1) Cocaine 1984: Introduction and Overview" (John Grabowski); (2) "Cocaine: A Growing Public Health Problem" (Edgar H. Adams and Jack Durell); (3) "Neural Mechanisms of the Reinforcing Action of…

  4. Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.

    PubMed

    Wright, Katherine N; Hollis, Fiona; Duclot, Florian; Dossat, Amanda M; Strong, Caroline E; Francis, T Chase; Mercer, Roger; Feng, Jian; Dietz, David M; Lobo, Mary Kay; Nestler, Eric J; Kabbaj, Mohamed

    2015-06-10

    Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway.

  5. Methyl Supplementation Attenuates Cocaine-Seeking Behaviors and Cocaine-Induced c-Fos Activation in a DNA Methylation-Dependent Manner

    PubMed Central

    Wright, Katherine N.; Hollis, Fiona; Duclot, Florian; Dossat, Amanda M.; Strong, Caroline E.; Francis, T. Chase; Mercer, Roger; Feng, Jian; Dietz, David M.; Lobo, Mary Kay; Nestler, Eric J.

    2015-01-01

    Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway. PMID:26063926

  6. Relationship between coronary artery ectasia, cocaine abuse and acute coronary syndromes

    PubMed Central

    Dendramis, Gregory; Paleologo, Claudia; Piraino, Davide; Assennato, Pasquale

    2016-01-01

    Coronary artery ectasia (CAE) often represents a coronary angiography finding casually detected or following the occurrence of an acute coronary syndrome. The pathogenetic role of cocaine abuse in the genesis of CAE is still little known and very few data are available in literature. We describe a case of a 31-year-old male cocaine user admitted to our department for typical acute chest pain. Coronary angiography showed diffuse coronary ectasia with slow flows and without hemodynamically significant stenosis. An increasing of matrix metalloproteinases values and a reduction of their tissue inhibitors was showed both during hospitalization and at one month after discharge. This case report emphasizes the close relationship between cocaine abuse, CAE and acute coronary syndromes in patients without hemodynamically significant coronary stenosis. As reported by Satran et al, cocaine abuse should be considered an important risk factor for CAE and these patients appear to be at increased risk of angina and acute myocardial infarct. Further studies that can strengthen this hypothesis would be useful to deepen and better analyze this interesting association. PMID:27231522

  7. Cocaine

    MedlinePlus

    ... The Brain & the Actions of Cocaine, Opiates, and Marijuana The first in a 5-part series, offers ... when a person uses cocaine, opiates (heroine), or marijuana. Download PDF 4.13 MB Chat Day Transcripts ...

  8. 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 ...

  9. Epigenetic modulation of brain gene networks for cocaine and alcohol abuse

    PubMed Central

    Farris, Sean P.; Harris, Robert A.; Ponomarev, Igor

    2015-01-01

    Cocaine and alcohol are two substances of abuse that prominently affect the central nervous system (CNS). Repeated exposure to cocaine and alcohol leads to longstanding changes in gene expression, and subsequent functional CNS plasticity, throughout multiple brain regions. Epigenetic modifications of histones are one proposed mechanism guiding these enduring changes to the transcriptome. Characterizing the large number of available biological relationships as network models can reveal unexpected biochemical relationships. Clustering analysis of variation from whole-genome sequencing of gene expression (RNA-Seq) and histone H3 lysine 4 trimethylation (H3K4me3) events (ChIP-Seq) revealed the underlying structure of the transcriptional and epigenomic landscape within hippocampal postmortem brain tissue of drug abusers and control cases. Distinct sets of interrelated networks for cocaine and alcohol abuse were determined for each abusive substance. The network approach identified subsets of functionally related genes that are regulated in agreement with H3K4me3 changes, suggesting cause and effect relationships between this epigenetic mark and gene expression. Gene expression networks consisted of recognized substrates for addiction, such as the dopamine- and cAMP-regulated neuronal phosphoprotein PPP1R1B/DARPP-32 and the vesicular glutamate transporter SLC17A7/VGLUT1 as well as potentially novel molecular targets for substance abuse. Through a systems biology based approach our results illustrate the utility of integrating epigenetic and transcript expression to establish relevant biological networks in the human brain for addiction. Future work with laboratory models may clarify the functional relevance of these gene networks for cocaine and alcohol, and provide a framework for the development of medications for the treatment of addiction. PMID:26041984

  10. Possibilities for discrimination between chewing of coca leaves and abuse of cocaine by hair analysis including hygrine, cuscohygrine, cinnamoylcocaine and cocaine metabolite/cocaine ratios.

    PubMed

    Rubio, Nelida Cristina; Hastedt, Martin; Gonzalez, Jorge; Pragst, Fritz

    2015-01-01

    Contrary to the illegal use of any form of manufactured cocaine, chewing of coca leaves and drinking of coca tea are allowed and are very common and socially integrated in several South American countries. Because of this different legal state, an analytical method for discrimination between use of coca leaves and abuse of processed cocaine preparations is required. In this study, the applicability of hair analysis for this purpose was examined. Hair samples from 26 Argentinean coca chewers and 22 German cocaine users were analysed for cocaine (COC), norcocaine (NC), benzoylecgonine (BE), ecgonine methyl ester (EME), cocaethylene (CE), cinnamoylcocaine (CIN), tropacocaine (TRO), cuscohygrine (CUS) and hygrine (HYG) by hydrophilic interaction liquid chromatography (HILIC) in combination with triplequad mass spectrometry (MS/MS) and hybrid quadrupole time-of-flight mass spectrometry (QTOF-MS). The following concentrations (range, median, ng/mg) were determined in hair of the coca chewers: COC 0.085-75.5, 17.0; NC 0.03-1.15, 0.12; BE 0.046-35.5, 6.1; EME 0.014-6.0, 0.66; CE 0.00-13.8, 0.38; CIN 0.005-16.8, 0.79; TRO 0.02-0.16, 0.023; CUS 0.026-26.7, 0.31. In lack of a reference substance, only qualitative data were obtained for HYG, and two metabolites of CUS were detected which were not found in hair of the cocaine users. For interpretation, the concentrations of the metabolites and of the coca alkaloids in relation to cocaine were statistically compared between coca chewers and cocaine users. By analysis of variance (ANOVA) significant differences were found for all analytes (α = 0.000 to 0.030) with the exception of TRO (α = 0.218). The ratios CUS/COC, CIN/COC and EME/COC appeared to be the most suitable criteria for discrimination between both groups with the means and medians 5-fold to 10-fold higher for coca chewers and a low overlap of the ranges between both groups. The same was qualitatively found for HYG. However, these criteria cannot exclude

  11. Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity

    PubMed Central

    Chen, Wei; Liu, Peng; Volkow, Nora D.; Pan, Yingtian; Du, Congwu

    2016-01-01

    Cocaine affects neuronal activity and constricts cerebral blood vessels, making it difficult to determine whether cocaine-induced changes in cerebral blood flow (CBF) reflect neuronal activation or its vasoactive effects. Here we assessed the effects of acute cocaine on both resting-state and stimulation responses to investigate cocaine’s effects on neurovascular coupling and to differentiate its effects on neuronal activity from its vasoactive actions. We concurrently measured cortical field potentials via thinned skull EEG recordings and CBF with laser Doppler flowmetry in the rat’s somatosensory cortex for both resting state and forepaw stimulation prior to and following cocaine administration (1mg/kg, i.v.). Results show both resting-state field potentials and CBF were depressed after cocaine administration (19.8±4.7% and 52.1±13.4%, respectively) and these changes were strongly correlated with each other (r=0.81, p<0.001) indicating that cocaine did not affect neurovascular coupling at rest and that the reduction in resting CBF reflected reduction in synchronized spontaneous neuronal activity rather than vasoconstriction. In contrast, the forepaw-stimulation-evoked neuronal activity was not changed by cocaine (p=0.244) whereas the CBF to the stimulation was reduced 49.9±2.6% (p=0.028) gradually recovering ~20min post cocaine injection, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling by cocaine during stimulation but not during rest indicates that distinct processes might underlie regulation of neurovascular coupling for spontaneous than for stimulation-induced activity. The greater reductions by cocaine to the stimulation-induced CBF increases than to the background CBF should be considered when interpreting fMRI studies comparing activation responses between controls and cocaine abusers. Neurovascular uncoupling could contribute to cocaine’s neurotoxicity particularly for

  12. Socioeconomic status is associated with striatal dopamine D2/D3 receptors in healthy volunteers but not in cocaine abusers

    PubMed Central

    Wiers, Corinde E.; Shokri-Kojori, Ehsan; Cabrera, Elizabeth; Cunningham, Samantha; Wong, Christopher; Tomasi, Dardo; Wang, Gene-Jack; Volkow, Nora D.

    2016-01-01

    Positron emission tomography (PET) studies in animals and humans have shown that social status is associated with striatal dopamine D2/D3 receptor (D2/D3R) availability. That is, higher social hierarchy and higher scores on questionnaires assessing social status correlated positively with striatal D2/D3R availability in animals and humans respectively. Furthermore, subordinate monkeys were vulnerable to cocaine self-administration, suggesting that alternations in social hierarchy can change D2/D3R availability and vulnerability to cocaine use. Here, we investigated whether socioeconomic status (SES) measured with the Hollingshead scale is associated with striatal D2D/3R availability using [11C]raclopride PET in 38 cocaine abusers and 42 healthy controls matched for age and education. Compared to controls, cocaine abusers showed lower D2/D3R availability in the caudate, putamen and ventral striatum (all p≤.001). Despite matching groups for education, SES scores were lower in cocaine abusers than controls (p<.001). In the control group only, SES scores significantly correlated with D2/D3R in caudate (r=.35, p=.024) and putamen (r=.39, p=.011) but not in ventral striatum (p=.61); all corrected for age. The study confirms that SES is associated with striatal D2/D3R availability in healthy human volunteers. However, reductions in D2/D3R availability in cocaine abusers may be driven by factors other than SES such as chronic cocaine exposure. PMID:26828302

  13. Cocaine induces cell death and activates the transcription nuclear factor kappa-b in pc12 cells

    PubMed Central

    Lepsch, Lucilia B; Munhoz, Carolina D; Kawamoto, Elisa M; Yshii, Lidia M; Lima, Larissa S; Curi-Boaventura, Maria F; Salgado, Thais ML; Curi, Rui; Planeta, Cleopatra S; Scavone, Cristoforo

    2009-01-01

    Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-κB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-κB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM) for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment) activated the p50/p65 subunit of NF-κB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-κB activation. Inhibition of NF-κB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis) and activates NF-κB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells. PMID:19183502

  14. Cocaine induces cell death and activates the transcription nuclear factor kappa-B in PC12 cells.

    PubMed

    Lepsch, Lucilia B; Munhoz, Carolina D; Kawamoto, Elisa M; Yshii, Lidia M; Lima, Larissa S; Curi-Boaventura, Maria F; Salgado, Thais M L; Curi, Rui; Planeta, Cleopatra S; Scavone, Cristoforo

    2009-02-01

    Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-kappaB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-kappaB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM) for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment) activated the p50/p65 subunit of NF-kappaB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-kappaB activation. Inhibition of NF-kappaB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis) and activates NF-kappaB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells.

  15. Executive Dysfunction and Reward Dysregulation: A High-Density Electrical Mapping Study in Cocaine Abusers

    PubMed Central

    Morie, Kristen P.; De Sanctis, Pierfilippo; Garavan, Hugh; Foxe, John J.

    2015-01-01

    Executive function deficits and reward dysregulation, which mainly manifests as anhedonia, are well documented in drug abusers. We investigated specific aspects of executive function (inhibitory control and cognitive control), as well as anhedonia, in a cohort of current cocaine abusers in order to ascertain to what extent these factors are associated with more severe drug dependence. Participants filled out questionnaires relating to anhedonia and their addiction history. Participants also performed a response inhibition task while high-density event-related potentials (ERPs) were recorded. Electrophysiological responses to successful inhibitions (N2/P3 components) and to commission errors (ERN/Pe components) were compared between 23 current users of cocaine and 27 non-using controls. A regression model was performed to determine the association of our measures of reward dysregulation and executive function with addiction severity. As expected, cocaine users performed more poorly than controls on the inhibitory control task and showed significant electrophysiological differences. They were also generally more anhedonic than controls. Higher levels of anhedonia were associated with more severe substance use, whereas the level of executive dysfunction was not associated with more severe substance use. However, N2 amplitude was associated with duration of drug use. Further, inhibitory control and anhedonia were correlated, but only in controls. These data suggest that while executive dysfunction characterizes drug abuse, it is anhedonia, independent of executive dysfunction, that is most strongly associated with more severe use. PMID:24911989

  16. Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.

    PubMed

    Puhl, Matthew D; Berg, Alexandra R; Bechtholt, Anita J; Coyle, Joseph T

    2015-06-01

    Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse.

  17. Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

    PubMed Central

    Siciliano, Cody A.; Fordahl, Steve C.

    2016-01-01

    Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a “primed” state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse. SIGNIFICANCE STATEMENT Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action

  18. The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration.

    PubMed

    Job, Martin O; Shen, Li L; Kuhar, Michael J

    2013-08-29

    CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.

  19. Acute myocardial infarction secondary to catecholamine release owing to cocaine abuse and pheochromocytoma crisis.

    PubMed

    Martinez-Quintana, Efren; Jaimes-Vivas, Ricardo; Cuba-Herrera, Javiel; Saiz-Udaeta, Beatriz; Rodríguez-Gonzalez, Fayna; Martinez-Martin, Maria Soledad

    2013-01-01

    Most pheochromocytomas are not suspected clinically while a high percentage of them are curable with surgery. We present the case of an adult cocaine-addicted male patient with an underlying pheochromocytoma and repeated myocardial infarctions. Computed tomography showed a left round adrenal mass, also high 24-hour urine levels of catecholamines and metanephrines were detected from urinalysis. The patient was given alpha and beta blockers, moreover a laparoscopic left adrenalectomy was performed. Cocaine can block the reuptake of noradrenaline, leading to increasing its concentration and consequently its effects as well, and induce local or diffuse coronary vasoconstriction in normal coronary artery segments per se, cocaine can also trigger pheochromocytoma crisis, and therefore, cardiac complications such as myocardial infarction due to these additive effects are intended to occur. For this reason, in the presence of typical clinical manifestations of pheochromocytoma, such as sustained or paroxysmal hypertension, headache, sweating, tachycardia and abdominal pain, probable association of this tumor in patients with cocaine abuse and associated cardiac complications must be ruled out.

  20. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

    PubMed

    Sakae, D Y; Marti, F; Lecca, S; Vorspan, F; Martín-García, E; Morel, L J; Henrion, A; Gutiérrez-Cuesta, J; Besnard, A; Heck, N; Herzog, E; Bolte, S; Prado, V F; Prado, M A M; Bellivier, F; Eap, C B; Crettol, S; Vanhoutte, P; Caboche, J; Gratton, A; Moquin, L; Giros, B; Maldonado, R; Daumas, S; Mameli, M; Jamain, S; El Mestikawy, S

    2015-11-01

    Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

  1. Block of a Ca(2+)-activated potassium channel by cocaine.

    PubMed

    Premkumar, L S

    2005-04-01

    The primary target for cocaine is believed to be monoamine transporters because of cocaine's high-affinity binding that prevents re-uptake of released neurotransmitter. However, direct interaction with ion channels has been shown to be important for certain pharmacological/toxicological effects of cocaine. Here I show that cocaine selectively blocks a calcium-dependent K(+) channel in hippocampal neurons grown in culture (IC(50)=approximately 30 microM). Single-channel recordings show that in the presence of cocaine, the channel openings are interrupted with brief closures (flicker block). As the concentration of cocaine is increased the open-time is reduced, whereas the duration of brief closures is independent of concentration. The association and dissociation rate constants of cocaine for the neuronal Ca(2+)-activated K(+ )channels are 261+/-37 microM: (-1)s(-1) and 11451+/-1467 s(-1). The equilibrium dissociation constant (K(B)) for cocaine, determined from single-channel parameters, is 43 microM. The lack of voltage dependence of block suggests that cocaine probably binds to a site at the mouth of the pore. Block of Ca(2+)-dependent K(+) channels by cocaine may be involved in functions that include broadening of the action potential, which would facilitate transmitter release, enhancement of smooth muscle contraction particularly in blood vessels, and modulation of repetitive neuronal firing by altering the repolarization and afterhyperpolarization phases of the action potential.

  2. Acupuncture reduces relapse to cocaine-seeking behavior via activation of GABA neurons in the ventral tegmental area.

    PubMed

    Jin, Wyju; Kim, Min Sun; Jang, Eun Young; Lee, Jun Yeon; Lee, Jin Gyeom; Kim, Hong Yu; Yoon, Seong Shoon; Lee, Bong Hyo; Chang, Suchan; Kim, Jae Hyo; Choi, Kwang H; Koo, Ho; Gwak, Young Seob; Steffensen, Scott C; Ryu, Yeon-Hee; Kim, Hee Young; Yang, Chae Ha

    2017-03-07

    There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA.

  3. The effects of housing costs on polydrug abuse patterns: a comparison of heroin, cocaine, and alcohol abusers.

    PubMed

    Petry, N M

    2001-02-01

    This study evaluated how price of housing affects hypothetical purchasing decisions. Participants (26 heroin, 28 cocaine, and 15 alcohol abusers, and 25 controls) were exposed to 4 conditions in which they "purchased" drugs, food, housing, and entertainment. Whereas income remained constant, housing prices varied across conditions. Except for 23% of heroin abusers, participants purchased housing regardless of cost, so that income increased as housing cost decreased. Demand for food was income inelastic, whereas demand for entertainment was income elastic. Each group showed income elastic demand for their drug of choice. Hypothetical choices were reliable; drug choices were correlated with urinalysis results, and willingness to forgo housing in the simulation was correlated with time spent homeless in real life. This study shows that changes in housing prices may affect choices for drug and nondrug reinforcers.

  4. Photoacoustic imaging to detect rat brain activation after cocaine hydrochloride injection

    NASA Astrophysics Data System (ADS)

    Jo, Janggun; Yang, Xinmai

    2011-03-01

    Photoacoustic imaging (PAI) was employed to detect small animal brain activation after the administration of cocaine hydrochloride. Sprague Dawley rats were injected with different concentrations (2.5, 3.0, and 5.0 mg per kg body) of cocaine hydrochloride in saline solution through tail veins. The brain functional response to the injection was monitored by photoacoustic tomography (PAT) system with horizontal scanning of cerebral cortex of rat brain. Photoacoustic microscopy (PAM) was also used for coronal view images. The modified PAT system used multiple ultrasonic detectors to reduce the scanning time and maintain a good signal-to-noise ratio (SNR). The measured photoacoustic signal changes confirmed that cocaine hydrochloride injection excited high blood volume in brain. This result shows PAI can be used to monitor drug abuse-induced brain activation.

  5. Cerebral abnormalities in cocaine abusers: Demonstration by SPECT perfusion brain scintigraphy. Work in progress

    SciTech Connect

    Tumeh, S.S.; Nagel, J.S.; English, R.J.; Moore, M.; Holman, B.L. )

    1990-09-01

    Single photon emission computed tomography (SPECT) perfusion brain scans with iodine-123 isopropyl iodoamphetamine (IMP) were obtained in 12 subjects who acknowledged using cocaine on a sporadic to a daily basis. The route of cocaine administration varied from nasal to intravenous. Concurrent abuse of other drugs was also reported. None of the patients were positive for human immunodeficiency virus. Brain scans demonstrated focal defects in 11 subjects, including seven who were asymptomatic, and no abnormality in one. Among the findings were scattered focal cortical deficits, which were seen in several patients and which ranged in severity from small and few to multiple and large, with a special predilection for the frontal and temporal lobes. No perfusion deficits were seen on I-123 SPECT images in five healthy volunteers. Focal alterations in cerebral perfusion are seen commonly in asymptomatic drug users, and these focal deficits are readily depicted by I-123 IMP SPECT.

  6. Cocaine abuse that presents with acute scrotal pain and mimics testicular torsion

    PubMed Central

    Tamanini, José Tadeu Nunes; Salzani, Vagner Tadeu; Tamanini, Juliana Milhomem; Iessenco, Filipe; Reis, Leonardo O.

    2016-01-01

    ABSTRACT Report case (s) relevant aspects: Man, 27 years old, complaining of acute testicular pain by 2 hours in the remaining left testicle. Denies fever, lower urinary tract symptoms such as dysuria, urinary frequency, concommitant or prior urethral discharge to the painful condition. He underwent right orchiectomy 13 years ago by testicular torsion. He is a chronic user of cocaine for 15 years and during the last three days the drug use was continuous and intense. Proposed premise substantiating case (s) description: Initial diagnostic hypothesis: Syndromic: Acute Scrotum Syndrome (SEA) Main Etiologic (testicular torsion)Secondary Etiologic (acute orchiepididymitis) Briefly delineates what might it add? Lines of research That Could be Addressed: In this challenging clinical case we presented an alternative and new etiologic diangosis for the acute scrotum which the main etiologic factor remains testicular torsion. This new diangosis is acute testicular ischemia as a complication of cocaine abuse. PMID:27583357

  7. The role of progestins in the behavioral effects of cocaine and other drugs of abuse: human and animal research.

    PubMed

    Anker, Justin J; Carroll, Marilyn E

    2010-11-01

    This review summarizes findings from human and animal research investigating the influence of progesterone and its metabolites allopreganolone and pregnanolone (progestins) on the effects of cocaine and other drugs of abuse. Since a majority of these studies have used cocaine, this will be the primary focus; however, the influence of progestins on other drugs of abuse will also be discussed. Collectively, findings from these studies support a role for progestins in (1) attenuating the subjective and physiological effects of cocaine in humans, (2) blocking the reinforcing and other behavioral effects of cocaine in animal models of drug abuse, and (3) influencing behavioral responses to other drugs of abuse such as alcohol and nicotine in animals. Administration of several drugs of abuse in both human and nonhuman animals significantly increased progestin levels, and this is explained in terms of progestins acting as homeostatic regulators that decrease and normalize heightened stress and reward responses which lead to increased drug craving and relapse. The findings discussed here highlight the complexity of progestin-drug interactions, and they suggest a possible use for these agents in understanding the etiology of and developing treatments for drug abuse.

  8. The Role of Progestins in the Behavioral Effects of Cocaine and Other Drugs of Abuse: Human and Animal Research

    PubMed Central

    Anker, Justin J.; Carroll, Marilyn E.

    2011-01-01

    This review summarizes findings from human and animal research investigating the influence of progesterone and its metabolites allopreganolone and pregnanolone (progestins) on the effects of cocaine and other drugs of abuse. Since a majority of these studies have used cocaine, this will be the primary focus; however, the influence of progestins on other drugs of abuse will also be discussed. Collectively, findings from these studies support a role for progestins in: 1) attenuating the subjective and physiological effects of cocaine in humans, 2) blocking the reinforcing and other behavioral effects of cocaine in animal models of drug abuse, and 3) influencing behavioral responses to other drugs of abuse such as alcohol and nicotine in animals. Administration of several drugs of abuse in both human and nonhuman animals significantly increased progestin levels, and this is explained in terms of progestins acting as homeostatic regulators that decrease and normalize heightened stress and reward responses which lead to increased drug craving and relapse. The findings discussed here highlight the complexity of progestin-drug interactions, and they suggest a possible use for these agents in understanding the etiology and developing treatments for drug abuse. PMID:20398693

  9. Effects of age of serotonin 5-HT2 receptors in cocaine abusers and normal subjects

    SciTech Connect

    Wang, G.J.; Volkow, N.D.; Logan, J.

    1995-05-01

    We measured the effect of age on serotonin 5-HT2 receptor availability and compared it with the effects on dopamine D2 receptors on 19 chronic cocaine abusers (35.2{plus_minus}9.8 years, range 18-54 years old) and 19 age matched normal controls using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was measure din frontal (FR), occipital (OC), cingulate (CI) and orbitofrontal (OF) cortices using the ratio of the distribution volume in the region of interest to that in the cerebelium (CB) which is a function of Bmax/Kd. D2 receptor availability in the basal ganglia was measured using the {open_quotes}ratio index{close_quotes} (slope of striatum/CB versus time over 180 min of the scan) which is a function of Bmax. 5-HT2 Receptor availability differed among regions and were as follows: CI>OF>OC>FC.5-HT2 Receptor availability decreased significantly with age. This effect was more accentuated for 5-HT2 receptor availability in FR than in OC(df=1, p<0.025). Striatal dopamine D2 receptors were also found to decrease significantly with age (r=0.63, p<0.007). In a given subject, D2 receptor availability was significantly correlated with 5-HT2 receptor availability in FR (r=0.51, p<0.035) but not in OC. The values for 5-HT2 receptor availability were not different in normal subjects and cocaine abusers. These results document a decline in 5-HT2 and D2 receptors with age and document an association between frontal 5-HT2 and striatal D2 receptor availability. These results did not show any changes in 5-HT2 receptor availability in cocaine abusers as compared to control subjects.

  10. Concentrations of delta 9-tetrahydrocannabinol, cocaine and 6-monoacetylmorphine in hair of drug abusers.

    PubMed

    Kauert, G; Röhrich, J

    1996-01-01

    Hair samples taken from 850 individuals with presumed drug abuse were tested simultaneously for delta 9-tetrahydrocannabinol (THC), cocaine, heroin, the primary heroin metabolite 6-monoacetylmorphine (6-MAM) and morphine. The drugs were extracted with methanol under sonication. Compared to other extraction procedures this solvent extraction technique provides high extraction yields and less experimental effort. The analyses were carried out using gas chromatography-mass spectrometry (GCMS) in selected ion monitoring (SIM) mode. This procedure allows the simultaneous detection of amphetamine, methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA) and methylenedioxylamphetamine (MDE). THC was found in 104 (12.2%), cocaine in 230 (27%) and 6-MAM in 141 (16.6%) samples. In addition to 6-MAM, morphine was detected in 87 (10.2%) and heroin in 38 samples (4.5%). The concentrations found were in a range 0.009-16.7 ng/mg for THC, 0.037-129.68 ng/mg for cocaine, 0.028-79.82 ng/mg for 6-MAM, 0.045-53.14 ng/mg for heroin and 0.011-7.800 ng/mg for morphine. The statistical distribution of the drug concentrations compared with the self-reported consumption behaviour of the users may possibly lead to a better understanding of the relationship between drug dosage and corresponding concentrations in hair.

  11. A miniaturised image based fluorescence detection system for point-of-care-testing of cocaine abuse

    NASA Astrophysics Data System (ADS)

    Walczak, Rafał; Krüger, Jan; Moynihan, Shane

    2015-08-01

    In this paper, we describe a miniaturised image-based fluorescence detection system and demonstrate its viability as a highly sensitive tool for point-of-care-analysis of drugs of abuse in human sweat with a focus on monitor individuals for drugs of abuse. Investigations of miniaturised and low power optoelectronic configurations and methodologies for real-time image analysis were successfully carried out. The miniaturised fluorescence detection system was validated against a reference detection system under controlled laboratory conditions by analysing spiked sweat samples in dip stick and then strip with sample pad. As a result of the validation studies, a 1 ng mL-1 limit of detection of cocaine in sweat and full agreement of test results with the reference detection system can be reported. Results of the investigations open the way towards a detection system that integrates a hand-held fluorescence reader and a wearable skinpatch, and which can collect and in situ analyse sweat for the presence of cocaine at any point for up to tenths hours.

  12. Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging.

    PubMed

    Nader, Michael A; Banks, Matthew L

    2014-01-01

    The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

  13. Resting state brain connectivity patterns before eventual relapse into cocaine abuse.

    PubMed

    Berlingeri, M; Losasso, D; Girolo, A; Cozzolino, E; Masullo, T; Scotto, M; Sberna, M; Bottini, G; Paulesu, E

    2017-01-03

    According to recent theories, drug addicted patients suffer of an impaired response inhibition and salience attribution (I-RISA) together with a perturbed connectivity between the nuclei accumbens (NAcs) and the orbito-prefrontal (oPFC) and dorsal prefrontal (dPFC) cortices, brain regions associated with motivation and cognitive control. To empirically test these assumptions, we evaluated the (neuro)psychological trait and the functional organization of the resting state brain networks associated with the NAcs in 18 former cocaine abusers (FCAs), while being in drug abstinence since 5 months. The psychological data were grouped into three empirical variables related with emotion regulation, emotion awareness and strategic and controlled behaviour. Comparison of the resting state patterns between the entire sample of FCAs and 19 controls revealed a reduction of functional connectivity between the NAcs and the dPFC and enhanced connectivity between the NAcs and the dorsal-striatum. In the 8 FCAs who relapsed into cocaine use after 3 months, the level of functional connectivity between the NAcs and dPFC was lower than the functional connectivity estimated in the group of patients that did not relapsed. Finally, in the entire sample of FCAs, the higher the connectivity between the NAc and the oPFC the lower was the level of strategic and controlled behaviour. Taken together, these results are compatible with models of the interactions between the NAcs, the dorsal striatum and frontal cortices in the I-RISA syndrome, showing that such interactions are particularly perturbed in patients at greater risk of relapse into cocaine abuse.

  14. Drug Abuse: The Crack Cocaine Epidemic Health Consequences and Treatment.

    DTIC Science & Technology

    1991-01-01

    Addicts agonists,2 such as bromocriptine and amantadine . Antidepressants and dopamine agonists help to alleviate the feelings of anhedonia or the... dopamine , a chemical found naturally in the brain, causing it to remain active longer than normal. This retention of dopamine changes brain activity...and dopamine I Although it has been used worldwide for over a decade without reports of important adverse effects, flupenthixol is not yet licensed

  15. Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients.

    PubMed

    Addai, Amma B; Pandhare, Jui; Paromov, Victor; Mantri, Chinmay K; Pratap, Siddharth; Dash, Chandravanu

    2015-04-01

    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.

  16. Use of drugs of abuse in less than 30-year-old drivers killed in a road crash in France: a spectacular increase for cannabis, cocaine and amphetamines.

    PubMed

    Mura, P; Chatelain, C; Dumestre, V; Gaulier, J M; Ghysel, M H; Lacroix, C; Kergueris, M F; Lhermitte, M; Moulsma, M; Pépin, G; Vincent, F; Kintz, P

    2006-07-13

    A collaborative study was conducted in France in order to determine the prevalence of cannabinoids, opiates, cocaine metabolites and amphetamines in blood samples from drivers killed in road accidents in 2003 and 2004 and to compare these values with those of a previous study performed during the period 2000-2001 involving 900 drivers. Blood samples were provided from 2003 under 30-year-old drivers, killed in a traffic accident. Drugs of abuse were determined by gas chromatography-mass spectrometry using the same analytical procedures in all the 12 laboratories. The most frequently observed compounds were by far cannabinoids, that tested positive in 39.6% of the total number of samples. Delta9 tetrahydrocannabinol (THC), the most active of the principle constituents in marijuana (cannabis sativa), was detected in the blood of 28.9% drivers and was the single drug of abuse in 80.2% of the positive cases. It was associated with amphetamines in 7.4% and with opiates and cocaine in 1.9 and 4.8%, respectively. Amphetamines were present in 3.1% of the total number of samples, cocaine metabolites in 3.0% and opiates in 3.5%. When comparing these results with those of a previous study performed 3 years before, a significant increase is observed for THC (28.9% versus 16.9%), cocaine metabolites (3.0% versus 0.2%) and amphetamines (3.1% versus 1.4%). This study demonstrates the critical necessity of implementing in France as soon as possible systematical roadside testing for drugs of abuse.

  17. Screening for marijuana and cocaine abuse by immunoanalysis and gas chromatography.

    PubMed

    Garcia-Jimenez, Sara; Heredia-Lezama, Karina; Bilbao-Marcos, Fernando; Fuentes-Lara, Griselda; Monroy-Noyola, Antonio; Deciga-Campos, Myrna

    2008-10-01

    Drug abuse among college students is characterized by lower academic performance and long-term negative consequences. Screening to detect students at high risk of consuming drugs is of primary importance to insure early identification and appropriate levels of care. As a result, this study aimed to determine the current or past use of drug abuse through a questionnaire applied to a student population at the Universidad Autónoma del Estado de Morelos. The results were confirmed by immunoanalysis and gas chromatography of urine. We interviewed 181 students aged 15 to 21 (gender was not considered in this study), and urine samples were collected for analytical analysis. For detection of metabolites Delta9-THCA-A and benzoylecgonine from marijuana and cocaine, respectively, a homogenous enzymatic inmmunoanalysis was used; subsequent samples were analyzed by a mass spectrometer with quadrupole detector. Seven samples of the total (181) did not completely fit the inclusion criteria and were eliminated. The results showed 0.50% and 1.16% positive samples for benzoylecgonine and Delta9-THCA-A, respectively. These results are not different from those of the National Questionnaire on Addiction. We can establish a program for detecting drug consumption in our students. This kind of study is important in order to implement programs that can help us to decrease the abuse of drugs in our college population.

  18. Individual differences in cocaine-induced locomotor activity of male Sprague-Dawley rats are not explained by plasma corticosterone levels.

    PubMed

    Nelson, Anna M; Kleschen, Melissa J; Zahniser, Nancy R

    2010-05-26

    Humans differ in their initial response to, and subsequent abuse of, addictive drugs like cocaine. Rodents also exhibit marked individual differences in responsiveness to cocaine. Previously, we classified male Sprague-Dawley rats as either low or high cocaine responders (LCRs or HCRs, respectively), based on their acute low-dose cocaine-induced locomotor activity, and found that with repeated drug exposure LCRs exhibit greater cocaine locomotor sensitization, reward and reinforcement than HCRs. Differential cocaine-induced increases in striatal dopamine help to explain the LCR/HCR phenotypes. Differential levels of stress and/or anxiety could also contribute but have not been explored. Here we measured open-field activity and plasma corticosterone levels both pre- and post-cocaine treatment in LCRs, HCRs, and saline-treated controls. The three groups did not differ in baseline locomotor activity or corticosterone levels. Importantly, LCR/HCR differences in corticosterone levels were also not observed following acute cocaine (10mg/kg, i.p.), when cocaine induced approximately 3.5-fold greater locomotor activity in HCRs than LCRs. Additionally, there were no LCR/HCR differences in plasma corticosterone levels following 5 days of once-daily cocaine, during which time LCRs developed locomotor sensitization such that their cocaine-induced locomotor activity no longer differed from that of HCRs. Likewise, there were no group activity differences in any of four concentric zones within the open-field chamber. In summary, neither plasma corticosterone levels nor thigmotaxis-type anxiety appears to be a factor that contributes to the observed cocaine-induced LCR/HCR behavioral differences.

  19. Effects of Nalbuphine on Anterior Pituitary and Adrenal Hormones and Subjective Responses in Male Cocaine Abusers

    PubMed Central

    Goletiani, Nathalie V.; Mendelson, Jack H.; Sholar, Michelle B.; Siegel, Arthur J.; Skupny, Alicja J.; Mello, Nancy K.

    2007-01-01

    Nalbuphine (Nubain®) is a mixed action mu-kappa agonist used clinically for the management of pain. Nalbuphine and other mu-kappa agonists decreased cocaine self-administration in preclinical models. Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effects of nalbuphine on the HPA axis are unknown. Analgesic doses (5 and 10 mg/70 kg) of IV nalbuphine were administered to healthy male cocaine abusers, and plasma levels of PRL, ACTH and cortisol were measured before and at 10, 17, 19, 23, 27, 31, 35, 40, 45, 60, 75, 105, 135 min after nalbuphine administration. Subjective effects were measured on a Visual Analog Scale (VAS). Prolactin (PRL) increased significantly within 17 min (P=.04) and reached peak levels of 22.1 ± 7.1 ng/ml and 54.1 ± 11.3 at 60 min after low and high dose nalbuphine administration, respectively. VAS reports of “Sick,” “Bad” and “Dizzy” were significantly higher after 10 mg/70 kg than after 5 mg/70 kg nalbuphine (P=.05−.0001), and were significantly correlated with increases in PRL (P=.05−.0003). However, sedation and emesis were observed only after a 10 mg/70 kg dose of nalbuphine. Interestingly, ACTH and cortisol levels did not change significantly after administration of either dose of nalbuphine. Taken together, these data suggest that nalbuphine had both mu- and kappa-like effects on PRL (PRL increase) but did not increase ACTH and cortisol. PMID:17391744

  20. Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

    PubMed

    Perrine, Shane A; Ghoddoussi, Farhad; Desai, Kirtan; Kohler, Robert J; Eapen, Ajay T; Lisieski, Michael J; Angoa-Perez, Mariana; Kuhn, Donald M; Bosse, Kelly E; Conti, Alana C; Bissig, David; Berkowitz, Bruce A

    2015-11-01

    A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.

  1. Brain activation to cocaine cues and motivation/treatment status.

    PubMed

    Prisciandaro, James J; McRae-Clark, Aimee L; Myrick, Hugh; Henderson, Scott; Brady, Kathleen T

    2014-03-01

    Motivation to change is believed to be a key factor in therapeutic success in substance use disorders; however, the neurobiological mechanisms through which motivation to change impacts decreased substance use remain unclear. Existing research is conflicting, with some investigations supporting decreased and others reporting increased frontal activation to drug cues in individuals seeking treatment for substance use disorders. The present study investigated the relationship between motivation to change cocaine use and cue-elicited brain activity in cocaine-dependent individuals using two conceptualizations of 'motivation to change': (1) current treatment status (i.e. currently receiving versus not receiving outpatient treatment for cocaine dependence) and (2) self-reported motivation to change substance use, using the Stages of Change Readiness and Treatment Eagerness Scale. Thirty-eight cocaine-dependent individuals (14 currently in treatment) completed a diagnostic assessment and an fMRI cocaine cue-reactivity task. Whole-brain analyses demonstrated that both treatment-seeking and motivated participants had lower activation to cocaine cues in a wide variety of brain regions in the frontal, occipital, temporal and cingulate cortices relative to non-treatment-seeking and less motivated participants. Future research is needed to explain the mechanism by which treatment and/or motivation impacts neural cue reactivity, as such work could potentially aid in the development of more effective therapeutic techniques for substance-dependent patients.

  2. Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The benztropine analog JHW 007 displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks effects of cocaine,including its self-administration. To determine sites responsible for the cocaine-antagonist effects of JHW 007, ...

  3. A pharmacological study of cocaine activity in planaria.

    PubMed

    Palladini, G; Ruggeri, S; Stocchi, F; De Pandis, M F; Venturini, G; Margotta, V

    1996-09-01

    Planaria has been proposed as a suitable research model in neurobiology because of its relatively simple organization. Dopaminergic agonists induce in this flatworm typical hyperkinesias that can be antagonized by dopaminergic blocking agents. The neurochemical basis of the effects of cocaine in vertebrates has not been fully elucidated, but the inhibition of catecholamine reuptake at a presynaptic level seems to play an important role. In this study we analyzed the involvement of the dopaminergic system in the mechanism of action of cocaine in planaria. The dose-related effects of cocaine on planaria motility and the response to cocaine treatment associated with the administration of specific D1 or D2 dopamine agonists and antagonists were investigated. The effects of reuptake inhibitors on cocaine activity were also studied. Planaria specimens treated with low doses of cocaine become motionless, whereas high doses induce a typical behavioural response, identical to the response induced by specific D2 agonists. This response is inhibited by a D2 selective blocking agent. Nomifensine, a specific dopamine reuptake inhibitor, induces a mixed D1/D2 response. The results of these experiments are discussed, also in relation with the conservation of dopaminergic receptors during evolution.

  4. Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release.

    PubMed

    Chartoff, Elena H; Ebner, Shayla R; Sparrow, Angela; Potter, David; Baker, Phillip M; Ragozzino, Michael E; Roitman, Mitchell F

    2016-03-01

    Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation-as occurs upon withdrawal from chronic cocaine-modulates vulnerability to cocaine in a time-dependent manner.

  5. Contingency management in cocaine abusers: a dose-effect comparison of goods-based versus cash-based incentives.

    PubMed

    Vandrey, Ryan; Bigelow, George E; Stitzer, Maxine L

    2007-08-01

    Goods-based contingency management interventions (e.g., those using vouchers or prizes as incentives) have demonstrated efficacy in reducing cocaine use, but cost has limited dissemination to community clinics. Recent research suggests that development of a cash-based contingency management approach may improve treatment outcomes while reducing operational costs of the intervention. However, the clinical safety of providing cash-based incentives to substance abusers has been a concern. The present 16-week study compared the effects of goods-based versus cash-based incentives worth $0, $25, $50, and $100 on short-term cocaine abstinence in a small sample of cocaine-dependent methadone patients (N = 12). A within-subject design was used; a 9-day washout period separated each of 8 incentive conditions. Higher magnitude ($50 and $100) cash-based incentives (checks) produced greater cocaine abstinence compared with the control ($0) condition, but a magnitude effect was not seen for goods-based incentives (vouchers). A trend was observed for greater rates of abstinence in the cash-based versus goods-based incentives at the $50 and $100 magnitudes. Receipt of $100 checks did not increase subsequent rates of cocaine use above those seen in control conditions. The efficacy and safety data provided in this and other recent studies suggest that use of cash-based incentives deserves consideration for clinical applications of contingency management, but additional confirmation in research using larger samples and more prolonged periods of incentive delivery is needed.

  6. Chemokines and cocaine: CXCR4 receptor antagonist AMD3100 attenuates cocaine place preference and locomotor stimulation in rats.

    PubMed

    Kim, Jae; Connelly, Krista L; Unterwald, Ellen M; Rawls, Scott M

    2016-08-26

    Plasma levels of the chemokine CXCL12 are elevated in mice following acute cocaine exposure and decreased in human cocaine abusers during withdrawal. CXCL12 is also one of the few chemokines located in the brain and can modulate dopamine transmission through activation of its receptor CXCR4. To assess a role for the CXCL12/CXCR4 system in behavioral effects of cocaine, we tested the hypothesis that AMD 3100 (Plerixafor), a CXCR4 antagonist, would inhibit conditioned place preference (CPP) and locomotor activation produced by cocaine. Rats injected with cocaine (10mg/kg) displayed CPP relative to saline-injected controls following 4 conditioning sessions. AMD 3100 (1, 2.5, 5mg/kg) administered prior to cocaine conditioning reduced development of cocaine CPP. AMD 3100 (5mg/kg) also inhibited expression of cocaine-induced CPP in a paradigm in which it was injected once (following cocaine conditioning and just prior to CPP testing). In addition, AMD 3100 (5, 10mg/kg) pretreatment reduced locomotor activation produced by an acute cocaine injection (15mg/kg) but did not affect basal locomotor activity relative to saline-injected controls. Repeated cocaine exposure produced a significant increase (1.49-fold) in CXCL12 mRNA expression in the ventral tegmental area (VTA). Our results suggest that the CXCL12/CXCR4 system in the brain reward circuit is impacted by cocaine exposure and influences behavioral effects related to the abuse liability of cocaine.

  7. Abstinence-Contingent Reinforcement and Engagement in Non-drug Related Activities among Illicit Drug Abusers

    PubMed Central

    Rogers, Randall E.; Higgins, Stephen T.; Silverman, Kenneth; Thomas, Colleen S.; Badger, Gary J.; Bigelow, George; Stitzer, Maxine

    2010-01-01

    Methadone-maintained cocaine abusers (n = 78) were randomly assigned to a 52-week intervention of either (1) usual care only (UC), (2) take-home methadone doses contingent on cocaine- and opiate-negative results (THM), or (3) take-home methadone doses for cocaine- and opiate-negative results and monetary-based vouchers contingent on cocaine-negative urinalysis results (THM+V). Cocaine use was assessed by urinalysis on a thrice-weekly schedule. Frequency and enjoyability of non-drug related activities were assessed with the Pleasant Events Schedule (PES) at baseline, mid-, and end-of-treatment. The THM+V condition achieved the greatest abstinence from cocaine and opiate use, followed by the THM and UC conditions. The THM+V condition had the highest PES Frequency ratings at mid- and end-of-treatment, followed by the THM and UC conditions. There were significant differences between the THM+V and UC conditions on 10 of 12 PES subscales. Analyses revealed that abstinence mediated the effects of treatment condition on frequency ratings. There were no significant differences in Enjoyability ratings. These results suggest that when contingency-management interventions increase abstinence from drug abuse they also increase engagement in non-drug related activities in naturalistic settings. PMID:19071979

  8. Abstinence-contingent reinforcement and engagement in non-drug-related activities among illicit drug abusers.

    PubMed

    Rogers, Randall E; Higgins, Stephen T; Silverman, Kenneth; Thomas, Colleen S; Badger, Gary J; Bigelow, George; Stitzer, Maxine

    2008-12-01

    Methadone-maintained cocaine abusers (N = 78) were randomly assigned to 1 of the following 52-week interventions: (a) usual care only (UC), (b) take-home methadone doses contingent on cocaine- and opiate-negative results (THM), or (c) take-home methadone doses for cocaine- and opiate-negative results and monetary-based vouchers contingent on cocaine-negative urinalysis results (THM + V). Cocaine use was assessed by urinalysis on a thrice-weekly schedule. Frequency and enjoyability of non-drug-related activities were assessed with the Pleasant Events Schedule (PES) at baseline, midtreatment, and end of treatment. The THM + V condition achieved the greatest abstinence from cocaine and opiate use, followed by the THM and UC conditions. The THM + V condition had the highest PES frequency ratings at midtreatment and at the end of treatment, followed by the THM and UC conditions. There were significant differences between the THM + V and UC conditions on 10 of 12 PES-derived subscales. Analyses revealed that abstinence mediated the effects of treatment condition on frequency ratings. There were no significant differences in enjoyability ratings. These results suggest that when contingency-management interventions increase abstinence from drug abuse, they also increase engagement in non-drug-related activities in naturalistic settings.

  9. Cocaine and crack cocaine abuse by pregnant or lactating mothers and analysis of its biomarkers in meconium and breast milk by LC-MS-A review.

    PubMed

    D'Avila, Felipe Bianchini; Limberger, Renata Pereira; Fröehlich, Pedro Eduardo

    2016-09-01

    Abusive use of drugs is a public health problem worldwide. The use of these substances by pregnant or lactating women can have many serious side effects in newborns. Among the commonest causes of addiction in drug users is cocaine in powdered form, inhaled, intravenously injected or smoked form (crack). Fast screening and a confirmation test using high specificity and sensitivity instruments such as LC-MS or GC/MS, can provide data to qualify and quantify chemical substances present in biological samples such as breast milk or meconium. Cocaine and/or crack can be detected through biomarkers or the unchanged molecule, enabling the form of cocaine use to be distinguished through the analytes. These methods must be carefully developed and validated according to internationally recognized guidelines. Thus, the study of biological matrices in which it can be detected through the development of simple and quick analytical methods can help prevent intoxication and diagnose the symptoms of dependency such as seizures, especially in babies, providing appropriate medical care.

  10. Effects of Histamine H3 Receptor Activation on the Behavioral-Stimulant Effects of Methamphetamine and Cocaine in Mice and Squirrel Monkeys

    PubMed Central

    Banks, Matthew L.; Manvich, Daniel F.; Bauzo, Rayna M.; Howell, Leonard L.

    2009-01-01

    Background Cocaine and methamphetamine (METH) are two commonly abused drugs that have behavioral-stimulant properties. These stimulant effects are partially mediated by the dopaminergic system. Recent evidence has suggested that the histamine H3 receptor (H3R) may modulate the release of dopamine induced by METH. The aim of the present study was to examine the role of H3R in the behavioral-stimulant effects of cocaine and METH in mice and monkeys. Methods Nonhabituated, experimentally naïve mice (n = 5–6) were pretreated with the H3R agonist imetit 30 min before METH or cocaine, and activity was measured for 90 min. The behavioral-stimulant effects of METH and cocaine were also studied in squirrel monkeys (n = 3) under a fixed-interval schedule of stimulus termination. Monkeys were pretreated with imetit 30 min before the peak behavioral-stimulant doses of METH or cocaine derived from individual subjects. Results Pretreatment with imetit did not affect basal activity in mice. Imetit significantly attenuated the behavioral-stimulant effects of METH, but not cocaine. In monkeys, no dose of imetit tested significantly altered the behavioral-stimulant effects of METH or cocaine. Conclusion These results suggest a role of H3R in the behavioral-stimulant effects of METH, but not cocaine, in mice and no role in monkeys. Copyright © 2009 S. Karger AG, Basel PMID:19145102

  11. Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats.

    PubMed

    Chen, Xiabin; Zheng, Xirong; Zhou, Ziyuan; Zhan, Chang-Guo; Zheng, Fang

    2016-11-25

    Accelerating cocaine metabolism through enzymatic hydrolysis at cocaine benzoyl ester is recognized as a promising therapeutic approach for cocaine abuse treatment. Our more recently designed A199S/F227A/S287G/A328W/Y332G mutant of human BChE, denoted as cocaine hydrolase-3 (CocH3), has a considerably improved catalytic efficiency against cocaine and has been proven active in blocking cocaine-induced toxicity and physiological effects. In the present study, we have further characterized the effects of CocH3 on the detailed metabolic profile of cocaine in rats administrated intravenously (IV) with 5 mg/kg cocaine, demonstrating that IV administration of 0.15 mg/kg CocH3 dramatically changed the metabolic profile of cocaine. Without CocH3 administration, the dominant cocaine-metabolizing pathway in rats was cocaine methyl ester hydrolysis to benzoylecgonine (BZE). With the CocH3 administration, the dominant cocaine-metabolizing pathway in rats became cocaine benzoyl ester hydrolysis to ecgonine methyl ester (EME), and the other two metabolic pathways (i.e. cocaine methyl ester hydrolysis to BZE and cocaine oxidation to norcocaine) became insignificant. The CocH3-catalyzed cocaine benzoyl ester hydrolysis to EME was so efficient such that the measured maximum blood cocaine concentration (∼38 ng/ml) was significantly lower than the threshold blood cocaine concentration (∼72 ng/ml) required to produce any measurable physiological effects.

  12. Functional photoacoustic imaging to observe regional brain activation induced by cocaine hydrochloride

    NASA Astrophysics Data System (ADS)

    Jo, Janggun; Yang, Xinmai

    2011-09-01

    Photoacoustic microscopy (PAM) was used to detect small animal brain activation in response to drug abuse. Cocaine hydrochloride in saline solution was injected into the blood stream of Sprague Dawley rats through tail veins. The rat brain functional change in response to the injection of drug was then monitored by the PAM technique. Images in the coronal view of the rat brain at the locations of 1.2 and 3.4 mm posterior to bregma were obtained. The resulted photoacoustic (PA) images showed the regional changes in the blood volume. Additionally, the regional changes in blood oxygenation were also presented. The results demonstrated that PA imaging is capable of monitoring regional hemodynamic changes induced by drug abuse.

  13. Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release

    PubMed Central

    Chartoff, Elena H; Ebner, Shayla R; Sparrow, Angela; Potter, David; Baker, Phillip M; Ragozzino, Michael E; Roitman, Mitchell F

    2016-01-01

    Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation—as occurs upon withdrawal from chronic cocaine—modulates vulnerability to cocaine in a time-dependent manner. PMID:26239494

  14. An Evaluation of Substance Abuse Treatment and HIV Education on Safe Sex Practices in Cocaine Dependent Individuals

    PubMed Central

    Winhusen, Theresa M.; Somoza, Eugene C.; Lewis, Daniel F.; Kropp, Frankie; Theobald, Jeff; Elkashef, Ahmed

    2014-01-01

    Background. There is a strong association between crack/cocaine use and increased sexual risk behavior, but little research on the efficacy of HIV education for decreasing such behavior in crack/cocaine-addicted individuals in substance abuse treatment. Method. Datasets from two cocaine dependence trials including either one or three HIV education sessions, respectively, were analyzed for changes over time in the proportion of participants practicing safe sex. A pooled dataset from two earlier trials not offering HIV education was also analyzed. Results. We included 83 participants from the 1-session trial and 65 participants from the 3-session trial. Both sets of participants evidenced a significant increase in the proportion of participants having safe sex with casual partners. Participants in the 3-session HIV education study also evidenced a significant increase in the proportion of participants having safe sex with regular partners. In the trials without HIV education, no change in safe sex practices was found, and change in condom use was observed only among female participants. Conclusions. These findings are consistent with recommendations that HIV education/counseling should be provided to individuals in substance abuse treatment. A randomized controlled trial to confirm these results may be warranted. This trial is registered with NCT00033033, NCT00086255, NCT00015106, and NCT00015132. PMID:25938124

  15. HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling

    PubMed Central

    Samikkannu, Thangavel; Atluri, Venkata S. R.; Nair, Madhavan P. N.

    2016-01-01

    HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression. PMID:27535703

  16. Purpose in Life Predicts Treatment Outcome Among Adult Cocaine Abusers in Treatment

    PubMed Central

    Martin, Rosemarie A.; MacKinnon, Selene; Johnson, Jennifer; Rohsenow, Damaris J.

    2010-01-01

    A sense of purpose in life has been positively associated with mental health and well-being and has been negatively associated with alcohol use in correlational and longitudinal studies, but has not been studied as a predictor of cocaine treatment outcome. This study examined pre-treatment purpose in life as a predictor of response to a 30-day residential substance use treatment program among 154 participants with cocaine dependence. Purpose in life was unrelated to cocaine or alcohol use during the 6 months pretreatment. After controlling for age, baseline use, and depressive symptoms, purpose in life significantly (p < .01) predicted relapse to any use of cocaine and to alcohol, and the number of days cocaine or alcohol was used in the six months after treatment. Findings suggest that increasing purpose in life may be an important aspect of treatment among cocaine dependent patients. PMID:21129893

  17. Short- and long-term adverse effects of cocaine abuse during pregnancy on the heart development.

    PubMed

    Meyer, Kurt D; Zhang, Lubo

    2009-02-01

    The effect of cocaine on the developing fetus is a topic of considerable interest and debate. One of the potential effects of fetal cocaine exposure is damage to the developing heart. This review provides an overview of the current understanding of the short- and long-term effects of fetal cocaine exposure on the heart in both humans and animal models. Human studies are still preliminary but have suggested that fetal cocaine exposure impacts on the developing heart. Studies in animal models provide strong evidence for a programming effect resulting in detrimental long-term changes to the heart induced by fetal cocaine exposure. In the rat model, fetal cocaine results in apoptosis in the term heart, left ventricular remodeling and myocyte hypertrophy, as well as increased sensitivity to ischemia/reperfusion injury in the adult male offspring. The rat model has also shown evidence of epigenetic modifications in response to intrauterine cocaine. Increased DNA methylation of promoter regions leads to a long-term decrease in the expression of the cardioprotective gene, PKCepsilon. The current data shows fetal cocaine exposure has significant immediate and long-term cardiac consequences in animal models and while human studies are still incomplete they suggest this phenomenon may also be significant in humans exposed to cocaine during development.

  18. Synthesis and biological activity of cocaine analogs I: N-alkylated norcocaine derivatives.

    PubMed

    Lazer, E S; Aggarwal, N D; Hite, G J; Nieforth, K A; Kelleher, R T; Spealman, R D; Schuster, C R; Wolverton, W

    1978-12-01

    N-Allylnorcocaine, N-dimethylallylnorcocaine, and N-cyclopropylmethylnorcocaine were prepared and examined for cocaine-like activity. The compounds were prepared by alkylation of norcocaine, which was obtained by demethylation of cocaine with 2,2,2-trichloroethyl chloroformate followed by zinc--acetic acid reduction. The compounds were evaluated by comparison with cocaine in causing disruption of milk intake in rats, behavioral modification in squirrel monkeys, and inhibition of 3H-serotonin uptake by rat synaptosomes. The compounds showed cocaine-like activity less potent than cocaine in the latter two tests and were inactive in the milk intake test.

  19. Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats.

    PubMed

    Collins, Stephanie L; Izenwasser, Sari

    2004-03-01

    Tobacco use is prevalent in the adolescent population. It is a major concern because tobacco is highly addictive and has also been linked to illicit drug use. There is not much research, however, on the interaction between nicotine and other stimulant drugs in animal models of early adolescence. This study examined the effects of chronic nicotine alone and on cocaine-stimulated activity in male and female periadolescent rats compared to male and female adult rats. During the seven-day nicotine pretreatment period, nicotine increased locomotor activity in all groups compared to vehicle controls. Male and female adult rats and female periadolescent rats developed sensitization to the locomotor-activating effects of nicotine over the 7-day treatment period, while male periadolescent rats did not. All groups treated with nicotine, however, exhibited sensitization to nicotine-induced repetitive motion over the 7-day nicotine treatment period. On day 8, male periadolescent rats pretreated with nicotine were more markedly sensitized to the locomotor-activating effects of cocaine than male adult rats, while female rats pretreated with nicotine were not sensitized to cocaine. In contrast, male and female periadolescent rats, but not adult rats, had increased amounts of repetitive beam breaks induced by cocaine after nicotine pretreatment. Overall, it appears that cross-sensitization to cocaine is greater in periadolescent than in adult rats, and that males are more sensitized than females. Thus, it may be that nicotine use during adolescence carries a greater risk than during adulthood and that male adolescents may be particularly vulnerable to the risk of cocaine abuse after nicotine use. This information should be taken into account so as to help us better understand the development of drug addiction in adolescents compared to adults.

  20. Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates.

    PubMed

    Foltin, Richard W; Haney, Margaret; Rubin, Eric; Reed, Stephanie C; Vadhan, Nehal; Balter, Rebecca; Evans, Suzette M

    2015-07-01

    Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how 'free' doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose-response function for cocaine self-administration (10 choices of 0.0125-0.1mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large 'free' self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

  1. Cocaine and kidney injury: a kaleidoscope of pathology

    PubMed Central

    Goel, Narender; Pullman, James M.; Coco, Maria

    2014-01-01

    Cocaine is abused worldwide as a recreational drug. It is a potent activator of the sympathetic nervous system leading to intense vasoconstriction, endothelial dysfunction, oxidative stress, platelet activation and decrease in prostaglandins E2 and prostacyclin. Cocaine can lead to widespread systemic adverse effects such as stroke, myocardial infarction, arterial dissection, vascular thrombosis and rhabdomyolysis. In human and rat kidneys, cocaine has been associated with glomerular, tubular, vascular and interstitial injury. It is not uncommon to diagnose cocaine-related acute kidney injury (AKI), malignant hypertension and chronic kidney disease. Cocaine abuse can lead to AKI by rhabdomyolysis, vasculitis, infarction, thrombotic microangiopathy and malignant hypertension. It is reported that 50–60% of people who use both cocaine and heroin are at increased risk of HIV, hepatitis and additional risk factors that can cause kidney diseases. While acute interstitial nephritis (AIN) is a known cause of AKI, an association of AIN with cocaine is unusual and seldom reported. We describe a patient with diabetes mellitus, hypertension and chronic hepatitis C, who presented with AKI. Urine toxicology was positive for cocaine and a kidney biopsy was consistent with AIN. Illicit drugs such as cocaine or contaminants may have caused AIN in this case and should be considered in the differential diagnosis of causes of AKI in a patient with substance abuse. We review the many ways that cocaine adversely impacts on kidney function. PMID:25859366

  2. Persistent cue-evoked activity of accumbens neurons after prolonged abstinence from self-administered cocaine.

    PubMed

    Ghitza, Udi E; Fabbricatore, Anthony T; Prokopenko, Volodymyr; Pawlak, Anthony P; West, Mark O

    2003-08-13

    Persistent neural processing of information regarding drug-predictive environmental stimuli may be involved in motivating drug abusers to engage in drug seeking after abstinence. The addictive effects of various drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens. We used single-unit recording in rats to test whether accumbens neurons exhibit responses to a discriminative stimulus (SD) tone previously paired with cocaine availability during cocaine self-administration. Presentation of the tone after 3-4 weeks of abstinence resulted in a cue-induced relapse of drug seeking under extinction conditions. Accumbens neurons did not exhibit tone-evoked activity before cocaine self-administration training but exhibited significant SD tone-evoked activity during extinction. Under extinction conditions, shell neurons exhibited significantly greater activity evoked by the SD tone than that evoked by a neutral tone (i.e., never paired with reinforcement). In contrast, core neurons responded indiscriminately to presentations of the SD tone or the neutral tone. Accumbens shell neurons exhibited significantly greater SD tone-evoked activity than did accumbens core neurons. Although the onset of SD tone-evoked activity occurred well before the earliest movements commenced (150 msec), this activity often persisted beyond the onset of tone-evoked movements. These results indicate that accumbens shell neurons exhibit persistent processing of information regarding reward-related stimuli after prolonged drug abstinence. Moreover, the accumbens shell appears to be involved in discriminating the motivational value of reward-related associative stimuli, whereas the accumbens core does not.

  3. DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.

    PubMed

    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

    2015-12-01

    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.

  4. 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

  5. Impact of DCS-facilitated cue exposure therapy on brain activation to cocaine cues in cocaine dependence

    PubMed Central

    Prisciandaro, James J.; Myrick, Hugh; Henderson, Scott; McRae-Clark, Aimee L.; Ana, Elizabeth J. Santa; Saladin, Michael E.; Brady, Kathleen T.

    2013-01-01

    Background The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with D-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Methods Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Results Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Conclusions Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. PMID:23497788

  6. Membranous glomerulonephritis and cellular crescents induced by levamisole-adulterated cocaine abuse: a case report

    PubMed Central

    Moll-Guillen, Jose-Luis; Espí-Reig, Jordi; Blanes-Julia, Marino; García-Martínez, Ana-María; Pujol-Marco, Conrad; Hernández-Jaras, Julio

    2015-01-01

    Levamisole is illicitly employed as a cocaine adulterant. The consumption of levamisole-adulterated cocaine can provoke anti-neutrophil cytoplasmic antibody (ANCA)-associated syndromes. Patients carrying an HLAB27 allele are known to be at higher risk of developing agranulocytosis when treated with levamisole. Likewise, patients with ANCA-associated vasculitis (AAV) and internal organ involvement have typically been exposed to offending agents for prolonged periods of time, often on the order of years. Here, we report an unusual case of a patient in which kidney biopsy showed membranous glomerulonephritis with cellular crescents associated with levamisole-contaminated cocaine use. PMID:26605317

  7. Dopamine D3 and D2 receptor mechanisms in the abuse-related behavioral effects of cocaine: studies with preferential antagonists in squirrel monkeys.

    PubMed

    Achat-Mendes, Cindy; Grundt, Peter; Cao, Jianjing; Platt, Donna M; Newman, Amy Hauck; Spealman, Roger D

    2010-08-01

    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

  8. A highly efficient cocaine detoxifying enzyme obtained by computational design

    PubMed Central

    Zheng, Fang; Xue, Liu; Hou, Shurong; Liu, Junjun; Zhan, Max; Yang, Wenchao; Zhan, Chang-Guo

    2014-01-01

    Compared to naturally occurring enzymes, computationally designed enzymes are usually much less efficient, with their catalytic activities being more than six orders of magnitude below the diffusion limit. Here we use a two-step computational design approach, combined with experimental work, to design a highly efficient cocaine hydrolising enzyme. We engineer E30-6 from human butyrylcholinesterase (BChE), which is specific for cocaine hydrolysis, and obtain a much higher catalytic efficiency for cocaine conversion than for conversion of the natural BChE substrate, acetylcholine (ACh). The catalytic efficiency of E30-6 for cocaine hydrolysis is comparable to that of the most efficient known naturally-occurring hydrolytic enzyme, acetylcholinesterase, the catalytic activity of which approaches the diffusion limit. We further show that E30-6 can protect mice from a subsequently administered lethal dose of cocaine, suggesting the enzyme may have therapeutic potential in the setting of cocaine detoxification or cocaine abuse. PMID:24643289

  9. Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

    PubMed Central

    Martinez, Luis A.; Gross, Kellie S.; Himmler, Brett T.; Emmitt, Nicole L.; Peterson, Brittni M.; Foster Olive, M.; Carroll, Marilyn E.; Meisel, Robert L.

    2016-01-01

    Abstract In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females. PMID:27822496

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

    SciTech Connect

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

    1999-05-28

    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 using [{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.

  11. Substance abuse treatment patients with early onset cocaine use respond as well to contingency management interventions as those with later onset cocaine use.

    PubMed

    Weiss, Lindsay M; Petry, Nancy M

    2014-08-01

    Early onset drug use is associated with increased risk of developing substance use disorders, but relatively little is known about the correlates of early drug use among adults receiving treatment. A retrospective analysis of a randomized study of contingency management treatment compared cocaine-dependent patients who reported initial cocaine use at age 14 or younger (n = 41) to those who began using after age 14 (n = 387). Patients with early onset cocaine use had more legal and psychiatric problems than those who initiated cocaine use later. Patients with early-onset cocaine use also dropped out of treatment sooner and achieved less sustained abstinence than those who began using at older ages, but the interaction between age of first use and treatment condition was not significant. Early-onset cocaine use is associated with persistent psychosocial problems and an overall poor response to treatment. However, contingency management is efficacious in improving outcomes in early onset cocaine users.

  12. Analysis of cocaine and nicotine metabolites in wastewater by liquid chromatography-tandem mass spectrometry. Cross abuse index patterns on a major community.

    PubMed

    Lopes, Alvaro; Silva, Nuno; Bronze, M R; Ferreira, João; Morais, José

    2014-07-15

    A method based on sample preparation by solid phase extraction and analysis by liquid chromatography and mass spectrometry was validated and used for simultaneous analysis of cocaine, benzoylecgonine and cotinine in samples collected at the major wastewater treatment plant in the city of Lisbon. The aim was to estimate the consumption of both cocaine and nicotine in this community and establish an index involving both drugs supported by the relevance of nicotine as a significant anthropogenic marker. The study was made on two different weekdays during a month in order to evaluate patterns of consumption outside weekends. Cocaine and nicotine ingestion levels were back-calculated and expressed as mass of pure drugs consumed per day and per 1000 inhabitants (mean: 0.604 g and 5.860 g respectively). Cocaine was also expressed on the basis of local drug purity levels (33.7%) with a corresponding increase on dose assessments, and community drug abuse profiles. The authors sustain that this approach should always be included in drug studies of this kind allowing a better drug abuse assessment. No significant different patterns of consumption were obtained during the working days studied with the exception of one case coincident with a national holiday that showed an increased typical profile found on other non-working day studies, namely weekends. A fairly significant relationship was found between nicotine and cocaine consumption that should be further evaluated in future studies. Pharmacokinetic considerations were made and proposed for cocaine assessment based on the impact on back calculations after common simultaneous consumption of cocaine and ethanol.

  13. Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND.

    PubMed

    Yang, Lu; Yao, Honghong; Chen, Xufeng; Cai, Yu; Callen, Shannon; Buch, Shilpa

    2016-03-01

    Cocaine abuse has been shown to accelerate the progression of human immunodeficiency virus (HIV)-1-associated neurological disorders (HANDs) partially through increasing neuroinflammatory response mediated by activated astrocytes; however, the detailed molecular mechanism of cocaine-mediated astrocyte activation is unclear. In the current study, we demonstrated increased astrogliosis in the cortical regions of brains from HIV(+) cocaine abusers compared with the HIV(+) group without cocaine abuse. We next sought to explore whether cocaine exposure could result in increased expression of glial fibrillary acidic protein (GFAP), a filament protein critical for astrocyte activation. Exposure of cocaine to astrocytes resulted in rapid translocation of sigma receptor to the plasma membrane with subsequent activation of downstream signaling pathways. Using a pharmacological approach, we provide evidence that cocaine-mediated upregulation of GFAP expression involved activation of mitogen-activated protein kinase (MAPK) signaling with subsequent downstream activation of the early growth response gene 1 (Egr-1). Egr-1 activation, in turn, caused transcriptional regulation of GFAP. Corroboration of these findings in vivo demonstrated increased expression of GFAP in the cortical region of mice treated with cocaine compared with the saline injected controls. A thorough understanding of how cocaine mediates astrogliosis could have implications for the development of therapeutic interventions aimed at HIV-infected cocaine abusers.

  14. Electrochemical simulation of cocaine metabolism-a step toward predictive toxicology for drugs of abuse.

    PubMed

    Mielczarek, Przemystaw; Raoof, Hana; Kotlinska, Joltanta H; Stefanowicz, Piotr; Szewczuk, Zbigniew; Suder, Piotr; Silberring, Jerzy

    2014-01-01

    Knowledge of the metabolic pathways and biotransformation of the most popular drugs, such as cocaine, amphetamine, morphine and others, is crucial for the elucidation of their possible toxicity and mechanism of action in the human body. In vitro studies on metabolism are mainly based on the incubation of drugs with liver celL homogenate and utilizing Living animals. These methods need to be followed by isolation and detection of metabolic products, which makes these techniques time-consuming and technically demanding. We show here that the oxidative metabolism that occurs in the liver cells and is mainly caused by cytochrome P450 can be successfully mimicked with the electrochemical system [EC] connected on-line with electrospray ionization mass spectrometry. Cocaine was chosen as a model drug for these studies and was analyzed with a previously described system under various conditions using the boron-doped diamond working electrode. The results were compared with the number of metabolites generated by a standard procedure based on the reaction with the rat Liver microsomes. Two electrochemical products of cocaine oxidation were created, of which one was a natural metabolite of cocaine in the human body-norcocaine. The EC provides a promising platform for the screening of the addictive drug phase I metabolism. The metabolites can be directly analyzed by mass spectrometry or collected and separated by Liquid chromatog- raphy. No Liver cell homogenate or microsome is necessary to generate these metabolites, which simplifies separation of the mixtures and reduces time and costs of all experiments.

  15. Rural Cocaine/Polydrug Abusing Families and Young Children: An Ethnographic Study of Intervention Needs.

    ERIC Educational Resources Information Center

    Krutilla, Jennifer O.; And Others

    This pilot study used a multidisciplinary, ethnographic approach to evaluate effects of prenatal drug exposure on four cocaine/polydrug-exposed infants and their rural mothers/caregivers and to begin development of a model training program. The study involved document review of hospital and social services records, participant observation,…

  16. The Ventral Pallidum: Proposed Integrator of Positive and Negative Factors in Cocaine Abuse

    PubMed Central

    James, Morgan H.; Aston-Jones, Gary

    2016-01-01

    In this issue of Neuron, Creed et al. (2016) describe how cocaine produces divergent forms of plasticity at synapses between specific neurons in nucleus accumbens and ventral pallidum, and how these changes are associated with positive and negative reward behaviors. PMID:27710789

  17. Rural Cocaine/Polydrug Abusing Families and Young Children: An Ethnographic Study of Intervention Needs.

    ERIC Educational Resources Information Center

    Krutilla, Jennifer O.

    Researchers have identified three variables to explain the diversity among children born to cocaine/polydrug using women: (1) the dysfunctional family histories of the maternal user; (2) the purity, dosage, and regularity of illicit drugs used during pregnancy; and (3) subsequent mother-child interaction following birth and during formative…

  18. 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.

  19. Reaction mechanism for cocaine esterase-catalyzed hydrolyses of (+)- and (-)-cocaine: unexpected common rate-determining step.

    PubMed

    Liu, Junjun; Zhao, Xinyun; Yang, Wenchao; Zhan, Chang-Guo

    2011-05-05

    First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to examine the catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. It has been shown that the acylation of (+)-cocaine consists of nucleophilic attack of the hydroxyl group of Ser117 on the carbonyl carbon of (+)-cocaine benzoyl ester and the dissociation of (+)-cocaine benzoyl ester. The first reaction step of deacylation of (+)-cocaine, which is identical to that of (-)-cocaine, is rate-determining, indicating that CocE-catalyzed hydrolyses of (+)- and (-)-cocaine have a common rate-determining step. The computational results predict that the catalytic rate constant of CocE against (+)-cocaine should be the same as that of CocE against (-)-cocaine, in contrast with the remarkable difference between human butyrylcholinesterase-catalyzed hydrolyses of (+)- and (-)-cocaine. The prediction has been confirmed by experimental kinetic analysis on CocE-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (-)-cocaine. The determined common rate-determining step indicates that rational design of a high-activity mutant of CocE should be focused on the first reaction step of the deacylation. Furthermore, the obtained mechanistic insights into the detailed differences in the acylation between the (+)- and (-)-cocaine hydrolyses provide indirect clues for rational design of amino acid mutations that could more favorably stabilize the rate-determining transition state in the deacylation and, thus, improve the catalytic activity of CocE. This study provides a valuable mechanistic base for rational design of an improved esterase for therapeutic treatment of cocaine abuse.

  20. Cocaine and the nervous system.

    PubMed

    Prakash, A; Das, G

    1993-12-01

    Cocaine abuse today has reached greater heights than it did during the first cocaine epidemic in the late nineteenth century. It is estimated that one out of every four Americans has used cocaine and some six million people in the US use it regularly. Although cocaine affects all systems in the body, the central nervous system (CNS) is the primary target. Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses. Almost all CNS effects of cocaine can be attributed to this mechanism. Euphoria, pharmacological pleasure and intense cocaine craving share basis in this system. The effects of cocaine on other organ systems, in addition to its effects on the CNS, account for the majority of the complications associated with cocaine abuse. In this paper, the CNS effects following cocaine administration and their treatment are discussed.

  1. Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.

    PubMed

    Li, Juan; Zhang, Lei; Chen, Zhenzhong; Xie, Minjuan; Huang, Lu; Xue, Jinhua; Liu, Yutong; Liu, Nuyun; Guo, Fukun; Zheng, Yi; Kong, Jiming; Zhang, Lin; Zhang, Lu

    2015-03-01

    Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.

  2. Phagocytosis of the protozoon Tetrahymena pyriformis as an endpoint in the estimation of cocaine salt and cocaine freebase toxicity.

    PubMed

    Stefanidou, M; Alevisopoulos, G; Maravelias, C; Loutsidis, C; Koutselinis, A

    1999-10-01

    Cells of the ciliated protozoon Tetrahymena pyriformis strain W, grown in a peptone-yeast medium, usually contain many phagocytic vacuoles. The phagocytic activity of this protozoon was studied in vivo using heat-inactivated yeast stained with carmine after exposing the cultures for 1 hour to different doses of cocaine hydrochloride or cocaine freebase (crack) (0.5, 1 or 2 mg/100 ml of protozoan culture).The number of vacuoles formed indicated the phagocytic activity. Cocaine hydrochloride and crack caused a decrease of the phagocytic activity of the protozoon (p < 0.05) when compared to the control cultures. Furthermore, the two chemical forms of cocaine, salt and free-base respectively, caused quantitatively different effects on the phagocytic activity. Crack produced an extensive decrease in phagocytosis, compared to equal concentrations of cocaine hydrochloride. These results suggest a possible relationship between cocaine abuse and the suppression of phagocytosis that may contribute to the impairment of immunity in drug misusers.

  3. Neuropsychiatric effects of cocaine use disorders.

    PubMed Central

    Nnadi, Charles U.; Mimiko, Olubansile A.; McCurtis, Henry L.; Cadet, Jean Lud

    2005-01-01

    Individuals who use cocaine report a variety of neuropsychiatric symptoms that are yet to be adequately targeted with treatment modalities. To address this problem requires an understanding of these symptoms and their neurobiological origins. Our paper reviewed the existing data on the neuropsychiatic implications of cocaine. We conducted a Medline search from 1984-2004 using terms, such as "cocaine", "cocaine addiction", "cocaine abuse", "cocaine neuropsychiatry" and "dual diagnosis". The search produced additional reference materials that were used in this review, although we focused on data that have likely clinical implications. The literature evidence suggested that, whereas acute cocaine overdose is potentially fatal, the ingestion of mild-to-moderate doses could result in fatal or nonfatal neuropsychiatric events. Also, chronic cocaine use may be associated with deficits in neurocognition, brain perfusion and brain activation patterns. Some of these deficits were unresolved with periods of abstinence ranging from 3-200 days. Taken together, these studies suggest the need for further investigations to fully characterize the neurobiological substrates of cocaine use disorders (CUDs) with the future possibility of more efficient treatment modalities. PMID:16334497

  4. Morphine and cocaine increase serum- and glucocorticoid-inducible kinase 1 activity in the ventral tegmental area.

    PubMed

    Heller, Elizabeth A; Kaska, Sophia; Fallon, Barbara; Ferguson, Deveroux; Kennedy, Pamela J; Neve, Rachael L; Nestler, Eric J; Mazei-Robison, Michelle S

    2015-01-01

    Drugs of abuse modulate the function and activity of the mesolimbic dopamine circuit. To identify novel mediators of drug-induced neuroadaptations in the ventral tegmental area (VTA), we performed RNA sequencing analysis on VTA samples from mice administered repeated saline, morphine, or cocaine injections. One gene that was similarly up-regulated by both drugs was serum- and glucocorticoid-inducible kinase 1 (SGK1). SGK1 activity, as measured by phosphorylation of its substrate N-myc downstream regulated gene (NDRG), was also increased robustly by chronic drug treatment. Increased NDRG phosphorylation was evident 1 but not 24 h after the last drug injection. SGK1 phosphorylation itself was similarly modulated. To determine the role of increased SGK1 activity on drug-related behaviors, we over-expressed constitutively active (CA) SGK1 in the VTA. SGK1-CA expression reduced locomotor sensitization elicited by repeated cocaine, but surprisingly had the opposite effect and promoted locomotor sensitization to morphine, without affecting the initial locomotor responses to either drug. SGK1-CA expression did not significantly affect morphine or cocaine conditioned place preference, although there was a trend toward increased conditioned place preference with both drugs. Further characterizing the role of this kinase in drug-induced changes in VTA may lead to improved understanding of neuroadaptations critical to drug dependence and addiction. We find that repeated, but not acute, morphine or cocaine administration induces an increase in serum- and glucocorticoid-inducible kinase (SGK1) gene expression and activity in the ventral tegmental area (VTA). This increase in SGK1 activity may play a role in drug-dependent behaviors and suggests a novel signaling cascade for potential intervention in drug dependence and addiction.

  5. Prostanoid production in the presence of platelet activation in hypoxic cocaine-treated rats.

    PubMed

    Togna, G; Graziani, M; Sorrentino, C; Caprino, L

    1996-01-01

    To extend our previous in vitro data, we investigated the effects of cocaine on thromboxane A2 (TXA2) and prostacyclin (PGI2) production in vivo in the rat. To obtain the slight platelet activation that our in vitro experiments showed useful to highlight the effect of cocaine, we infused cocaine in rats in the presence of platelet-activating factors (circulation of blood through a perspex vascular device or by infusion of sodium arachidonate) and in various respiratory conditions. Experiments were conducted in rats breathing atmospheric air (normoxic conditions) and in rats breathing an oxygen-poor mixture (hypoxic conditions). In rats under hypoxic conditions cocaine invariably increased TXA2 plasma levels, whereas in normoxic conditions it increased TXA2 only in the presence of platelet-activating factors. Cocaine significantly increased PGI2 plasma levels in arachidonate-treated rats in hypoxic respiratory conditions; in normoxic conditions cocaine left PGI2 levels unchanged. These results support the hypothesis that in cocaine users who have concomitant pathological conditions able to activate platelets, such as atherosclerosis, coronary vasospasm or ischaemia, or both, cocaine may contribute to the onset of thrombotic phenomena by interfering with the prostaglandin system.

  6. An enhanced positive reinforcement model for the severely impaired cocaine abuser.

    PubMed

    Foote, J; Seligman, M; Magura, S; Handelsman, L; Rosenblum, A; Lovejoy, M; Arrington, K; Stimmel, B

    1994-01-01

    This article describes a cognitive-behavioral treatment approach that has been extensively modified to work with inner-city methadone-maintained cocaine users. Modifications were deemed essential to address the problems of engagement and retention in treatment that are typically encountered with this population. While this approach relies on such basic tenets of treatment as relapse prevention, cognitive restructuring, and psychoeducation, an understanding of the particular psychological vulnerabilities of this population has been incorporated into the model. The modified approach utilizes positive reinforcement extensively. This includes use of concrete reinforcers to facilitate initial engagement, and use of interpersonal reinforcers (therapist positive regard, attention, and respect) to increase program retention and sustain posttreatment change. Preliminary results indicate that 63% of patients can complete this intensive 6-month program, with considerable reductions in cocaine use and significant change in drug injection behavior.

  7. Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking

    PubMed Central

    Augur, Isabel F.; Wyckoff, Andrew R.; Aston-Jones, Gary; Kalivas, Peter W.

    2016-01-01

    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. SIGNIFICANCE STATEMENT 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. PMID:27683912

  8. Financing a Voucher Program for Cocaine Abusers through Community Donations in Spain

    ERIC Educational Resources Information Center

    Garcia-Rodriguez; Olaya; Secades-Villa, Roberto; Higgins, Stephen T.; Fernandez-Hermida, Jose R.; Carballo, Jose L.

    2008-01-01

    This study analyzed the viability of financing a voucher program for cocaine addicts in Spain through public and private donations. Of the 136 companies contacted, 52 (38%) provided donations. The difference between the benefits (15,670[euros]/$20,371) and the costs (3,734[euros]/$4,854) was 11,936[euros]/$15,517. The type of reinforcer a company…

  9. Increased conditioned place preference for cocaine in high anxiety related behavior (HAB) mice is associated with an increased activation in the accumbens corridor

    PubMed Central

    Prast, Janine M.; Schardl, Aurelia; Sartori, Simone B.; Singewald, Nicolas; Saria, Alois; Zernig, Gerald

    2014-01-01

    Anxiety disorders and substance use disorders are strongly associated in humans. Accordingly, a widely held but controversial concept in the addiction field, the so-called “self-medication hypothesis,” posits that anxious individuals are more vulnerable for drug dependence because they use drugs of abuse to alleviate their anxiety. We tested this hypothesis under controlled experimental conditions by quantifying the conditioned place preference (CPP) to 15 mg/kg i.p. cocaine given contingently (COCAINE) in CD1 mice selectively bred for high anxiety-related behavior (HAB) vs. normal anxiety-related behavior (NAB). Cocaine was conditioned to the initially non-preferred compartment in an alternate day design (cocaine vs. saline, four pairings each). HAB and NAB mice were also tested for the effects of non-contingent (NONCONT) cocaine administration. HAB mice showed a slightly higher bias for one of the conditioning compartments during the pretest than NAB mice that became statistically significant (p = 0.045) only after pooling COCAINE and NONCONT groups. Cocaine CPP was higher (p = 0.0035) in HAB compared to NAB mice. The increased cocaine CPP was associated with an increased expression of the immediate early genes (IEGs) c-Fos and Early Growth Related Protein 1 (EGR1) in the accumbens corridor, i.e., a region stretching from the anterior commissure to the interhemispheric border and comprising the medial nucleus accumbens core and shell, the major island of Calleja and intermediate part of the lateral septum, as well as the vertical limb of the diagonal band and medial septum. The cocaine CPP-induced EGR1 expression was only observed in D1- and D2-medium spiny neurons, whereas other types of neurons or glial cells were not involved. With respect to the activation by contingent vs. non-contingent cocaine EGR1 seemed to be a more sensitive marker than c-Fos. Our findings suggest that cocaine may be more rewarding in high anxiety individuals, plausibly due to an

  10. 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.…

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

    SciTech Connect

    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 compulsively 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.

  12. Reconsolidation of a cocaine associated memory requires DNA methyltransferase activity in the basolateral amygdala.

    PubMed

    Shi, Hai-Shui; Luo, Yi-Xiao; Yin, Xi; Wu, Hong-Hai; Xue, Gai; Geng, Xu-Hong; Hou, Yan-Ning

    2015-08-20

    Drug addiction is considered an aberrant form of learning, and drug-associated memories evoked by the presence of associated stimuli (drug context or drug-related cues) contribute to recurrent craving and reinstatement. Epigenetic changes mediated by DNA methyltransferase (DNMT) have been implicated in the reconsolidation of fear memory. Here, we investigated the role of DNMT activity in the reconsolidation of cocaine-associated memories. Rats were trained over 10 days to intravenously self-administer cocaine by nosepokes. Each injection was paired with a light/tone conditioned stimulus (CS). After acquisition of stable self-administration behaviour, rats underwent nosepoke extinction (10 d) followed by cue-induced reactivation and subsequent cue-induced and cocaine-priming + cue-induced reinstatement tests or subsequently tested to assess the strength of the cocaine-associated cue as a conditioned reinforcer to drive cocaine seeking behaviour. Bilateral intra-basolateral amygdala (BLA) infusion of the DNMT inhibitor5-azacytidine (5-AZA, 1 μg per side) immediately following reactivation decreased subsequent reinstatement induced by cues or cocaine priming as well as cue-maintained cocaine-seeking behaviour. In contrast, delayed intra-BLA infusion of 5-AZA 6 h after reactivation or 5-AZA infusion without reactivation had no effect on subsequent cue-induced reinstatement. These findings indicate that memory reconsolidation for a cocaine-paired stimulus depends critically on DNMT activity in the BLA.

  13. Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse.

    PubMed

    Syed, Shariq A; Newman, Amy H; Othman, Ahmed A; Eddington, Natalie D

    2008-05-01

    A second generation of N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]-tropanes (GA 1-69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague-Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t l/2: 4.1-5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3-2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1-69) to several fold elevation (approximately 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure-response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1-0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted.

  14. Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse.

    PubMed

    Kivell, Bronwyn M; Ewald, Amy W M; Prisinzano, Thomas E

    2014-01-01

    Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.

  15. Salvinorin A analogs and other kappa opioid receptor compounds as treatments for cocaine abuse

    PubMed Central

    Kivell, Bronwyn M; Ewald, Amy WM; Prisinzano, Thomas E

    2014-01-01

    Acute activation of κ opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic κ opioid agonists have undesired side effects such as sedation, aversion and depression which restrict their clinical use. Salvinorin A (Sal A), a novel κ opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional κ opioid agonists and several new analogues. Sal A retains the anti-addictive properties of traditional κ opioid receptors agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, κ opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogues with improved pharmacokinetic profiles have been shown to have anti-addiction effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addiction therapeutics. PMID:24484985

  16. Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.

    PubMed

    Maurer, Hans H; Sauer, Christoph; Theobald, Denis S

    2006-06-01

    This review summarizes the major metabolic pathways of the drugs of abuse, tetrahydrocannabinol, cocaine, heroin, morphine, and codeine, in humans including the involvement of isoenzymes. This knowledge may be important for predicting their possible interactions with other xenobiotics, understanding pharmaco-/toxicokinetic and pharmacogenetic variations, toxicological risk assessment, developing suitable toxicological analysis procedures, and finally for understanding certain pitfalls in drug testing. The detection times of these drugs and/or their metabolites in biological samples are summarized and the implications of the presented data on the possible interactions of drugs of abuse with other xenobiotics, ie, inhibition or induction of individual polymorphic and nonpolymorphic isoenzymes, discussed.

  17. Reduced activity in functional networks during reward processing is modulated by abstinence in cocaine addicts.

    PubMed

    Costumero, Víctor; Bustamante, Juan Carlos; Rosell-Negre, Patricia; Fuentes, Paola; Llopis, Juan José; Ávila, César; Barrós-Loscertales, Alfonso

    2017-03-01

    Cocaine addiction is characterized by alterations in motivational and cognitive processes. Recent studies have shown that some alterations present in cocaine users may be related to the activity of large functional networks. The aim of this study was to investigate how these functional networks are modulated by non-drug rewarding stimuli in cocaine-dependent individuals. Twenty abstinent cocaine-dependent and 21 healthy matched male controls viewed erotic and neutral pictures while undergoing a functional magnetic resonance imaging scan. Group independent component analysis was then performed in order to investigate how functional networks were modulated by reward in cocaine addicts. The results showed that cocaine addicts, compared with healthy controls, displayed diminished modulation of the left frontoparietal network in response to erotic pictures, specifically when they were unpredicted. Additionally, a positive correlation between the length of cocaine abstinence and the modulation of the left frontoparietal network by unpredicted erotic images was found. In agreement with current addiction models, our results suggest that cocaine addiction contributes to reduce sensitivity to rewarding stimuli and that abstinence may mitigate this effect.

  18. Inhibiting AP-1 activity alters cocaine induced gene expression and potentiates sensitization

    PubMed Central

    Paletzki, Ronald F.; Myakishev, Max V.; Polesskaya, Oksana; Orosz, Andras; Hyman, Steven E.; Vinson, Charles

    2008-01-01

    We have expressed A-FOS, an inhibitor of AP-1 DNA binding, in adult mouse striatal neurons. We observe normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral responses to cocaine. We analyzed mRNA from the striatum before and 4 and 24 hours after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 hours following cocaine treatment relative to controls. However, 24 hours after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. 56 gene are down regulated while 28 genes are up regulated including previously identified candidates for addiction including BDNF and Per1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared to human genome scans of addiction to identify potential genes in humans that are involved in addiction. PMID:18355967

  19. 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.

  20. Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study.

    PubMed

    Perez, Pablo D; Hall, Gabrielle; Zubcevic, Jasenka; Febo, Marcelo

    2017-02-24

    Manganese enhanced magnetic resonance imaging (MEMRI) has been previously used to determine the effect of acute cocaine on calcium-dependent synaptic activity in male rats. However, there have been no MEMRI studies examining sex differences in the functional neural circuits affected by repeated cocaine. In the present study, we used MEMRI to investigate the effects of repeated cocaine on brain activation in female and male rats. Adult female and male rats were scanned at 4.7 Tesla three days after final treatment with saline, a single cocaine injection (15 mg kg(-1), i.p. × 1 day) or repeated cocaine injections (15 mg kg(-1), i.p. × 10 days). A day before imaging rats were provided with an i.p. injection of manganese chloride (70 mg kg(-1)). Cocaine produced effects on MEMRI activity that were dependent on sex. In females, we observed that a single cocaine injection reduced MEMRI activity in hippocampal CA3, ventral tegmental area (VTA), and median Raphé, whereas repeated cocaine increased MEMRI activity in dentate gyrus and interpeduncular nucleus. In males, repeated cocaine reduced MEMRI activity in VTA. Overall, it appeared that female rats showed a general trend towards increase MEMRI activity with single cocaine and reduced activity with repeated exposure, while male rats showed a trend towards opposite effects. Our results provide evidence for sex differences in the in vivo neural response to cocaine, which involves primarily hippocampal, amygdala and midbrain areas.

  1. Cocaine Use in America: Epidemiologic and Clinical Perspectives. National Institute on Drug Abuse (NIDA) Research Monograph Series 61.

    ERIC Educational Resources Information Center

    Kozel, Nicholas J., Ed.; Adams, Edgar H., Ed.

    This monograph is based on papers presented at a technical review of patterns of cocaine use in the United States which was held in 1984. The foreword by Jerome H. Jaffe acknowledges that, over the past 10 years, cocaine has become a major public health threat in this country. Papers contained in this monograph include: (1) "Cocaine Use in…

  2. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor.

    PubMed

    Zernig, Gerald; Pinheiro, Barbara S

    2015-09-01

    Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus

  3. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor

    PubMed Central

    Pinheiro, Barbara S.

    2015-01-01

    Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus

  4. The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse.

    PubMed

    Othman, Ahmed A; Newman, Amy H; Eddington, Natalie D

    2008-12-01

    GA2-50 is a novel N-substituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2-50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse. In vitro transport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2-50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2-50 showed high transcellular permeability despite being a P-glycoprotein substrate. GA2-50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values. In vivo, GA2-50 showed high brain uptake (R(i) approximately 10), large volume of distribution (V(ss) = 37 L/kg), and long elimination half-life (t((1/2)) = 19 h). GA2-50 resulted in 1.6- and 2.7-fold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2-50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2-50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2-50 possesses several attributes sought after for a substitute medication for cocaine abuse.

  5. Nonhuman Primate Neuroimaging and Cocaine Medication Development

    PubMed Central

    Howell, Leonard L.

    2011-01-01

    Given the important role of the dopamine transporter (DAT) in the addictive properties of cocaine, the development and use of compounds that target the DAT represents a reasonable approach for the pharmacological treatment of cocaine abuse. The present report describes a series of studies conducted in nonhuman primates that evaluated the effectiveness of DAT inhibitors in reducing cocaine self-administration. In addition, drug substitution studies evaluated the abuse liability of the DAT inhibitors. PET neuroimaging studies quantified DAT occupancy at behaviorally relevant doses, characterized the time-course of drug uptake in brain, and documented drug-induced changes in cerebral blood flow as a model of brain activation. Selective DAT inhibitors were effective in reducing cocaine use but high (>70%) levels of DAT occupancy were associated with significant reductions in cocaine self-administration. The selective DAT inhibitors were reliably self-administered but rates of responding were lower than those maintained by cocaine even at higher levels of DAT occupancy. A profile of slow rate of drug uptake in brain accompanied by a gradual increase in extracellular dopamine may account for the more limited reinforcing effectiveness of the DAT inhibitors. Selective serotonin transporter (SERT) inhibitors were also effective in reducing cocaine use and blocked cocaine-induced brain activation and increases in extracellular dopamine. Co-administration of SERT inhibitors with a selective DAT inhibitor was more effective than the DAT inhibitor administered alone, even at comparable levels of DAT occupancy. The results indicate that combined inhibition of DAT and SERT may be a viable approach to treat cocaine addiction. PMID:19086766

  6. Activation of amygdaloid PKC pathway is necessary for conditioned cues-provoked cocaine memory performance.

    PubMed

    Lai, Yu-Ting; Fan, Hsin-Yi; Cherng, Chianfang G; Chiang, Chih-Yuan; Kao, Gour-Shenq; Yu, Lung

    2008-07-01

    Drug-associated cues are critical in reinstating the drug taking behavior even during prolonged abstinence and thus are thought to be a key factor to induce drug craving and to cause relapse. Amygdaloid complex has been known for its physiological function in mediating emotional experience storage and emotional cues-regulated memory retrieval. This study was undertaken to examine the role of basolateral nuclei of amygdala and the intracellular signaling molecule in drug cues-elicited cocaine memory retrieval. Systemic anisomycin treatment prior to the retrieval test abolished the cues-provoked cocaine conditioned place preference (CPP) memory. Likewise, a similar blockade of cues-provoked cocaine CPP performance was achieved by infusion of anisomycin and cycloheximide into the basolateral nuclei of amygdala before the test. Intra-amygdaloid infusion of H89, a protein kinase A inhibitor, or U0126, a MEK inhibitor, did not affect retrieval of the cues-elicited cocaine CPP memory. In contrast, intra-amygdaloid infusion of NPC 15437, a PKC inhibitor, abolished the cues-elicited cocaine CPP expression, while left the memory per se intact. Intra-amygdaloid infusion of NPC 15437 did not seem to affect locomotor activity or exert observable aversive effect. Taken together, our results suggest that activation of PKC signaling pathway and probably downstream de novo protein synthesis in the basolateral nuclei of amygdala is required for the cues-elicited cocaine memory performance. However, temporary inhibition of this signaling pathway does not seem to affect cocaine CPP memory per se.

  7. A case of iloperidone overdose in a 27-year-old man with cocaine abuse

    PubMed Central

    Amon, Jin; Stephen, Elsa; El-Mallakh, Rif S

    2016-01-01

    Introduction: Iloperidone is a recently introduced antipsychotic medication. It is approved for the treatment of schizophrenia. There are no published reports of iloperidone overdosage, but there are eight cases that have been reported to the US Food and Drug Administration. Case report: A case of a 27-year-old man who took 84 mg of iloperidone while also smoking cocaine is described. He developed a prolonged QTc (527 ms) without arrhythmias and respiratory failure with mandated respiratory support. He ultimately recovered without sequelae. Discussion: The information regarding previous cases of toxicity on the US Food and Drug Administration website is incomplete. However, there were no fatalities due to iloperidone over-ingestion. Prolongation of the QTc may be a common feature. PMID:27570623

  8. Effects of endogenous and exogenous progesterone on emotional intelligence in cocaine dependent men and women who also abuse alcohol

    PubMed Central

    Milivojevic, V; Sinha, R; Morgan, PT; Sofuoglu, M; Fox, HC

    2015-01-01

    Objective As sex differences in substance dependence may impinge upon the perception and regulation of emotion, we assess Emotional Intelligence (EI) as a function of gender, menstrual cycle (MC) phase and hormonal changes in early abstinent cocaine dependent individuals who abuse alcohol (CDA). Methods Study 1: The Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT) was administered to 98 CDA (55M/43F) and 56 healthy (28M/28F) individuals. Performance in women was also assessed by MC phase. Study 2: The MSCEIT was administered to 18 CDA (19M/9F) who received exogenous progesterone (400mg/day) versus placebo for 7 days. (Study 2). Results Study 1: Healthy females were better than healthy males at facilitating thought and managing emotions. This gender discrepancy was not observed in the CDA group. Additionally, all women in the high compared with the low progesterone phase of their MC were better at managing their emotions. Study 2: Exogenous progesterone improved ability to facilitate thought in both males and females. Conclusions CDA women may be vulnerable to difficulties managing and regulating emotions. Gonadal hormones may contribute to this gender effect, as increases in both endogenous and exogenous progesterone improved selective aspects of EI. PMID:25363303

  9. Cocaine (Coke, Crack) Facts

    MedlinePlus

    ... Families? Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Use Hurts Other People Drug Use Hurts ... This Section Signs of Cocaine Use and Addiction Effects of Cocaine on Brains and Bodies Previous Index Next ... About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | ...

  10. Effect of cocaine, ethanol or nicotine on ornithine decarboxylase activity in early chick embryo brain.

    PubMed

    Beeker, K; Smith, C; Pennington, S

    1992-09-18

    Fetal drug exposure causes multiple deficits in the developing child. For both humans and animal models, the single most common drug-related problem is fetal growth suppression. This defect is associated with significant perinatal morbidity and mortality and may also be related to significant behavioral problems appearing later in life. Studies focussed on the molecular mechanism of fetal drug effects in placental models are complicated by multiple interactions of the drug with mother, placenta and fetus. Using early (76-168 h) chick embryos as a non-placental model, and three common drugs of abuse (nicotine, ethanol and cocaine) it was found that each drug suppressed the peak in fetal brain ornithine decarboxylase (ODC) activity that normally occurs at 120 h of development. For each drug, the decrease in ODC activity at 120 h was followed by a small but significant increase in ODC. Thus, although the drug-treated embryos were smaller in size, they appeared to be undergoing compensatory growth and, in fact, became equal in weight to the vehicle-treated animals, if allowed to hatch.

  11. Brain Activity During Cocaine Craving and Gambling Urges: An fMRI Study.

    PubMed

    Kober, Hedy; Lacadie, Cheryl M; Wexler, Bruce E; Malison, Robert T; Sinha, Rajita; Potenza, Marc N

    2016-01-01

    Although craving states are important to both cocaine dependence (CD) and pathological gambling (PG), few studies have directly investigated neurobiological similarities and differences in craving between these disorders. We used functional magnetic resonance imaging (fMRI) to assess brain activity in 103 participants (30 CD, 28 PG, and 45 controls) while they watched videos depicting cocaine, gambling, and sad scenarios to investigate the neural correlates of craving. We observed a three-way urge type × video type × diagnostic group interaction in self-reported craving, with CD participants reporting strong cocaine cravings to cocaine videos, and PG participants reporting strong gambling urges to gambling videos. Neuroimaging data revealed a diagnostic group × video interaction in anterior cingulate cortex/ventromedial prefrontal cortex (mPFC), activating predominantly to cocaine videos in CD participants, and a more dorsal mPFC region that was most strongly activated for cocaine videos in CD participants, gambling videos in PG participants, and sad videos in control participants. Gender × diagnosis × video interactions identified dorsal mPFC and a region in posterior insula/caudate in which female but not male PG participants showed increased responses to gambling videos. Findings illustrate both similarities and differences in the neural correlates of drug cravings and gambling urges in CD and PG. Future studies should investigate diagnostic- and gender-specific therapies targeting the neural systems implicated in craving/urge states in addictions.

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

    PubMed Central

    García-Fuster, M. Julia; Perez, Javier A.; Clinton, Sarah M.; Watson, Stanley J; Akil, Huda

    2014-01-01

    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 BrdU for older cells born prior to sensitization. Results show that: (1) bHRs exhibited greater psychomotor response to cocaine than bLRs. (2) Acute cocaine did not alter cell proliferation in bLR/bHR rats. (3) Chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence. (4) Neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype. (5) Cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine. (6) 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 versus 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. PMID:20104651

  13. Intravenous nicotine and caffeine: subjective and physiological effects in cocaine abusers.

    PubMed

    Garrett, B E; Griffiths, R R

    2001-02-01

    The subjective and physiological effects of intravenously administered caffeine and nicotine were compared in nine subjects with histories of using caffeine, tobacco, and cocaine. Subjects abstained from tobacco cigarette smoking for at least 8 h before each session. Dietary caffeine was eliminated throughout the study; however, to maintain consistency with the nicotine intake, subjects were administered caffeine (150 mg/70 kg b.i.d.) in capsules, with the last dose administered 15 to 18 h before each session. Under double-blind conditions, subjects received placebo, caffeine (100, 200, and 400 mg/70 kg), and nicotine (0.75, 1.5, and 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after drug or placebo administration. Compared with the highest dose of caffeine, the highest dose of nicotine produced greater subjective ratings on a number of scales. At doses that produced comparable ratings of drug effect (1.5 mg/70 kg of nicotine and 400 mg/70 kg of caffeine), both drugs produced similar increases in ratings of good effect, liking, high, stimulated, and bad effect. Nicotine showed a somewhat faster time to peak subjective effects than caffeine (2 versus 4 min). Subjective ratings that differentiated caffeine and nicotine were ratings of rush, blurry vision, and stimulant identification (elevated by nicotine) and ratings of unusual smell and/or taste (elevated by caffeine). Both caffeine and nicotine decreased skin temperature and increased diastolic blood pressure; however, caffeine decreased whereas nicotine increased heart rate. The study documents both striking similarities and some notable differences between caffeine and nicotine, which are among the most widely used mood-altering drugs.

  14. 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.

  15. 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.

  16. Blockade of melanocortin transmission inhibits cocaine reward

    PubMed Central

    Hsu, Richard; Taylor, Jane R.; Newton, Samuel S.; Alvaro, John D.; Haile, Colin; Han, G.; Hruby, Victor J.; Nestler, Eric J.; Duman, Ronald S.

    2009-01-01

    Abstract Melanocortins and the melanocortin-4 receptor (MC4-R) are enriched in the nucleus accumbens, a brain region that has been implicated in the rewarding action of cocaine and other drugs of abuse. In the present study we use a number of rat behavioral models to show that infusion of a melanocortin peptide antagonist into the nucleus accumbens blocks the reinforcing, incentive motivational, and locomotor sensitizing effects of cocaine. We also show that locomotor responses to repeated cocaine exposure are completely blocked in MC4-R null mutant mice and reduced in Agouti mice that overexpress an endogenous inhibitor of melanocortins in the brain. The results also demonstrate that cocaine administration increases the expression of MC4-R in the nucleus accumbens and striatum, and that MC4-R is co-localized with prodynorphin in medium spiny neurons in the nucleus accumbens. Together, these findings indicate that the behavioral actions of cocaine are dependent on activation of MC4-R, and suggest that upregulation of this receptor by drug exposure may contribute to sensitization of these behavioral responses. Modulation of cocaine reward is a novel action of the melanocortin–MC4-R system and could be targeted for the development of new medications for cocaine addiction. PMID:15869520

  17. Effects of cocaine on norepinephrine stimulated phosphoinositide hydrolysis and locomotor activity in rat

    SciTech Connect

    Mosaddeghi, M.

    1989-01-01

    The function of {alpha}{sub 1}-adrenoceptors was determined by stimulating cortical tissue slices, which were pre-labeled with ({sup 3}H)inositol, with norepinephrine (NE) in the presence of 8 mM LiCl. Results of in vitro studies showed that cocaine 10 {mu}M potentiated maximal NE-stimulated PI hydrolysis by 30%. In addition, the EC{sub 50} was decreased from 3.93 {plus minus} 0.42 to 1.91 {plus minus} 0.31 {mu}M NE. Concentrations of 0.1-100 {mu}M and 0.1-10 {mu}M cocaine enhanced PI hydrolysis stimulated by 0.3 and 3 {mu}M NE, respectively. The concentration-effect curves for NE-stimulated PI hydrolysis were shifted to the right 100-fold in the presence of 0.1 {mu}M prazosin. Cocaine (10 {mu}M) did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 {mu}M prazosin. ({sup 3}H)Prazosin saturation and NE ({sup 3}H)prazosin competition binding studies using crude membrane preparations showed that 10 {mu}M cocaine did not alter binding parameters B{sub max}, K{sub d}, Hill slope, and IC{sub 50}. Together, these results implied that cocaine in vitro potentiated NE-stimulated PI hydrolysis by blocking NE reuptake. For in vivo studies, the locomotor activity was determined after an acute or chronic injections of either cocaine or saline. Cocaine or saline-treated rats were killed after measurement of the locomotor activity, and NE-stimulated PI hydrolysis was measured. Acute administration of cocaine 3.2-42 mg/kg (i.p.) produced an inverted U shaped dose-response curve on locomotor activity. The peak increase in locomotor activity was at 32 mg/kg cocaine. A dose of 42 mg/kg cocaine produced a significant depression of maximal NE-stimulated PI hydrolysis.

  18. Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling.

    PubMed

    Goertz, Richard Brandon; Wanat, Matthew J; Gomez, Jorge A; Brown, Zeliene J; Phillips, Paul E M; Paladini, Carlos A

    2015-03-13

    Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.

  19. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  20. Nociceptin receptor activation does not alter acquisition, expression, extinction and reinstatement of conditioned cocaine preference in mice.

    PubMed

    Sartor, G C; Powell, S K; Wiedner, H J; Wahlestedt, C; Brothers, S P

    2016-02-01

    Growing evidence indicates that targeting nociceptin receptor (NOP) signaling may have therapeutic efficacy in treating alcohol and opioid addiction. However, little is known about the therapeutic value of selective NOP agonists for the treatment of cocaine dependence. Recently, we identified a highly selective, brain-penetrant NOP small molecule agonist (SR-8993), and using this compound, we previously showed that nociceptin receptor activation attenuated consolidation of fear-related memories. Here, we sought to determine whether SR-8993 also affects the rewarding properties of cocaine. Using a conditioned place preference (CPP) procedure, we show that SR-8993 (3 or 10 mg/kg) failed to disrupt acquisition or expression of cocaine CPP (7.5 or 15 mg/kg) in C57BL/6 mice. Additionally, SR-8993 did not affect rate of extinction or reinstatement (yohimbine- and cocaine-induced) of cocaine CPP. These studies indicate that selective activation of NOP may not be sufficient in reducing behavioral responses to cocaine.

  1. Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems.

    PubMed

    Bhat, R V; Baraban, J M

    1993-10-01

    Acute administration of cocaine increases expression of the transcription factor genes c-fos and zif268 in the striatum. This response is thought to be mediated via D1 dopamine (DA) receptors, as it is blocked by the selective D1 receptor antagonist SCH 23390. However, the directly acting D1 receptor agonists, apomorphine and SKF 38393, do not mimic cocaine's activation of these genes raising the possibility that D1 receptor activation is necessary, but not sufficient, to trigger transcription factor expression. Because cocaine blocks uptake of norepinephrine (NE) and serotonin (5-HT), as well as DA, we examined whether cocaine's ability to inhibit NE and 5-HT uptake may contribute to its induction of c-fos and zif268 expression in striatum. In examining the effects of selective monoamine uptake inhibitors, we observed that fluoxetine or citalopram, selective inhibitors of 5-HT uptake, potentiated the ability of mazindol, a DA and NE uptake inhibitor, to induce zif268 and c-fos expression, even though these 5-HT uptake inhibitors had no effect when administered alone. In contrast, the selective NE uptake inhibitor, desipramine, administered alone, or in combination with fluoxetine, did not increase expression of zif268 or c-fos. Furthermore, selective denervation of 5-HT projections by p-chloroamphetamine treatment attenuated the increase in zif268 and c-fos expression induced by cocaine in the striatum. In contrast, selective lesions of NE projections with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride failed to block cocaine's activation of these genes in the striatum. Taken together, these findings indicate that cocaine's ability to induce striatal expression of c-fos and zif268 is mediated by its effects on both the 5-HT and DA systems.

  2. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects

    PubMed Central

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R.

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  3. Prime-, Stress- and Cue-Induced Reinstatement of Extinguished Drug-Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

    PubMed Central

    Beardsley, Patrick M.; Shelton, Keith L.

    2012-01-01

    This unit describes the testing of rats in prime-, footshock- and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self-administered drugs could readily be substituted with little modification to the procedures. PMID:23093352

  4. Conditioned place preference and locomotor activity in response to methylphenidate, amphetamine and cocaine in mice lacking dopamine D4 receptors

    SciTech Connect

    Thanos, P.K.; Thanos, P.K.; Bermeo, C.; Rubinstein, M.; Suchland, K.L.; Wang, G.-J.; Grandy, D.K.; Volkow, N.D.

    2010-05-01

    Methylphenidate (MP) and amphetamine (AMPH) are the most frequently prescribed medications for the treatment of attention-deficit/hyperactivity disorder (ADHD). Both drugs are believed to derive their therapeutic benefit by virtue of their dopamine (DA)-enhancing effects, yet an explanation for the observation that some patients with ADHD respond well to one medication but not to the other remains elusive. The dopaminergic effects of MP and AMPH are also thought to underlie their reinforcing properties and ultimately their abuse. Polymorphisms in the human gene that codes for the DA D4 receptor (D4R) have been repeatedly associated with ADHD and may correlate with the therapeutic as well as the reinforcing effects of responses to these psychostimulant medications. Conditioned place preference (CPP) for MP, AMPH and cocaine were evaluated in wild-type (WT) mice and their genetically engineered littermates, congenic on the C57Bl/6J background, that completely lack D4Rs (knockout or KO). In addition, the locomotor activity in these mice during the conditioning phase of CPP was tested in the CPP chambers. D4 receptor KO and WT mice showed CPP and increased locomotor activity in response to each of the three psychostimulants tested. D4R differentially modulates the CPP responses to MP, AMPH and cocaine. While the D4R genotype affected CPP responses to MP (high dose only) and AMPH (low dose only) it had no effects on cocaine. Inasmuch as CPP is considered an indicator of sensitivity to reinforcing responses to drugs these data suggest a significant but limited role of D4Rs in modulating conditioning responses to MP and AMPH. In the locomotor test, D4 receptor KO mice displayed attenuated increases in AMPH-induced locomotor activity whereas responses to cocaine and MP did not differ. These results suggest distinct mechanisms for D4 receptor modulation of the reinforcing (perhaps via attenuating dopaminergic signalling) and locomotor properties of these stimulant drugs

  5. Daily treadmill exercise attenuates cocaine cue-induced reinstatement and cocaine induced locomotor response but increases cocaine-primed reinstatement

    PubMed Central

    Thanos, Panayotis K.; Stamos, Joshua; Robison, Lisa S.; Heyman, Gary; Tucci, Andrew; Wang, Gene-Jack; Robinson, John K.; Anderson, Brenda J.; Volkow, Nora D.

    2013-01-01

    Exercise affects neuroplasticity and neurotransmission including dopamine (DA), which modulates drug-taking behavior. Previous research in rodents has shown that exercise may attenuate the rewarding effects of drugs of abuse. The present study examined the effects of high and low exercise on cocaine responses in male Wistar rats that had been trained to self-administer and were compared to a group of sedentary rats. High exercise rats (HE) ran daily on a treadmill for 2 h and low exercise (LE) ran daily for 1 h. After 6 weeks of this exercise regimen, rats were tested over 2 days for reinstatement (day 1: cue-induced reinstatement; day 2: cocaine-primed reinstatement). During cue-induced reinstatement, the sedentary rats showed the expected increase in active lever responses when compared to maintenance, whereas these increased responses were inhibited in the exercised rats (HE and LE). During cocaine-primed reinstatement, however, there was a significant increase in active lever presses when compared to maintenance only in the HE group. This data suggests that chronic exercise during abstinence attenuates the cue-induced reinstatement seen in the sedentary rats by 26% (LE) and 21% (HE). In contrast, only the high exercise rats exhibited sensitized cocaine-seeking behavior (active lever presses) following cocaine-primed reinstatement. Finally, while sedentary rats increased locomotor activity during cocaine-primed reinstatement over that seen with cocaine during maintenance, this was not observed in the exercised rats, suggesting that exercise may interfere with the sensitized locomotor response during cocaine reinstatement. PMID:23103403

  6. Locomotor activating effects of cocaine and scopolamine combinations in rats: isobolographic analysis.

    PubMed

    Thomsen, Morgane

    2014-08-01

    Muscarinic cholinergic receptors are currently receiving renewed interest as viable targets for treating various psychiatric disorders. Dopaminergic and muscarinic systems interact in complex ways. The goal of this study was to quantify the interaction between a systemically administered psychomotor stimulant and muscarinic antagonist at the behavioral level. Through isobolographic analysis of locomotor activity data, we assessed the effects of three cocaine/scopolamine mixtures in terms of deviation from simple dose addition (additivity), at four effect levels. All three mixtures produced some more-than-additive (synergistic) effects, as lower doses were needed to produce the given effects relative to the calculated effect of additive doses. A mixture with comparable contributions from cocaine and scopolamine produced significantly more-than-additive effects at all but the lowest effect level examined. A mostly-cocaine mixture was more-than-additive only at low effect levels, whereas a mostly-scopolamine mixture produced effects more consistent with additivity, with only the highest effect level barely reaching significant synergism. Our study confirms and quantifies previous findings that suggested synergistic effects of stimulants and muscarinic antagonists. The synergism implies that cocaine and scopolamine stimulate locomotor activity through nonidentical pathways, and was most pronounced for a mixture containing cocaine and scopolamine in comparable proportions.

  7. Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction.

    PubMed

    Volkow, Nora D; Wang, Gene-Jack; Ma, Yeming; Fowler, Joanna S; Wong, Christopher; Ding, Yu-Shin; Hitzemann, Robert; Swanson, James M; Kalivas, Peter

    2005-04-13

    Drugs of abuse are rewarding to addicted and nonaddicted subjects, but they trigger craving and compulsive intake only in addicted subjects. Here, we used positron emission tomography (PET) and [18F] deoxyglucose to compare the brain metabolic responses (marker of brain function) of cocaine-addicted subjects (n = 21) and controls (n = 15) to identify brain regions that are uniquely activated in addicted subjects by intravenous methylphenidate (a drug that cocaine-addicted subjects report to be similar to cocaine). In parallel, we also measured the changes in dopamine (DA) induced by intravenous methylphenidate (using PET and [11C] raclopride) in the striatum and in the thalamus. Metabolic responses between groups differed significantly only in the right medial orbital prefrontal cortex [Brodmann's area (BA) 25 and medial BA 11], where methylphenidate increased metabolism in addicted subjects but decreased metabolism in controls. These changes were associated in all subjects with increased "desire for methylphenidate" and in the addicted subjects with "cocaine craving." In addicted subjects, increases in BA 25 were also associated with mood elevation. Methylphenidate-induced increases in metabolism in the medial orbital prefrontal cortex were associated with its increase of DA in the thalamus but not in the striatum. These findings provide evidence that enhanced sensitivity of BA 25 (region involved with emotional reactivity) and BA 11 (region involved with salience attribution and motivation) in cocaine-addicted subjects may underlie the strong emotional response to the drug and the intense desire to procure it that results in craving and compulsive drug intake. It also suggests that the mesothalamic DA pathway may contribute to these processes.

  8. 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).

  9. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation.

    PubMed

    Vassoler, Fair M; White, Samantha L; Hopkins, Thomas J; Guercio, Leonardo A; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D; Pierce, R Christopher

    2013-09-04

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents.

  10. Effectiveness of secondary prevention and treatment interventions for crack-cocaine abuse: a comprehensive narrative overview of English-language studies.

    PubMed

    Fischer, Benedikt; Blanken, Peter; Da Silveira, Dartiu; Gallassi, Andrea; Goldner, Elliot M; Rehm, Jürgen; Tyndall, Mark; Wood, Evan

    2015-04-01

    There are an estimated several million crack-cocaine users globally; use is highest in the Americas. Most crack users are socio-economically marginalized (e.g., homeless), and feature elevated risks for morbidity (e.g., blood-borne viruses), mortality and crime/violence involvement, resulting in extensive burdens. No comprehensive reviews of evidence-based prevention and/or treatment interventions specifically for crack use exist. We conducted a comprehensive narrative overview of English-language studies on the efficacy of secondary prevention and treatment interventions for crack (cocaine) abuse/dependence. Literature searches (1990-2014) using pertinent keywords were conducted in main scientific databases. Titles/abstracts were reviewed for relevance, and full studies were included in the review if involving a primary prevention/treatment intervention study comprising a substantive crack user sample. Intervention outcomes considered included drug use, health risks/status (e.g., HIV or sexual risks) and select social outcome indicators. Targeted (e.g., behavioral/community-based) prevention measures show mixed and short-term effects on crack use/HIV risk outcomes. Material (e.g., safer crack use kit distribution) interventions also document modest efficacy in risk reduction; empirical assessments of environmental (e.g., drug consumption facilities) for crack smokers are not available. Diverse psycho-social treatment (including contingency management) interventions for crack abuse/dependence show some positive but also limited/short-term efficacy, yet likely constitute best currently available treatment options. Ancillary treatments show little effects but are understudied. Despite ample studies, pharmaco-therapeutic/immunotherapy treatment agents have not produced convincing evidence; select agents may hold potential combined with personalized approaches and/or psycho-social strategies. No comprehensively effective 'gold-standard' prevention

  11. Cocaine reduces cytochrome oxidase activity in the prefrontal cortex and modifies its functional connectivity with brainstem nuclei

    PubMed Central

    Vélez-Hernández, M.E.; Padilla, E.; Gonzalez-Lima, F.; Jiménez-Rivera, C.A.

    2014-01-01

    Cocaine-induced psychomotor stimulation may be mediated by metabolic hypofrontality and modification of brain functional connectivity. Functional connectivity refers to the pattern of relationships among brain regions, and one way to evaluate this pattern is using interactivity correlations of the metabolic marker cytochrome oxidase among different regions. This is the first study of how repeated cocaine modifies: (1) mean cytochrome oxidase activity in neural areas using quantitative enzyme histochemistry, and (2) functional connectivity among brain regions using inter-correlations of cytochrome oxidase activity. Rats were injected with 15 mg/kg i.p. cocaine or saline for 5 days, which lead to cocaine-enhanced total locomotion. Mean cytochrome oxidase activity was significantly decreased in cocaine-treated animals in the superficial dorsal and lateral frontal cortical association areas Fr2 and Fr3 when compared to saline-treated animals. Functional connectivity showed that the cytochrome oxidase activity of the noradrenergic locus coeruleus and the infralimbic cortex were positively inter-correlated in cocaine but not in control rats. Positive cytochrome oxidase activity inter-correlations were also observed between the dopaminergic substantia nigra compacta and Fr2 and Fr3 areas and the lateral orbital cortex in cocaine-treated animals. In contrast, cytochrome oxidase activity in the interpeduncular nucleus was negatively correlated with that of Fr2, anterior insular cortex, and lateral orbital cortex in saline but not in cocaine groups. After repeated cocaine specific prefrontal areas became hypometabolic and their functional connectivity changed in networks involving noradrenergic and dopaminergic brainstem nuclei. We suggest that this pattern of hypofrontality and altered functional connectivity may contribute to cocaine-induced psychomotor stimulation. PMID:24505625

  12. Effects of active chronic cocaine use on cardiac sympathetic neuronal function assessed by carbon-11-hydroxyephedrine

    SciTech Connect

    Melon, P.G.; Boyd, C.J.; McVey, S. |

    1997-03-01

    Cardiac toxicity of cocaine has been linked to its inhibitory effect on norepinephrine reuptake by sympathetic nerve terminals of the heart. Carbon-11-hydroxyephedrine is a positron-emitting tracer that has been validated as a highly specific marker for norepinephrine transporter activity of the sympathetic nerve terminals and thus makes possible in vivo assessment of the effect of cocaine on norepinephrine reuptake and storage in the cardiac sympathetic nerve terminals. The aim of the study was to use the catecholamine analog {sup 11}C-hydroxyephedrine with PET to determine whether active chronic use of cocaine in women modifies the function of sympathetic nerve terminals of the heart. Six normal female volunteers and nine female active chronic cocaine users were studied. Cardiac regional {sup 11}C-hydroxyephedrine uptake and blood flow, as assessed with {sup 13}N-ammonia, were determined using semi-quantitative polar map analysis of myocardial tracer distribution. Carbon-11-hydroxyephedrine cardiac retention was quantified using dynamic data acquisition and kinetic analysis of blood and tissue activity. 27 refs., 4 figs., 3 tabs.

  13. 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

  14. Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

    PubMed

    Mello, Nancy K; Newman, Jennifer L

    2011-06-01

    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 twofold: 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.

  15. Cocaine promotes oxidative stress and microglial-macrophage activation in rat cerebellum

    PubMed Central

    López-Pedrajas, Rosa; Ramírez-Lamelas, Dolores T.; Muriach, Borja; Sánchez-Villarejo, María V.; Almansa, Inmaculada; Vidal-Gil, Lorena; Romero, Francisco J.; Barcia, Jorge M.; Muriach, María

    2015-01-01

    Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction. PMID:26283916

  16. 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

  17. Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine.

    PubMed

    Fitzgerald, Paul J

    2013-10-13

    A wide range of commonly abused drugs have effects on the noradrenergic neurotransmitter system, including alterations during acute intoxication and chronic use of these drugs. It is not established, however, that individual differences in noradrenergic signaling, which may be present prior to use of drugs, predispose certain persons to substance abuse. This paper puts forth the novel hypothesis that elevated noradrenergic signaling, which may be raised largely due to genetics but also due to environmental factors, is an etiological factor in the abuse of a wide range of substances, including alcohol, nicotine, marijuana, heroin, cocaine, and caffeine. Data are reviewed for each of these drugs comprising their interaction with norepinephrine during acute intoxication, long-term use, subsequent withdrawal, and stress-induced relapse. In general, the data suggest that these drugs acutely boost noradrenergic signaling, whereas long-term use also affects this neurotransmitter system, possibly suppressing it. During acute withdrawal after chronic drug use, noradrenergic signaling tends to be elevated, consistent with the observation that norepinephrine lowering drugs such as clonidine reduce withdrawal symptoms. Since psychological stress can promote relapse of drug seeking in susceptible individuals and stress produces elevated norepinephrine release, this suggests that these drugs may be suppressing noradrenergic signaling during chronic use or instead elevating it only in reward circuits of the brain. If elevated noradrenergic signaling is an etiological factor in the abuse of a broad range of substances, then chronic use of pharmacological agents that reduce noradrenergic signaling, such as clonidine, guanfacine, lofexidine, propranolol, or prazosin, may help prevent or treat drug abuse in general.

  18. Online extraction LC-MS/MS method for the simultaneous quantitative confirmation of urine drugs of abuse and metabolites: amphetamines, opiates, cocaine, cannabis, benzodiazepines and methadone.

    PubMed

    de Jager, Andrew D; Bailey, Neville L

    2011-09-01

    A rapid LC-MS/MS method for confirmatory testing of five major categories of drugs of abuse (amphetamine-type substances, opiates, cocaine, cannabis metabolites and benzodiazepines) in urine has been developed. All drugs of abuse mandated by the Australian/New Zealand Standard AS/NZS 4308:2008 are quantified in a single chromatographic run. Urine samples are diluted with a mixture of isotope labelled internal standards. An on-line trap-and-flush approach, followed by LC-ESI-MS/MS has been successfully used to process samples in a functioning drugs of abuse laboratory. Following injection of diluted urine samples, compounds retained on the trap cartridge are flushed onto a reverse-phase C18 HPLC column (5-μm particle size) with embedded hydrophylic functionality. A total chromatographic run-time of 15 min is required for adequate resolution. Automated quantitation software algorithms have been developed in-house using XML scripting to partially automate the identification of positive samples, taking into account ion ratio (IR) and retention times (Rt). The sensitivity of the assay was found to be adequate for the quantitation of drugs in urine at and below the confirmation cut-off concentrations prescribed by AS/NZS 4308:2008.

  19. 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

  20. Neural Correlates of the Severity of Cocaine, Heroin, Alcohol, MDMA and Cannabis Use in Polysubstance Abusers: A Resting-PET Brain Metabolism Study

    PubMed Central

    Moreno-López, Laura; Stamatakis, Emmanuel A.; Fernández-Serrano, Maria José; Gómez-Río, Manuel; Rodríguez-Fernández, Antonio; Pérez-García, Miguel; Verdejo-García, Antonio

    2012-01-01

    Introduction Functional imaging studies of addiction following protracted abstinence have not been systematically conducted to look at the associations between severity of use of different drugs and brain dysfunction. Findings from such studies may be relevant to implement specific interventions for treatment. The aim of this study was to examine the association between resting-state regional brain metabolism (measured with 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and the severity of use of cocaine, heroin, alcohol, MDMA and cannabis in a sample of polysubstance users with prolonged abstinence from all drugs used. Methods Our sample consisted of 49 polysubstance users enrolled in residential treatment. We conducted correlation analyses between estimates of use of cocaine, heroin, alcohol, MDMA and cannabis and brain metabolism (BM) (using Statistical Parametric Mapping voxel-based (VB) whole-brain analyses). In all correlation analyses conducted for each of the drugs we controlled for the co-abuse of the other drugs used. Results The analysis showed significant negative correlations between severity of heroin, alcohol, MDMA and cannabis use and BM in the dorsolateral prefrontal cortex (DLPFC) and temporal cortex. Alcohol use was further associated with lower metabolism in frontal premotor cortex and putamen, and stimulants use with parietal cortex. Conclusions Duration of use of different drugs negatively correlated with overlapping regions in the DLPFC, whereas severity of cocaine, heroin and alcohol use selectively impact parietal, temporal, and frontal-premotor/basal ganglia regions respectively. The knowledge of these associations could be useful in the clinical practice since different brain alterations have been associated with different patterns of execution that may affect the rehabilitation of these patients. PMID:22768136

  1. Relationship between cocaine-induced subjective effects and dopamine transporter occupancy

    SciTech Connect

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

    1997-05-01

    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 cocaines 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}.

  2. PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

    SciTech Connect

    Zhang Xiuwu . E-mail: xwzhang@duke.edu; Mi Jing; Wetsel, William C.; Davidson, Colin; Xiong Xieying; Chen Qiang; Ellinwood, Everett H.; Lee, Tong H.

    2006-02-24

    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.

  3. The effect of active and passive intravenous cocaine administration on the extracellular signal-regulated kinase (ERK) activity in the rat brain.

    PubMed

    Miszkiel, Joanna; Detka, Jan; Cholewa, Joanna; Frankowska, Małgorzata; Nowak, Ewa; Budziszewska, Bogusława; Przegaliński, Edmund; Filip, Małgorzata

    2014-08-01

    According to a current hypothesis of learning processes, recent papers pointed out to an important role of the extracellular signal-regulated kinase (ERK), in drug addiction. We employed the Western blotting techniques to examine the ERK activity immediately after cocaine iv self-administration and in different drug-free withdrawal periods in rats. To distinguish motivational vs. pharmacological effects of the psychostimulant intake, a "yoked" procedure was used. Animals were decapitated after 14 daily cocaine self-administration sessions or on the 1st, 3rd or 10th extinction days. At each time point the activity of the ERK was assessed in several brain structures, including the prefrontal cortex, hippocampus, dorsal striatum and nucleus accumbens. Passive, repeated iv cocaine administration resulted in a 45% increase in ERK phosphorylation in the hippocampus while cocaine self-administration did not change brain ERK activity. On the 1st day of extinction, the activity of the ERK in the prefrontal cortex was decreased in rats with a history of cocaine chronic intake: by 66% for "active" cocaine group and by 35% for "yoked" cocaine group. On the 3rd day the reduction in the ERK activity (25-34%) was observed in the hippocampus for both cocaine-treated groups, and also in the nucleus accumbens for "yoked" cocaine group (40%). On the 10th day of extinction there was no significant alteration in ERK activity in any group of rats. Our findings suggest that cortical ERK is involved in cocaine seeking behavior in rats. They also indicate the time and regional adaptations in this enzyme activity after cocaine withdrawal.

  4. The skinny on cocaine: insights into eating behavior and body weight in cocaine-dependent men.

    PubMed

    Ersche, Karen D; Stochl, Jan; Woodward, Jeremy M; Fletcher, Paul C

    2013-12-01

    There is a general assumption that weight loss associated with cocaine use reflects its appetite suppressing properties. We sought to determine whether this was justified by characterizing, in detail, alterations in dietary food intake and body composition in actively using cocaine-dependent individuals. We conducted a cross-sectional case-control comparison of 65 male volunteers from the local community, half of whom satisfied the DSM-IV-TR criteria for cocaine dependence (n=35) while the other half had no personal or family history of a psychiatric disorder, including substance abuse (n=30). Assessments were made of eating behavior and dietary food intake, estimation of body composition, and measurement of plasma leptin. Although cocaine users reported significantly higher levels of dietary fat and carbohydrates as well as patterns of uncontrolled eating, their fat mass was significantly reduced compared with their non-drug using peers. Levels of leptin were associated with fat mass, and with the duration of stimulant use. Tobacco smoking status or concomitant use of medication did not affect the significance of the results. Weight changes in cocaine users reflect fundamental perturbations in fat regulation. These are likely to be overlooked in clinical practice but may produce significant health problems when cocaine use is discontinued during recovery.

  5. Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats.

    PubMed

    Salazar-Juárez, Alberto; Barbosa-Méndez, Susana; Jurado, Noe; Hernández-Miramontes, Ricardo; Leff, Philippe; Antón, Benito

    2016-07-04

    Cocaine abuse is a major health problem worldwide. Treatment based on both 5-HT2A/C and 5-HT3 receptor antagonists attenuate not only the effects of cocaine abuse but also the incentive/motivational effect related to cocaine-paired cues. Mirtazapine, an antagonist of postsynaptic α2-adrenergic, 5-HT2A/C and 5HT3 receptors and inverse agonist of the 5-HT2C receptor, has been shown to effectively modify, at the preclinical and clinical levels, various behavioral alterations induced by drugs abuse. Therefore, it is important to assess whether chronic dosing of mirtazapine alters locomotor effects of cocaine as well as induction and expression of cocaine sensitization. Our results reveal that a daily mirtazapine regimen administered for 30days effectively induces a significant attenuation of cocaine-dependent locomotor activity and as well as the induction and expression of behavioral sensitization. These results suggest that mirtazapine may be used as a potentially effective therapy to attenuate induction and expression of cocaine-induced locomotor sensitization.

  6. Cocaine withdrawal symptoms identify "Type B" cocaine-dependent patients.

    PubMed

    Ahmadi, Jamshid; Kampman, Kyle; Dackis, Charles; Sparkman, Thorne; Pettinati, Helen

    2008-01-01

    Recent studies of substance dependence typologies briefly show that multivariate systems originally developed for identifying subtypes of alcoholics, such as Babor's Type A and B system, may also be valid in abusers of other substances, such as cocaine. Type B patients are characterized by an earlier onset of addiction and more severe symptoms of their addiction, psychopathology, and impulsivity. The Type B classification has also been associated with deficits in serotonergic function. We have found that patients who exhibit more severe cocaine withdrawal symptoms, as measured by scores on the Cocaine Selective Severity Assessment (CSSA), have poor treatment outcome and share many characteristics with "Type B" patients. In this paper, we review baseline characteristics of cocaine-dependent patients from several recently completed outpatient cocaine dependence treatment trials to assess the association of cocaine withdrawal symptom severity and the Type B profile. Identifying subtypes of cocaine-dependent patients may improve our ability to treat cocaine dependence by targeting treatments for specific subtypes of patients. We examined the ability of the CSSA scores to capture Type B characteristics in cocaine dependence by analyzing a series of cocaine medication trials that included 255 cocaine-dependent subjects. High CSSA scores at baseline were associated with a history of violent behavior, a family history of substance abuse, antisocial personality disorder, higher addiction severity, and co-morbid psychiatric diseases. Patients with high CSSA scores are also more likely to meet criteria for Type B (Type II) cocaine dependence. Identifying Type B cocaine-dependent patients may help to develop targeted psychosocial or pharmacological treatments for these difficult-to-treat patients.

  7. Substance Abuse in the Military

    MedlinePlus

    ... Charts Emerging Trends and Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine ... Drugs Anabolic Steroids Cigarettes and Other Tobacco Products Cocaine Cough and Cold Medicine Abuse Electronic Cigarettes (e- ...

  8. Cocaine-induced mesenteric ischaemia.

    PubMed

    Osorio, J; Farreras, N; Ortiz De Zárate L; Bachs, E

    2000-01-01

    We report a 33-year-old man with distal ileum infarction after intravenous abuse of cocaine. He underwent resection of a gangrenous bowel segment and survived. We review the literature regarding intestinal ischaemia related to cocaine. To date, 19 cases have been published. Like most previously reported cases, our patient was young and had no previous history of arteriosclerosis. He suffered cocaine-induced rhabdomyolysis and acute renal failure. Mesenteric ischaemia should be considered in the differential diagnosis of acute or chronic abdominal pain in cocaine consumers.

  9. Effects of subacute treatment with cocaine on activities of n-demethylase, UDP-glucuronyltransferase and sulfotransferase in WKY and SHR rat liver - sex and strain differences

    SciTech Connect

    Watanabe, H.K.; Hoskins, B.; Ho, I.K.

    1988-01-01

    The effects of subacute treatment with cocaine on activities of cocaine N-demethylase, UDP-glucuronyltransferase (GT) toward 4-nitrophenol and phenolphthalein and sulfotransferase (ST) toward androsterone and 4-nitrophenol in livers from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated. Hepatic metabolism of cocaine was different between the sexes (with males having higher N-demethylase activity) and the strains (with WKY rats having higher activity). The effects of subacute cocaine administration on the activity of cocaine N-demethylase were also sex- and strain-related. Whereas cocaine administration increased activity of hepatic N-demethylase in both female strains, it decreased activity in male WKY and had no effect on activity in male SHR. Sex and strain-related as well as cocaine-induced differences were also found in activities of hepatic GT toward 4-nitrophenol and phenolphtalein as well as in activity of hepatic ST towards andersterone and 4-nitrophenol. These results suggest that some of the individual variation in the effects of cocaine may be due to sex and genetic differences in the hepatic metabolism of cocaine and/or in sexually and/or genetically-determined differences in how cocaine affects hepatic metabolism of other xenobiotics. 20 references, 4 figures.

  10. 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.

  11. Re-appraisal of negative emotions in cocaine dependence: dysfunctional corticolimbic activation and connectivity.

    PubMed

    Albein-Urios, Natalia; Verdejo-Román, Juan; Asensio, Samuel; Soriano-Mas, Carles; Martínez-González, José M; Verdejo-García, Antonio

    2014-05-01

    Cocaine dependence is associated with pronounced elevations of negative affect and deficient regulation of negative emotions. We aimed to investigate the neural substrates of negative emotion regulation in cocaine-dependent individuals (CDI), as compared to non-drug-using controls, using functional magnetic resonance imaging (fMRI) during a re-appraisal task. Seventeen CDI abstinent for at least 15 days and without other psychiatric co-morbidities and 18 intelligence quotient-matched non-drug-using controls participated in the study. Participants performed the re-appraisal task during fMRI scanning: they were exposed to 24 blocks of negative affective or neutral pictures that they should Observe (neutral pictures), Maintain (sustain the emotion elicited by negative pictures) or Suppress (regulate the emotion elicited by negative pictures through previously trained re-appraisal techniques). Task-related activations during two conditions of interest (Maintain>Observe and Suppress>Maintain) were analyzed using the general linear model in SPM8 software. We also performed psychophysiological interaction (PPI) seed-based analyses based on one region from each condition: the dorsolateral prefrontal cortex (dlPFC-Maintain>Observe) and the inferior frontal gyrus (IFG-Suppress>Maintain). Results showed that cocaine users had increased right dlPFC and bilateral temporoparietal junction activations during Maintain>Observe, whereas they showed decreased right IFG, posterior cingulate cortex, insula and fusiform gyrus activations during Suppress>Maintain. PPI analyses showed that cocaine users had increased functional coupling between the dlPFC and emotion-related regions during Maintain>Observe, whereas they showed decreased functional coupling between the right IFG and the amygdala during Suppress>Maintain. These findings indicate that CDI have dysfunctional corticolimbic activation and connectivity during negative emotion experience and re-appraisal.

  12. Anti-cocaine vaccine development

    PubMed Central

    Kinsey, Berma M; Kosten, Thomas R; Orson, Frank M

    2010-01-01

    Cocaine abuse is an ongoing and serious problem which has lead to the growth of a brutal criminal enterprise, particularly in the Americas and Europe. At present, there are no effective pharmacological agents available to treat the addiction by blocking cocaine or reversing its effects. In order to help motivated addicts conquer their addiction, vaccines against cocaine are being developed, and one has progressed to clinical trials. This review will discuss the concept of anti-drug vaccines in general, the successes and limitations of the various anti-cocaine vaccine approaches, the results of the clinical trials with an anti-cocaine vaccine, and some new vaccine-mediated approaches to combat cocaine addiction. PMID:20822352

  13. Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings

    PubMed Central

    Fox, Helen C.; Seo, Dongju; Tuit, Keri; Hansen, Julie; Kimmerling, Anne; Morgan, Peter T.; Sinha, Rajita

    2013-01-01

    Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of α2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal. PMID:22234929

  14. Lesions of the oral mucosa in cocaine users who apply the drug topically.

    PubMed

    Gandara-Rey, J M; Diniz-Freitas, M; Gandara-Vila, P; Blanco-Carrion, A; Garcia-Garcia, A

    2002-01-01

    The use and abuse of cocaine is increasingly frequent in many countries, and the associated problems are increasingly evident. The effects of cocaine in the oral cavity vary depending on the form used and the route of self-administration. In the present study we describe the lesions observed in four patients with a history of topical self-application of cocaine to the oral and/or nasal mucosa, with the aim of relieving pain produced by cocaine-induced cluster headache. In three of the four patients this practice has led to erythematous lesions, while the remaining patient showed gingival recession and bone sequestration. These lesions can probably be attributed to the vasoconstrictor activity of cocaine, and to its caustic effects on the mucosa.

  15. Cocaine Exposure Reorganizes Cell-Type and Input-Specific Connectivity in the Nucleus Accumbens

    PubMed Central

    MacAskill, Andrew F.; Cassel, John M.; Carter, Adam G.

    2014-01-01

    Exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the Nucleus Accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we use whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine alters connectivity in the mouse NAc medial shell. We first determine that cocaine selectively enhances amygdala innervation of D1-MSNs relative to D2-MSNs. We then show that amygdala activity is required for cocaine-induced changes to behavior and connectivity. Finally, we establish how heightened amygdala innervation can explain the structural and functional changes induced by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell-type and input-specific connectivity in the NAc. PMID:25108911

  16. Repeated cocaine administration suppresses HVA-Ca2+ potentials and enhances activity of K+ channels in rat nucleus accumbens neurons.

    PubMed

    Hu, Xiu-Ti; Basu, Somnath; White, Francis J

    2004-09-01

    The nucleus accumbens (NAc) is an important forebrain area involved in sensitization, withdrawal effects, and self-administration of cocaine. However, little is known about cocaine-induced alterations in the neuronal excitability and whole cell neuroplasticity in this region that may affect behaviors. Our recent investigations have demonstrated that repeated cocaine administration decreases voltage-sensitive sodium and calcium currents (VSSCs and VSCCs, respectively) in freshly dissociated NAc neurons of rats. In this study, current-clamp recordings were performed in slice preparations to determine the effects of chronic cocaine on evoked Ca(2+) potentials and voltage-sensitive K(+) currents in NAc neurons. Repeated cocaine administration with 3-4 days of withdrawal caused significant alterations in Ca(2+) potentials, including suppression of Ca(2+)-mediated spikes, increase in the intracellular injected current intensity required for generation of Ca(2+) potentials (rheobase), reduced duration of Ca(2+) plateau potentials, and abolishment of secondary Ca(2+) potentials associated with the primary Ca(2+) plateau potential. Application of nickel (Ni(2+)), which blocks low-voltage activated T-type Ca(2+) channels, had no impact on evoked Ca(2+) plateau potentials in NAc neurons, indicating that these Ca(2+) potentials are high-voltage activated (HVA). In addition, repeated cocaine pretreatment also hyperpolarized the resting membrane potential, increased the amplitude of afterhyperpolarization in Ca(2+) spikes, and enhanced the outward rectification observed during membrane depolarization. These findings indicate that repeated cocaine administration not only suppressed HVA-Ca(2+) potentials but also significantly enhanced the activity of various K(+) channels in NAc neurons. They also demonstrate an integrative role of whole cell neuroplasticity during cocaine withdrawal, by which the subthreshold membrane excitability of NAc neurons is significantly decreased.

  17. 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

  18. 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.

  19. Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats.

    PubMed

    Harris Bozer, Amber L; Li, Ai-Ling; Sibi, Jiny E; Bobzean, Samara A M; Peng, Yuan B; Perrotti, Linda I

    2016-03-01

    The ventral tegmental area (VTA) has been established as a critical nucleus for processing behavioral changes that occur during psychostimulant use. Although it is known that cocaine induced locomotor activity is initiated in the VTA, not much is known about the electrical activity in real time. The use of our custom-designed wireless module for recording local field potential (LFP) activity provides an opportunity to confirm and identify changes in neuronal activity within the VTA of freely moving rats. The purpose of this study was to investigate the changes in VTA LFP activity in real time that underlie cocaine induced changes in locomotor behavior. Recording electrodes were implanted in the VTA of rats. Locomotor behavior and LFP activity were simultaneously recorded at baseline, and after saline and cocaine injections. Results indicate that cocaine treatment caused increases in both locomotor behavior and LFP activity in the VTA. Specifically, LFP activity was highest during the first 30 min following the cocaine injection and was most robust in Delta and Theta frequency bands; indicating the role of low frequency VTA activity in the initiation of acute stimulant-induced locomotor behavior. Our results suggest that LFP recording in freely moving animals can be used in the future to provide valuable information pertaining to drug induced changes in neural activity.

  20. Effect of 1 GeV/n Fe particles on cocaine-stimulated locomotor activity

    NASA Astrophysics Data System (ADS)

    Vazquez, M.; Bruneus, M.; Gatley, J.; Russell, S.; Billups, A.

    Space travel beyond the Earth's protective magnetic field (for example, to Mars) will involve exposure of astronauts to irradiation by high-energy nuclei such as 56Fe (HZE radiation), which are a component of galactic cosmic rays. These particles have high linear energy transfer (LET) and are expected to irreversibly damage cells they traverse. Our working hypothesis is that long-term behavioral alterations are induced after exposure of the brain to 1 GeV/n iron particles with fluences of 1 to 8 particles/cell targets. Previous studies support this notion but are not definitive, especially with regard to long-term effects. Using the Alternating Gradient Synchrotron (AGS) we expose C57 mice to 1 GeV/n 56Fe radiation (head only) at doses of 0, 15, 30, 60, 120 and 240 cGy. There were originally 19 mice per group. The ability of cocaine to increase locomotor activity in 16 of these animals in response to an intraperitoneal injection of cocaine has been measured so far at 1, 4, 8, 12, 16, 20, 24 and 28 weeks. Cocaine-stimulated locomotor activity was chosen in part because it is a behavioral assay with which we have considerable experience. More importantly, the ability to respond to cocaine is a complex behavior involving many neurotransmitter systems and brain circuits. Therefore, the probability of alteration of this behavior by HZE particles was considered high. However, the central circuit is the nigrostriatal dopamine system, in which dopamine is released in striatum from nerve terminals whose cell bodies are located in the substantia nigra. Cocaine activates behavior by blocking dopamine transporters on striatal nerve terminals and therefore elevating the concentration of dopamine in the synapse. Dopamine activates receptors on striatal GABAergic cells that project via other brain regions to the thalamus. Activation of the motor cortex by glutamatergic projections from the thalamus leads ultimately to increased locomotion. The experimental paradigm involves

  1. Effects of the selective sigma receptor ligand, 1-(2-phenethyl)piperidine oxalate (AC927), on the behavioral and toxic effects of cocaine

    PubMed Central

    Matsumoto, Rae R.; Li, Su-Min; Katz, Jonathan L.; Fantegrossi, William E.; Coop, Andrew

    2011-01-01

    BACKGROUND Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions. METHODS In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals. RESULTS Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine. CONCLUSION The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse. PMID:21420799

  2. Nicotine produces long-term increases in cocaine reinforcement in adolescent but not adult rats.

    PubMed

    Reed, Stephanie Collins; Izenwasser, Sari

    2017-01-01

    Studies have shown that many smokers begin using nicotine during adolescence, yet the influence of early nicotine use on the response to other drugs of abuse in adulthood is not fully understood. In the current study, nicotine was administered to adolescent and adult rats for seven days. Thirty days later, cocaine-induced locomotor activity and cocaine self-administration were examined when the rats pretreated as adolescents were adults. Rats exposed to nicotine during early adolescence were sensitized thirty days later to the locomotor-activating effects of cocaine and self-administered a greater number of cocaine infusions than adolescent rats pretreated with vehicle. As a result of this increased intake, the cocaine self-administration dose-response curve was shifted upward indicating an increase in cocaine reinforcement. Rats pretreated with nicotine as adults, however, did not show a difference in locomotor activity or cocaine self-administration thirty days later compared to adult rats pretreated with vehicle. These findings suggest that early exposure to nicotine has long-term consequences on cocaine use. These data further suggest that nicotine use may carry a greater risk during adolescence than adulthood and adolescents who smoke may be particularly vulnerable to stimulant use. This article is part of a Special Issue entitled SI: Adolescent plasticity.

  3. SKF 38393 reverses cocaine-conditioned place preference in mice.

    PubMed

    Sabioni, Pamela; D'Almeida, Vânia; Andersen, Monica L; Andreatini, Roberto; Galduróz, José C F

    2012-04-04

    Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.

  4. Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

    PubMed

    Welder, A A; Melchert, R B

    1993-04-01

    Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

  5. Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways.

    PubMed

    Barr, Jeffrey L; Deliu, Elena; Brailoiu, G Cristina; Zhao, Pingwei; Yan, Guang; Abood, Mary E; Unterwald, Ellen M; Brailoiu, Eugen

    2015-08-01

    Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, cocaine augmented the [Ca(2+)]i increase elicited by extracellularly applying an IP3-generating molecule (ATP), via σ1Rs. The cocaine-induced enhancement of the IP3/ATP-mediated Ca(2+) elevation occurred at pharmacologically relevant concentrations and was mediated by transient receptor potential canonical channels (TRPC). IP3 microinjection elicited a slight, transient depolarization, further converted to a greatly enhanced, prolonged response, by cocaine co-injection. The cocaine-triggered augmentation was σ1R-dependent, TRPC-mediated and contingent on [Ca(2+)]i elevation. ATP-induced depolarization was similarly enhanced by cocaine. Thus, we identify a novel mechanism by which cocaine promotes activation of D1-expressing nAcc neurons: enhancement of IP3R-mediated responses via σ1R activation at the endoplasmic reticulum, resulting in augmented Ca(2+) release and amplified depolarization due to subsequent stimulation of TRPC. In vivo, intra-accumbal blockade of σ1R or TRPC significantly diminished cocaine-induced hyperlocomotion and locomotor sensitization, endorsing a physio-pathological significance of the pathway

  6. A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation

    PubMed Central

    Tozzi, Alessandro; de Iure, Antonio; Marsili, Valentina; Romano, Rosaria; Tantucci, Michela; Di Filippo, Massimiliano; Costa, Cinzia; Napolitano, Francesco; Mercuri, Nicola Biagio; Borsini, Franco; Giampà, Carmen; Fusco, Francesca Romana; Picconi, Barbara; Usiello, Alessandro; Calabresi, Paolo

    2012-01-01

    Background Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. Principal Findings Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. Conclusions The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine. PMID:22715379

  7. Abuse

    MedlinePlus

    ... member, a trusted teacher, a doctor, or a school or religious youth counselor. Many teachers and counselors have training in how to recognize and report abuse. Telephone and online directories list local child abuse and family violence hotline numbers that you can call for help. ...

  8. Genes and pathways co-associated with the exposure to multiple drugs of abuse, including alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine, and/or nicotine: a review of proteomics analyses.

    PubMed

    Wang, Ju; Yuan, Wenji; Li, Ming D

    2011-12-01

    Drug addiction is a chronic neuronal disease. In recent years, proteomics technology has been widely used to assess the protein expression in the brain tissues of both animals and humans exposed to addictive drugs. Through this approach, a large number of proteins potentially involved in the etiology of drug addictions have been identified, which provide a valuable resource to study protein function, biochemical pathways, and networks related to the molecular mechanisms underlying drug dependence. In this article, we summarize the recent application of proteomics to profiling protein expression patterns in animal or human brain tissues after the administration of alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine/heroin/butorphanol, or nicotine. From available reports, we compiled a list of 497 proteins associated with exposure to one or more addictive drugs, with 160 being related to exposure to at least two abused drugs. A number of biochemical pathways and biological processes appear to be enriched among these proteins, including synaptic transmission and signaling pathways related to neuronal functions. The data included in this work provide a summary and extension of the proteomics studies on drug addiction. Furthermore, the proteins and biological processes highlighted here may provide valuable insight into the cellular activities and biological processes in neurons in the development of drug addiction.

  9. Combating Drug Abuse by Targeting Toll-Like Receptor 4 (TLR4)

    DTIC Science & Technology

    2013-10-01

    to preserve the desired effects of   3   opioids ( pain -relief) while diminishing unwanted effects (analgesic tolerance and reward...significant progress anticipated in the coming project period. 15. SUBJECT TERMS toll like receptor 4 (TLR4); TLR4 agonists non- opioid (+)-naloxone and...naltrexone; drug abuse; glial activation; therapeutic approach to treating drug abuse; opioids ; cocaine 16. SECURITY CLASSIFICATION OF: 17

  10. Cocaine dependent individuals with attenuated striatal activation during reinforcement learning are more susceptible to relapse.

    PubMed

    Stewart, Jennifer L; Connolly, Colm G; May, April C; Tapert, Susan F; Wittmann, Marc; Paulus, Martin P

    2014-08-30

    Cocaine-dependent individuals show altered brain activation during decision making. It is unclear, however, whether these activation differences are related to relapse vulnerability. This study tested the hypothesis that brain-activation patterns during reinforcement learning are linked to relapse 1 year later in individuals entering treatment for cocaine dependence. Subjects performed a Paper-Scissors-Rock task during functional magnetic resonance imaging (fMRI). A year later, we examined whether subjects had remained abstinent (n=15) or relapsed (n=15). Although the groups did not differ on demographic characteristics, behavioral performance, or lifetime substance use, abstinent patients reported greater motivation to win than relapsed patients. The fMRI results indicated that compared with abstinent individuals, relapsed users exhibited lower activation in (1) bilateral inferior frontal gyrus and striatum during decision making more generally; and (2) bilateral middle frontal gyrus and anterior insula during reward contingency learning in particular. Moreover, whereas abstinent patients exhibited greater left middle frontal and striatal activation to wins than losses, relapsed users did not demonstrate modulation in these regions as a function of outcome valence. Thus, individuals at high risk for relapse relative to those who are able to abstain allocate fewer neural resources to action-outcome contingency formation and decision making, as well as having less motivation to win on a laboratory-based task.

  11. Cocaine dependent individuals with attenuated striatal activation during reinforcement learning are more susceptible to relapse

    PubMed Central

    Stewart, Jennifer L.; Connolly, Colm G.; May, April C.; Tapert, Susan F.; Wittmann, Marc; Paulus, Martin P.

    2014-01-01

    Cocaine-dependent individuals show altered brain activation during decision making. It is unclear, however, whether these activation differences are related to relapse vulnerability. This study tested the hypothesis that brain-activation patterns during reinforcement learning are linked to relapse 1 year later in individuals entering treatment for cocaine dependence. Subjects performed a Paper-Scissors-Rock task during functional magnetic resonance imaging (fMRI). A year later, we examined whether subjects had remained abstinent (n=15) or relapsed (n=15). Although the groups did not differ on demographic characteristics, behavioral performance, or lifetime substance use, abstinent patients reported greater motivation to win than relapsed patients. The fMRI results indicated that compared with abstinent individuals, relapsed users exhibited lower activation in (1) bilateral inferior frontal gyrus and striatum during decision making more generally; and (2) bilateral middle frontal gyrus and anterior insula during reward contingency learning in particular. Moreover, whereas abstinent patients exhibited greater left middle frontal and striatal activation to wins than losses, relapsed users did not demonstrate modulation in these regions as a function of outcome valence. Thus, individuals at high risk for relapse relative to those who are able to abstain allocate fewer neural resources to action-outcome contingency formation and decision making, as well as having less motivation to win on a laboratory-based task. PMID:24862388

  12. 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

  13. Psychiatric morbidity among cocaine and heroin users in the community.

    PubMed

    Tortajada, Silvia; Herrero, Ma Jesús; Domingo-Salvany, Antònia; Molist, Gemma; Barrio, Gregorio; de la Fuente, Luís; Brugal, Ma Teresa

    2012-01-01

    Drug abuse is a serious public health problem. Moreover, co-occurring mental health and substance abuse disorders are common among drug users. This paper examines psychiatric disorders of young cocaine and heroin users using the World Mental Health Composite International Diagnostic Interview (WMH-CIDI). A cohort of 1266 young (18-30 years) current regular cocaine (705) and heroin (561) users were recruited outside the health services in Barcelona, Madrid and Seville, Spain. The WMH-CIDI was used to evaluate mental disorders; the Severity of Dependence Scale (SDS) measured the degree of dependence; and the Duke-UNC Functional Social Support Questionnaire (FSSQ) assessed social support, in a crosssectional study design. About 43% was diagnosed with a lifetime mental disorder. The most common diagnoses were depression (37.5%) and specific phobia (6.8%). During the last 12 months, prevalence rates were also slightly higher in heroin group (26.4%) than in cocaine cohort (21.7%). Every day cocaine consumption, having unstable living conditions and low social support were variables highly associated with psychiatric morbidity in cocaine cohort. In heroin cohort, earning money through illegal activities was associated with psychiatric morbidity, while the moderate use of alcohol acted as a protective factor for mental pathology. Morbidity was associated to having received psychiatric/psychological treatment during the last 12 months in both cohorts. This study has shown a relatively high prevalence of psychiatric morbidity in cocaine and heroin users recruited in non-clinical settings. Future studies examining differences between cocaine and heroin patterns of consumption associated with mental diseases are necessary.

  14. Subchronic cannabinoid agonist (WIN 55,212-2) treatment during cocaine abstinence alters subsequent cocaine seeking behavior.

    PubMed

    González-Cuevas, Gustavo; Aujla, Harinder; Martin-Fardon, Rémi; López-Moreno, José Antonio; Navarro, Miguel; Weiss, Friedbert

    2007-11-01

    The co-abuse of marijuana with cocaine is widespread, but it has not been until recently that the relationship between the behavioral effects of cannabinoids and cocaine has begun to be unveiled in animal models. Male Wistar rats were trained to intravenously self-administer cocaine until a stable baseline was reached. Rats then were subjected to a 5-day cocaine deprivation period during which they were treated daily with the cannabinoid receptor agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.3, 1, and 3 mg/kg; i.p.). Following this subchronic treatment, rats were tested, in counterbalanced order, in a test of anxiety (elevated plus-maze), as well as extinction and cue-induced reinstatement tests, the latter conducted according to a between-within procedure. Subchronic administration of WIN 55,212-2 was found to produce dose-dependent alterations of performance in the extinction, reinstatement, and anxiety tests with the lowest dose of WIN 55,212-2 producing the highest resistance to extinction and reinstatement, and the highest dose of WIN 55,212-2 producing the highest anxiolytic activity. Subchronic treatment with WIN 55,212-2 in rats without a history of cocaine self-administration did not affect anxiety levels. The results suggest an important role of the cannabinoid system in neuronal processes underlying cocaine seeking behavior. However, further studies will be necessary to understand possible implications of these findings for a role of the cannabinoid system as a treatment target for human cocaine abuse.

  15. Abuse

    MedlinePlus

    ... people to control their actions. Certain types of personality disorders or mental illness might also interfere with ... self-control. Of course, not everyone with a personality disorder or mental illness becomes abusive. Fortunately, people ...

  16. Abuse

    MedlinePlus

    ... Stages Early-Stage Caregiving Middle-Stage Caregiving Late-Stage Caregiving Behaviors Aggression & Anger Anxiety & Agitation Depression Hallucinations Memory Loss & Confusion Repetition Sleep Issues & Sundowning Suspicion & Delusions Wandering Abuse Start Here ...

  17. Decreased dopamine activity predicts relapse in methamphetamine abusers

    SciTech Connect

    Wang G. J.; Wang, G.-J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

    2011-01-20

    Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

  18. Effects of Quetiapine Treatment on Cocaine Self-Administration and Behavioral Indices of Sleep in Adult Rhesus Monkeys

    PubMed Central

    Brutcher, Robert E.; Nader, Michael A.

    2014-01-01

    Rationale Clinical literature suggests a link between substance abuse and sleep disturbances. Quetiapine, an atypical antipsychotic has shown efficacy in treating sleep disturbances, with clinical studies showing promise for quetiapine as a treatment for cocaine abuse. Objective The goal of this study was to examine the effects of quetiapine on cocaine self-administration and behavioral indices of sleep in monkeys. Methods Seven adult male rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a choice paradigm of food (1.0-g pellets) and cocaine (0.003–0.3 mg/kg per injection) presentation. First, monkeys received acute pretreatment (45 min) with quetiapine (25–75 mg, p.o.) prior to choice sessions; three cocaine doses were studied in combination with quetiapine. Next, the effect of chronic (14–16 days) quetiapine treatment (25–250 mg, p.o., BID) was examined in combination with the lowest preferred cocaine dose (≥ 80% cocaine choice). Behavioral indices of sleep, based on activity measures obtained during lights-out, were recorded throughout the study. Results Acute quetiapine decreased cocaine choice in four of the seven monkeys. Chronic quetiapine treatment resulted in initial decreases, but tolerance developed to these effects. Acute doses of quetiapine did not improve sleep efficiency the following night, nor did chronic quetiapine. The first night after discontinuing quetiapine treatment resulted in significant decreases in sleep efficiency and increases in nighttime activity. Conclusions These findings do not offer support for the use of quetiapine as a monotherapy for treatment of cocaine abuse nor as an adjunct therapy to treat sleep disturbances associated with stimulant abuse. PMID:25030802

  19. Cocaine withdrawal

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000947.htm Cocaine withdrawal To use the sharing features on this page, please enable JavaScript. Cocaine withdrawal occurs when someone who has used a ...

  20. Evaluating effects of methylphenidate on brain activity in cocaine addiction: a machine-learning approach

    NASA Astrophysics Data System (ADS)

    Rish, Irina; Bashivan, Pouya; Cecchi, Guillermo A.; Goldstein, Rita Z.

    2016-03-01

    The objective of this study is to investigate effects of methylphenidate on brain activity in individuals with cocaine use disorder (CUD) using functional MRI (fMRI). Methylphenidate hydrochloride (MPH) is an indirect dopamine agonist commonly used for treating attention deficit/hyperactivity disorders; it was also shown to have some positive effects on CUD subjects, such as improved stop signal reaction times associated with better control/inhibition,1 as well as normalized task-related brain activity2 and resting-state functional connectivity in specific areas.3 While prior fMRI studies of MPH in CUDs have focused on mass-univariate statistical hypothesis testing, this paper evaluates multivariate, whole-brain effects of MPH as captured by the generalization (prediction) accuracy of different classification techniques applied to features extracted from resting-state functional networks (e.g., node degrees). Our multivariate predictive results based on resting-state data from3 suggest that MPH tends to normalize network properties such as voxel degrees in CUD subjects, thus providing additional evidence for potential benefits of MPH in treating cocaine addiction.

  1. SIV/macaque model of HIV infection in cocaine users: minimal effects of cocaine on behavior, virus replication, and CNS inflammation.

    PubMed

    Weed, Michael; Adams, Robert J; Hienz, Robert D; Meulendyke, Kelly A; Linde, Michael E; Clements, Janice E; Mankowski, Joseph L; Zink, M Christine

    2012-06-01

    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.

  2. Children of Cocaine: Treatment and Child Care.

    ERIC Educational Resources Information Center

    Howze, Kate; Howze, Wendell M.

    Information concerning the treatment and care of children addicted to cocaine is provided. Contents: (1) describe the drug; (2) put cocaine use in its historical and demographic perspectives; (3) report findings of a study documenting the incidence of maternal substance abuse in Pinellas County, Florida; (4) point out false perceptions,…

  3. [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.

  4. A silent synapse-based mechanism for cocaine-induced locomotor sensitization.

    PubMed

    Brown, Travis E; Lee, Brian R; Mu, Ping; Ferguson, Deveroux; Dietz, David; Ohnishi, Yoshinori N; Lin, Ying; Suska, Anna; Ishikawa, Masago; Huang, Yanhua H; Shen, Haowei; Kalivas, Peter W; Sorg, Barbara A; Zukin, R Suzanne; Nestler, Eric J; Dong, Yan; Schlüter, Oliver M

    2011-06-01

    Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

  5. 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.

  6. 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

  7. Cocaine Conditioned Behavior: A Cocaine Memory Trace or an Anti-Habituation Effect

    PubMed Central

    Carey, Robert J.; Damianopoulos, Ernest N.; Shanahan, Arielle B.

    2008-01-01

    Whether cocaine locomotor conditioning represents a cocaine positive effect; i.e., a Pavlovian cocaine conditioned response; or, a cocaine negative effect; i.e., interference with habituation to the test environment, is a subject of some controversy. Three separate experiments were conducted to compare the behavior (locomotion and grooming) of separate groups of rats given 1, 9 or 14 cocaine (10 mg/kg) treatments paired/unpaired with placement into an open-field arena. The behavior of the cocaine groups on subsequent saline tests were compared with the habituation rates of saline treated rats. After one cocaine pairing with the test environment, the subsequent behavior of the cocaine-paired group on saline tests was similar to a non-habituated control group. In the two experiments with repeated cocaine pairings to the test environment, the subsequent behavior of the cocaine treated groups did not parallel that of the non-habituated saline control groups. These results were not explicable in terms of cocaine anti-habituation effects. It is suggested that cocaine contextual cues paired with cocaine treatment can activate cocaine memory traces which with subsequent cocaine treatments are reinforced and strengthened. In this way repeated cocaine use can forge conditioned stimulus connections to the cocaine behavioral response that are highly resistant to extinction. PMID:18571225

  8. Unaltered cocaine self-administration in the prenatal LPS rat model of schizophrenia.

    PubMed

    Santos-Toscano, Raquel; Borcel, Érika; Ucha, Marcos; Orihuel, Javier; Capellán, Roberto; Roura-Martínez, David; Ambrosio, Emilio; Higuera-Matas, Alejandro

    2016-08-01

    Although cocaine abuse is up to three times more frequent among schizophrenic patients, it remains unclear why this should be the case and whether sex influences this relationship. Using a maternal immune activation model of schizophrenia, we tested whether animals at higher risk of developing a schizophrenia-like state are more prone to acquire cocaine self-administration behavior, and whether they show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction. Pregnant rats were injected with lipopolysaccharide on gestational day 15 and 16, and the offspring (both male and female) were tested in working memory (T-maze), social interaction and sensorimotor gating (prepulse inhibition of the acoustic startle response) paradigms. After performing these tests, the rats were subjected to cocaine self-administration regimes (0.5mg/kg), assessing their dose-response and extinction. Male rats born to dams administered lipopolysaccharide showed impaired working memory but no alterations to their social interactions, and both male and female rats showed prepulse inhibition deficits. Moreover, similar patterns of cocaine self-administration acquisition, responsiveness to dose shifts and extinction curves were observed in both control and experimental rats. These results suggest that the higher prevalence of cocaine abuse among schizophrenic individuals is not due to a biological vulnerability directly associated to the disease and that other factors (social, educational, economic, familial, etc.) should be considered given the multifactorial nature of this illness.

  9. Suppression of activity-regulated cytoskeleton-associated gene expression in the dorsal striatum attenuates extinction of cocaine-seeking.

    PubMed

    Hearing, Matthew C; Schwendt, Marek; McGinty, Jacqueline F

    2011-07-01

    The caudate putamen (CPu) has been implicated in habit learning and neuroadaptive changes that mediate the compulsive nature of drug-seeking following chronic cocaine self-administration. Re-exposure to an operant chamber previously associated with cocaine, but not yoked-saline, increases activity-regulated cytoskeleton-associated (Arc) gene mRNA expression within the dorsolateral (dl) CPu following prolonged abstinence. In this study, we tested the hypothesis that antisense gene knockdown of Arc within the dlCPu would alter cocaine-seeking. Initial studies showed that a single infusion of Arc antisense oligodeoxynucleotide (ODN) into the dlCPu significantly attenuated the induction of Arc mRNA and Arc protein by a single cocaine exposure (20 mg/kg i.p.) compared to scrambled-ODN-infused controls. In cocaine self-administering rats, infusion of Arc antisense ODN into the dlCPu 3 h prior to a test of context-driven drug-seeking significantly attenuated Arc protein induction, but failed to alter responding during testing, suggesting striatal Arc does not facilitate context-induced drug-seeking following prolonged abstinence. However, Arc antisense ODN infusion blunted the decrease in responding during subsequent 1-h extinction tests 24 and 48 h later. Following re-exposure to a cocaine-paired context, surface expression of the AMPA-type glutamate receptor GluR1 was significantly reduced whereas GluR2 was significantly increased in the dlCPu, independent of Arc antisense ODN infusion. Together, these findings indicate an important role for Arc in neuroadaptations within brain regions responsible for drug-seeking after abstinence and direct attention to changes occurring within striatal circuitry that are necessary to break down the habitual behaviour that leads to relapse.

  10. Cross-sensitization between testosterone and cocaine in adolescent and adult rats.

    PubMed

    Engi, Sheila A; Cruz, Fabio C; Crestani, Carlos C; Planeta, Cleopatra S

    2015-11-01

    Cocaine and anabolic-androgenic steroids are substances commonly co-abused. The use of anabolic steroids and cocaine has increased among adolescents. However, few studies investigated the consequences of the interaction between anabolic-androgenic steroids in animals' model of adolescence. We examined the effects of acute and repeated testosterone administration on cocaine-induced locomotor activity in adult and adolescent rats. Rats received ten once-daily subcutaneous (s.c.) injections of testosterone (10mg/kg) or vehicle. Three days after the last testosterone or vehicle injections rats received an intraperitoneal (i.p.) challenge injection of either saline or cocaine (10mg/kg). A different subset of rats was treated with a single injection of testosterone (10mg/kg) or vehicle and three days later was challenged with cocaine (10mg/kg, i.p.) or saline. Immediately after cocaine or saline injections the locomotor activity was recorded during forty minutes. Our results demonstrated that repeated testosterone induced locomotor sensitization to cocaine in adolescent but not adult rats.

  11. Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion.

    PubMed

    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.

  12. Cocaine induces nuclear export and degradation of neuronal retinoid X receptor-γ via a TNF-α/JNK- mediated mechanism.

    PubMed

    Kovalevich, Jane; Yen, William; Ozdemir, Ahmet; Langford, Dianne

    2015-03-01

    Cocaine abuse represents an immense societal health and economic burden for which no effective treatment currently exists. Among the numerous intracellular signaling cascades impacted by exposure to cocaine, increased and aberrant production of pro-inflammatory cytokines in the CNS has been observed. Additionally, we have previously reported a decrease in retinoid-X-receptor-gamma (RXR-γ) in brains of mice chronically exposed to cocaine. Through obligate heterodimerization with a number of nuclear receptors, RXRs serve as master regulatory transcription factors, which can potentiate or suppress expression of a wide spectrum of genes. Little is known about the regulation of RXR levels, but previous studies indicate cellular stressors such as cytokines negatively regulate levels of RXRs in vitro. To evaluate the mechanism underlying the cocaine-induced decreases in RXR-γ levels observed in vivo, we exposed neurons to cocaine in vitro and examined pathways which may contribute to disruption in RXR signaling, including activation of stress pathways by cytokine induction. In these studies, we provide the first evidence that cocaine exposure disrupts neuronal RXR-γ signaling in vitro by promoting its nuclear export and degradation. Furthermore, we demonstrate this effect may be mediated, at least in part, by cocaine-induced production of TNF-α and its downstream effector c-Jun-NH-terminal kinase (JNK). Findings from this study are therefore applicable to both cocaine abuse and to pathological conditions characterized by neuroinflammatory factors, such as neurodegenerative disease.

  13. Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications.

    PubMed

    Iso, Yasuyoshi; Grajkowska, Ewa; Wroblewski, Jarda T; Davis, Jared; Goeders, Nicholas E; Johnson, Kenneth M; Sanker, Subramaniam; Roth, Bryan L; Tueckmantel, Werner; Kozikowski, Alan P

    2006-02-09

    Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.

  14. Activation of exchange protein activated by cAMP in the rat basolateral amygdala impairs reconsolidation of a memory associated with self-administered cocaine.

    PubMed

    Wan, Xun; Torregrossa, Mary M; Sanchez, Hayde; Nairn, Angus C; Taylor, Jane R

    2014-01-01

    The intracellular mechanisms underlying memory reconsolidation critically involve cAMP signaling. These events were originally attributed to PKA activation by cAMP, but the identification of Exchange Protein Activated by cAMP (Epac), as a distinct mediator of cAMP signaling, suggests that cAMP-regulated processes that subserve memory reconsolidation are more complex. Here we investigated how activation of Epac with 8-pCPT-cAMP (8-CPT) impacts reconsolidation of a memory that had been associated with cocaine self-administration. Rats were trained to lever press for cocaine on an FR-1 schedule, in which each cocaine delivery was paired with a tone+light cue. Lever pressing was then extinguished in the absence of cue presentations and cocaine delivery. Following the last day of extinction, rats were put in a novel context, in which the conditioned cue was presented to reactivate the cocaine-associated memory. Immediate bilateral infusions of 8-CPT into the basolateral amygdala (BLA) following reactivation disrupted subsequent cue-induced reinstatement in a dose-dependent manner, and modestly reduced responding for conditioned reinforcement. When 8-CPT infusions were delayed for 3 hours after the cue reactivation session or were given after a cue extinction session, no effect on cue-induced reinstatement was observed. Co-administration of 8-CPT and the PKA activator 6-Bnz-cAMP (10 nmol/side) rescued memory reconsolidation while 6-Bnz alone had no effect, suggesting an antagonizing interaction between the two cAMP signaling substrates. Taken together, these studies suggest that activation of Epac represents a parallel cAMP-dependent pathway that can inhibit reconsolidation of cocaine-cue memories and reduce the ability of the cue to produce reinstatement of cocaine-seeking behavior.

  15. Cocaine users with comorbid Cluster B personality disorders show dysfunctional brain activation and connectivity in the emotional regulation networks during negative emotion maintenance and reappraisal.

    PubMed

    Albein-Urios, Natalia; Verdejo-Román, Juan; Soriano-Mas, Carles; Asensio, Samuel; Martínez-González, José Miguel; Verdejo-García, Antonio

    2013-12-01

    Cocaine dependence often co-occurs with Cluster B personality disorders. Since both disorders are characterized by emotion regulation deficits, we predicted that cocaine comorbid patients would exhibit dysfunctional patterns of brain activation and connectivity during reappraisal of negative emotions. We recruited 18 cocaine users with comorbid Cluster B personality disorders, 17 cocaine users without comorbidities and 21 controls to be scanned using functional magnetic resonance imaging (fMRI) during performance on a reappraisal task in which they had to maintain or suppress the emotions induced by negative affective stimuli. We followed region of interest (ROI) and whole-brain approaches to investigate brain activations and connectivity associated with negative emotion experience and reappraisal. Results showed that cocaine users with comorbid personality disorders had reduced activation of the subgenual anterior cingulate cortex during negative emotion maintenance and increased activation of the lateral orbitofrontal cortex and the amygdala during reappraisal. Amygdala activation correlated with impulsivity and antisocial beliefs in the comorbid group. Connectivity analyses showed that in the cocaine comorbid group the subgenual cingulate was less efficiently connected with the amygdala and the fusiform gyri and more efficiently connected with the anterior insula during maintenance, whereas during reappraisal the left orbitofrontal cortex was more efficiently connected with the amygdala and the right orbitofrontal cortex was less efficiently connected with the dorsal striatum. We conclude that cocaine users with comorbid Cluster B personality disorders have distinctive patterns of brain activation and connectivity during maintenance and reappraisal of negative emotions, which correlate with impulsivity and dysfunctional beliefs.

  16. Repeated dosing with oral cocaine in humans: assessment of direct effects, withdrawal, and pharmacokinetics.

    PubMed

    Walsh, Sharon L; Stoops, William W; Moody, David E; Lin, Shen-Nan; Bigelow, George E

    2009-08-01

    Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.

  17. Cocaine self-administration in Wistar-Kyoto rats: a behavioral and biochemical analysis.

    PubMed

    Jastrzębska, Joanna; Frankowska, Małgorzata; Szumiec, Łukasz; Sadakierska-Chudy, Anna; Haduch, Anna; Smaga, Irena; Bystrowska, Beata; Daniel, Wladyslawa A; Filip, Małgorzata

    2015-10-15

    Depression and cocaine abuse disorders are common concurrent diagnoses. In the present study, we employed Wistar-Kyoto (WKY) rats that showed a depressive-like phenotype to study intravenous cocaine self-administration and extinction/reinstatement procedures. We also investigated the basal tissue level of neurotransmitters, their metabolites and plasma corticosterone (CORT) concentrations in WKY rats, bulbectomized (OBX) rats, and control rats. The WKY rats exhibited an attenuation of the cocaine-associated lever presses and cocaine intake during the acquisition/maintenance of cocaine self-administration only under specific conditions. Active lever presses exhibited by the WKY rats and control animals did not differ during the extinction training and cocaine-seeking behaviors. The WKY rats demonstrated alterations in the basal levels of dopamine, norepinephrine, and serotonin in selected brain structures involved in depression and drug addiction. The changes in the level of neurotransmitters in these animals refer not only to the control (Wistar) rats but also to bulbectomized animals, which represent another depression model. Furthermore, we identified unchanged levels of CORT in the WKY and OBX rats during the light phase and free-stress conditions. This finding suggests that WKY rats should not be used to investigate the co-occurrence of depression and cocaine addiction, as this rat strain does not show an enhanced risk of relapse.

  18. Abnormal regulation for progesterone production in placenta with prenatal cocaine exposure in rats.

    PubMed

    Wu, L; Yan, J; Qu, S C; Feng, Y Q; Jiang, X L

    2012-12-01

    Cocaine abuse in pregnant women is currently a significant public hygiene problem and is tightly associated with elevated risk for preterm delivery. Placental steroidogenesis especially progesterone production was essential for success and maintenance of pregnancy in humans and rodents. In the present study, we determined the impact of prenatal cocaine exposure on pathways of placental progesterone synthesis in rats. Pregnant rats were treated cocaine twice daily (15 mg/kg/day) during the third trimester, and the maternal and fetal plasma progesterone and pregnenolone concentrations were detected. We also examined both the protein and mRNA expression of some key enzymes and regulators for progesterone production in placenta. Results showed that, after maternal cocaine use during pregnancy, progesterone and pregnenolone concentrations in both maternal and fetal rats were significantly decreased. Although prenatal cocaine exposure had no effects on placental 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) expression, protein and mRNA expression of the cholesterol side-chain cleavage enzyme (P450scc/CYP11a) in placenta was significantly inhibited. Moreover, protein and mRNA expressions of MLN64 that regulating cholesterol transport and activating protein 2γ (AP2γ/Tfap2c) that controlling P450scc/CYP11a gene expression in placenta were both decreased following maternal cocaine use in pregnancy. Collectively, this study suggested that prenatal cocaine exposure could insult the placental progesterone production in rats possibly associated with the high risk for preterm delivery.

  19. Neurocognitive impairment and medication adherence in HIV patients with and without cocaine dependence

    PubMed Central

    Meade, Christina S.; Conn, Nina A.; Skalski, Linda M.; Safren, Steven A.

    2010-01-01

    Cocaine abuse among HIV patients is associated with faster disease progression and mortality. This study examined the relationship between neurocognitive functioning and medication adherence in HIV patients with (n= 25) and without (n= 39) current cocaine dependence. Active users had greater neurocognitive impairment (mean T-score= 35.16 vs. 40.97, p < .05) and worse medication adherence (mean z-score= −0.44 vs. 0.27, p < .001). In a multiple regression model, neurocognitive functioning (β= .33, p < .01) and cocaine dependence (β= −.36, p < .01) were predictive of poorer adherence. There was a significant indirect effect of cocaine dependence on medication adherence through neurocognitive impairment (estimate= −0.15, p < .05), suggesting that neurocognitive impairment partially mediated the relationship between cocaine dependence and poorer adherence. These results confirm that cocaine users are at high risk for poor HIV outcomes and underscore the importance of treating both neurocognitive impairment and cocaine dependence among HIV patients. PMID:20857187

  20. Chronic cocaine disrupts mesocortical learning mechanisms.

    PubMed

    Buchta, William C; Riegel, Arthur C

    2015-12-02

    The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extrasynaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts.

  1. Chronic cocaine disrupts mesocortical learning mechanisms

    PubMed Central

    Buchta, William C.; Riegel, Arthur C.

    2016-01-01

    The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

  2. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

    PubMed

    Sørensen, Gunnar; Reddy, India A; Weikop, Pia; Graham, Devon L; Stanwood, Gregg D; Wortwein, Gitta; Galli, Aurelio; Fink-Jensen, Anders

    2015-10-01

    Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

  3. Cocaine effects on pregnancy and infant outcome: do we really know how bad it is?

    PubMed

    Dungy-Poythress, L J

    1995-01-01

    While cocaine abuse in pregnancy is associated with a number of negative outcomes for both mothers and infants, it is unclear to what extent cocaine is specifically responsible for these negative outcomes and how its effects are distinct from those associated with substance abuse in general. Use of other drugs commonly associated with cocaine abuse, such as alcohol, marijuana, and tobacco, has also been associated with adverse pregnancy outcomes. Untoward pregnancy effects often ascribed to cocaine abuse in pregnancy may be more appropriately attributed to these or other drugs or to the unhealthy life-style associated with the long-term abuser rather than to cocaine itself. Epidemiologic data concerning cocaine use in pregnancy describe only associations of drug use and do not prove causality. Future research and longitudinal studies are needed to examine the roles of maternal and environmental factors in predicting differences in cocaine-exposed and nonexposed pregnancies.

  4. The First American Cocaine Epidemic.

    ERIC Educational Resources Information Center

    Courtwright, David T.

    1991-01-01

    Discusses the wave of cocaine abuse that followed the drug's recommendation by the late nineteenth-century medical community as a cure all. Details drug addiction among ethnic and social groups at the turn of the century. Warns that drug epidemics have important social and legal consequences. Suggests legal pressure may alter the form of drug…

  5. 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

  6. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.

    PubMed

    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; Castilla-Ortega, Estela

    2017-03-01

    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.

  7. Transdermal nicotine maintenance attenuates the subjective and reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking stimulant abusers.

    PubMed

    Sobel, Bai-Fang X; Sigmon, Stacey C; Griffiths, Roland R

    2004-05-01

    The effects of transdermal nicotine maintenance on the subjective, reinforcing, and cardiovascular effects of intravenously administered cocaine, caffeine, and nicotine were examined using double-blind procedures in nine volunteers with histories of using tobacco, caffeine, and cocaine. Each participant was exposed to two chronic drug maintenance phases (21 mg/day nicotine transdermal patch and placebo transdermal patch). Within each drug phase, the participant received intravenous injections of placebo, cocaine (15 and 30 mg/70 kg), caffeine (200 and 400 mg/70 kg), and nicotine (1.0 and 2.0 mg/70 kg) in mixed order across days. Subjective and cardiovascular data were collected before and repeatedly after drug or placebo injection. Reinforcing effects were also assessed after each injection with a Drug vs Money Multiple-Choice Form. Intravenous cocaine produced robust dose-related increases in subjective and reinforcing effects; these effects were not altered by nicotine maintenance. Intravenous caffeine produced elevations on several subjective ratings; nicotine maintenance did not affect these ratings. Under the placebo maintenance condition, intravenous nicotine produced robust dose-related subjective effects, with maximal increases similar to the high dose of cocaine; nicotine maintenance significantly decreased the subjective and reinforcing effects of intravenous nicotine. The results of the present study demonstrate that chronic nicotine maintenance produces tolerance to the effects of intravenous nicotine, but does not affect the subjective or reinforcing effects of cocaine or caffeine.

  8. Acute Cocaine Induces Fast Activation of D1R and Progressive Deactivation of D2R Striatal Neurons: In vivo Optical MicroProbe [Ca2+]i Imaging

    PubMed Central

    Luo, Zhongchi; Volkow, Nora D.; Heintz, Nathaniel; Pan, Yingtian; Du, Congwu

    2011-01-01

    Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine’s reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca2+]i) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R versus D2R expressing neurons in striatum. Acute cocaine (8 mg/kg ip) rapidly increased [Ca2+]i in D1R expressing neurons (10.6±3.2%) in striatum within 8.3±2.3min after cocaine administration after which the increases plateaued; these fast [Ca2+]i increases were blocked by pretreatment with a D1R antagonist (SCH 23390). In contrast cocaine induced progressive decreases in [Ca2+]i in D2R expressing neurons (10.4±5.8%) continuously throughout the 30min that followed cocaine administration; these slower [Ca2+]i decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R expressing neurons (direct-pathway) enhances cocaine reward whereas activation of D2R expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine’s rewarding effects entail both its fast stimulation of D1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer lasting deactivation of indirect-pathway neurons). We also provide direct in-vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration. PMID:21917801

  9. 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.

  10. Differential roles of GABAB1 subunit isoforms on locomotor responses to acute and repeated administration of cocaine.

    PubMed

    Jacobson, Laura H; Sweeney, Fabian F; Kaupmann, Klemens; O'Leary, Olivia F; Gassmann, Martin; Bettler, Bernhard; Cryan, John F

    2016-02-01

    GABAB receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABAB receptors are functional heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABAB1 subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABAB1b(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a(-/-) mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABAB1a(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABAB1b(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with deletion of GABAB1a enhancing cocaine-induced locomotor activity and deletion of GABAB1b protecting from cocaine-induced sensitisation.

  11. Liking and wanting of drug and nondrug rewards in active cocaine users: the STRAP-R questionnaire

    SciTech Connect

    Goldstein, R.Z.; Goldstein, R.Z.; Woicik, P.A..; Moeller, S.J.; Telang, F.; Jayne, M.; Wong, C.; Wang, G-J.; Fowler, J.S.; Volkow, N.D.

    2008-10-01

    Few studies have examined the subjective value attributed to drug rewards specifically as it compares with the value attributed to primary non-drug rewards in addicted individuals. The objective of this study is to assess liking and wanting of expected drug rewards as compared to food and sex while respondents report about three different situations (current, and hypothetical in general, and under drug influence). In all, 20 cocaine-addicted individuals (mean abstinence = 2 days) and 20 healthy control subjects were administered the STRAP-R (Sensitivity To Reinforcement of Addictive and other Primary Rewards) questionnaire after receiving an oral dose of the dopamine agonist methylphenidate (20 mg) or placebo. The reinforcers relative value changed within the addicted sample when reporting about the under drug influence situation (drug > food; otherwise, drug < food). This change was highest in the addicted individuals with the youngest age of cocaine use onset. Moreover, drug wanting exceeded drug liking in the addicted subjects when reporting about this situation during methylphenidate. Thus, cocaine-addicted individuals assign the highest subjective valence to drug rewards but only when recalling cue-related situations. When recalling this situation, they also report higher drug wanting than hedonic liking, a motivational shift that was only significant during methylphenidate. Together, these valence shifts may underlie compulsive stimulant abuse upon pharmacological or behavioural cue exposure in addicted individuals. Additional studies are required to assess the reliability of the STRAP-R in larger samples and to examine its validity in measuring the subjective value attributed to experienced reinforcers or in predicting behaviour.

  12. iMStrong: Deployment of a Biosensor System to Detect Cocaine Use

    PubMed Central

    Zhang, Jianying; Wittbold, Kelley; Weng, Shicheng; Mullins, Rachel; Smelson, David; Boyer, Edward W.

    2016-01-01

    Biosensor systems are increasingly promoted for use in behavioral interventions. Portable biosensors might offer advancement over self-report use and can provide improved opportunity for detection and intervention in patients undergoing drug treatment programs. Fifteen participants wore a biosensor wristband capable of detecting multiple physiologic markers of sympathetic nervous system (SNS) arousal for 30 days. Urine drug screening and drug use self-report were obtained twice per week. A parameter trajectory description method was applied to capture abrupt changes in magnitude of three measures of SNS activity: Electrodermal activity (EDA), skin temperature and motion. Drug use events detected by the biosensor were verified using a triad of parameters: the biosensor data, urine drug screens, and patient self-report of substance use. Twelve positive cocaine urine screens were identified. Thirteen self-reported episodes of cocaine use were recorded. Distinct episodes with biometric parameters consistent with cocaine use were identified on biosensor data. Eleven potential cocaine use episodes were identified by biosensors that were missed by both self-report and drug screening. Study participants found mobile biosensors to be acceptable, and compliance with the protocol was high. Episodes of cocaine use, as measured by supraphysiologic changes in biophysiometric parameters, were detected by analysis of biosensor data in instances when self-report or drug screening or both failed. Biosensors have substantial potential in detecting substance abuse, in understanding the context of use in real time, and in evaluating the efficacy of behavioral interventions for drug abuse. PMID:26490144

  13. Probing the effects of hapten stability on cocaine vaccine immunogenicity.

    PubMed

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

    2013-11-04

    Judicious hapten design has been shown to be of importance when trying to generate a viable vaccine against a drug of abuse. Hapten design has typically been predicated upon faithfully emulating the unique chemical architecture that each drug presents. However, the need for drug-hapten congruency may also compromise vaccine immunogenicity if the drug-hapten conjugate possesses chemical epitope instability. There has been no systematic study on the impact of hapten stability as it relates to vaccine immunogenicity. As a starting point, we have probed the stability of a series of cocaine haptens through varying several of its structural elements, including functionality at the C2-position, the nature of the linker, and its site of attachment. Accordingly, a hydrolytic stability profile of four cocaine haptens (GNNA, GNNS, GNE, and GNC) was produced, and these results were compared through each hapten's immunological properties, which were generated via active vaccination. From this group of four, three of the haptens, GNE, GNNA, and GNC, were further examined in an animal behavioral model, and findings here were again measured in relationship to hapten stability. We demonstrate a corresponding relationship between the half-life of the hapten and its immunogenicity, wherein haptens presenting a fully representative cocaine framework elicited higher concentrations of cocaine-specific IgG in sera and also conferred better protection against cocaine-induced locomotor activity. Our results indicate that hapten half-life plays an important role in vaccine immunogenicity and this in turn can impact animal behavioral effects when challenged with a drug of abuse.

  14. Genetic depletion of glutathione peroxidase-1 potentiates nephrotoxicity induced by multiple doses of cocaine via activation of angiotensin II AT1 receptor.

    PubMed

    Mai, Huynh Nhu; Chung, Yoon Hee; Shin, Eun-Joo; Kim, Dae-Joong; Jeong, Ji Hoon; Nguyen, Thuy-Ty Lan; Nam, Yunsung; Lee, Yu Jeung; Nah, Seung-Yeol; Yu, Dae-Yeul; Jang, Choon-Gon; Ho, Ye-Shih; Lei, Xin Gen; Kim, Hyoung-Chun

    2016-01-01

    We investigated the possible roles of angiotensin II type 1 receptor (AT1R) and oxidative stress responsive nuclear factor κB (NFκB) in renal damage caused by multiple doses of cocaine in glutathione peroxidase (GPx)-1 gene-depleted mice. Treatment with cocaine resulted in significant increases in malondialdehyde, protein carbonyl, and pro-apoptotic Bax expression and decreases in the ratio of glutathione (GSH) and its oxidized form (GSSG), GSH-dependent enzymes, and anti-apoptotic factors in the kidney. These alterations were more pronounced in GPx-1 knockout (-/-) mice than in wild type (WT) mice. Notably, the AT1R antagonist losartan protected against the renal toxicity induced by cocaine, whereas the NFκB inhibitor pyrrolidine dithiocarbamate was not protective. The toxicity was more pronounced in GPx-1 (-/-) mice than in WT mice. The protective effect afforded by losartan against cocaine toxicity appeared to be more sensitive in GPx-1 (-/-) mice than that in WT mice. These losartan-mediated protective effects were inhibited by the phosphatidyl-inositol-3-kinase (PI3K) inhibitor LY294002, indicating that losartan provides significant protection from cocaine-induced renal toxicity through PI3K/Akt signaling. Our results suggest that genetic inhibition of GPx-1 potentiates cocaine-induced renal damage via activation of AT1R by inhibition of PI3K-Akt signaling, and that AT1R can be a therapeutic target against renal toxicity induced by cocaine.

  15. 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.

  16. 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,…

  17. Modeling Causal Relationship Between Brain Regions Within the Drug-Cue Processing Network in Chronic Cocaine Smokers.

    PubMed

    Ray, Suchismita; Haney, Margaret; Hanson, Catherine; Biswal, Bharat; Hanson, Stephen José

    2015-12-01

    The cues associated with drugs of abuse have an essential role in perpetuating problematic use, yet effective connectivity or the causal interaction between brain regions mediating the processing of drug cues has not been defined. The aim of this fMRI study was to model the causal interaction between brain regions within the drug-cue processing network in chronic cocaine smokers and matched control participants during a cocaine-cue exposure task. Specifically, cocaine-smoking (15M; 5F) and healthy control (13M; 4F) participants viewed cocaine and neutral cues while in the scanner (a Siemens 3 T magnet). We examined whole brain activation, including activation related to drug-cue processing. Time series data extracted from ROIs determined through our General Linear Model (GLM) analysis and prior publications were used as input to IMaGES, a computationally powerful Bayesian search algorithm. During cocaine-cue exposure, cocaine users showed a particular feed-forward effective connectivity pattern between the ROIs of the drug-cue processing network (amygdala → hippocampus → dorsal striatum → insula → medial frontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex) that was not present when the controls viewed the cocaine cues. Cocaine craving ratings positively correlated with the strength of the causal influence of the insula on the dorsolateral prefrontal cortex in cocaine users. This study is the first demonstration of a causal interaction between ROIs within the drug-cue processing network in cocaine users. This study provides insight into the mechanism underlying continued substance use and has implications for monitoring treatment response.

  18. Preventive role of social interaction for cocaine conditioned place preference: correlation with FosB/DeltaFosB and pCREB expression in rat mesocorticolimbic areas.

    PubMed

    El Rawas, Rana; Klement, Sabine; Salti, Ahmad; Fritz, Michael; Dechant, Georg; Saria, Alois; Zernig, Gerald

    2012-01-01

    The worsening of drug abuse by drug-associated social interaction is a well-studied phenomenon. In contrast, the molecular mechanisms of the beneficial effect of social interaction, if offered as a mutually exclusive choice to drugs of abuse, are under-investigated. In a rat place preference conditioning (CPP) paradigm, four 15 min episodes of social interaction with a gender- and weight-matched male early-adult conspecific inhibited cocaine-induced reinstatement of cocaine CPP, a model of relapse. These protective effects of social interaction were paralleled by a reduced activation, as assessed by Zif268 expression, in brain areas known to play pivotal roles in drug-seeking behavior. Here we show that social interaction during extinction of cocaine CPP also reduced cocaine-CPP-stimulated FosB expression in the nucleus accumbens shell and core. In addition, social interaction during cocaine CPP extinction increased pCREB (cAMP response element binding protein) expression in the nucleus accumbens shell and the cingulate cortex area 1 (Cg1). Our results show that FosB and pCREB may be implicated in the protective effect of social interaction against cocaine-induced reinstatement of CPP. Thus, social interaction, if offered in a context that is clearly distinct from the previously drug-associated one, may profoundly inhibit relapse to cocaine addiction.

  19. Effects of Conditional Central Expression of HIV-1 Tat Protein to Potentiate Cocaine-Mediated Psychostimulation and Reward Among Male Mice

    PubMed Central

    Paris, Jason J; Carey, Amanda N; Shay, Christopher F; Gomes, Stacey M; He, Johnny J; McLaughlin, Jay P

    2014-01-01

    As a major neuropathogenic factor associated with human immunodeficiency virus (HIV) infection, HIV-1 Tat protein is known to synergize with psychostimulant drugs of abuse to cause neurotoxicity and exacerbate the progression of central nervous system pathology. However, the functional consequences of the interaction between HIV-1 Tat and abused drugs on behavior are little known. We tested the hypothesis that HIV-1 Tat expression in brain would modulate the psychostimulant effects of cocaine. Using the GT-tg bigenic mouse model, where brain-selective Tat expression is induced by activation of a doxycycline (Dox) promotor, we tested the effects of Tat on cocaine (10 mg/kg, s.c.) induced locomotion and conditioned place preference (CPP). Compared with uninduced littermates or C57BL/6J controls, cocaine-induced hyperlocomotion was sustained for a significantly longer duration among Tat-induced mice. Moreover, although all groups displayed similar saline-CPP, Tat-induced GT-tg mice demonstrated a three-fold increase in cocaine-CPP over the response of either uninduced littermates or Dox-treated C57BL/6J control mice. Induction of Tat also increased the magnitude of a previously established cocaine-CPP after an additional cycle of cocaine place-conditioning. Despite Tat-induced potentiation, extinction of place preference occurred within 21 days, commensurate with cocaine-extinction among saline-treated littermates and C57BL/6J controls. Re-exposure to cocaine produced reinstatement of an equivalent place preference in Tat-induced GT-tg or C57BL/6J mice; however, induction of Tat protein after the extinction of CPP also produced reinstatement without additional exposure to cocaine. Together, these data suggest that central HIV-1 Tat expression can potentiate the psychostimulant behavioral effects of cocaine in mice. PMID:23945478

  20. Effects of acute cocaine on ERK and DARPP-32 phosphorylation pathways in the caudate-putamen of Fischer rats

    PubMed Central

    Sun, Wei-Lun; Zhou, Luyi; Hazim, Ruhal; Quinones-Jenab, Vanya; Jenab, Shirzad

    2010-01-01

    Activation of extracellular signal-regulated kinase (ERK) and dopamine- and cAMP-regulated phosphoprotein (DARPP-32) pathways has been implicated in biochemical and behavioral effects induced by various drugs of abuse. In this study, we investigated the phosphorylation pathways of these two proteins in response to acute cocaine administration. A single cocaine administration (30 mg/kg) increased ERK-mediated signaling proteins, phosphoryation of cAMP response element-binding protein (CREB) kinase, pp90 ribosomal S6 kinase (RSK), and c-Fos protein levels in the caudate/putamen of Fischer rats. Acute cocaine administration also induced phosphorylation of the striatal-enriched protein tyrosine phosphatase (STEP) and decreased the phosphorylation of DARPP-32 protein at the Thr-75 site. The phosphorylation states of these inhibitors of ERK and DARPP-32 proteins may thus contribute to the effects of cocaine on ERK- and DARPP-32-mediated cascades, on gene expression and on behaviors. PMID:17920048

  1. Short- and long-lasting behavioral and neurochemical adaptations: relationship with patterns of cocaine administration and expectation of drug effects in rats.

    PubMed

    Puig, S; Noble, F; Benturquia, N

    2012-10-23

    Cocaine dependence is a significant public health problem, characterized by periods of abstinence. Chronic exposure to drugs of abuse induces important modifications on neuronal systems, including the dopaminergic system. The pattern of administration is an important factor that should be taken into consideration to study the neuroadaptations. We compared the effects of intermittent (once daily) and binge (three times a day) cocaine treatments for 1 (WD1) and 14 (WD14) days after the last cocaine injection on spontaneous locomotor activity and dopamine (DA) levels in the nucleus accumbens (Nac). The intermittent treatment led to a spontaneous increase in DA (WD1/WD14), and in locomotor activity (WD1) at the exact hour which rats were habituated to receive a cocaine injection. These results underline that taking into consideration the hours of the day at which the experiments are performed is crucial. We also investigated these behavioral and neurochemical adaptations in response to an acute cocaine challenge on WD1 and WD14. We observed that only the binge treatment led to sensitization of locomotor effects of cocaine, associated to a DA release sensitization in the Nac, whereas the intermittent treatment did not. We demonstrate that two different patterns of administration induced distinct behavioral and neurochemical consequences. We unambiguously demonstrated that the intermittent treatment induced drug expectation associated with higher basal DA level in the Nac when measured at the time of chronic cocaine injection and that the binge treatment led to behavioral and sensitization effects of cocaine.

  2. 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

  3. "A 28-Day Program Ain't Helping the Crack Smoker" -- Perceptions of Effective Drug Abuse Prevention Interventions by North Central Florida African Americans Who Use Cocaine

    ERIC Educational Resources Information Center

    Brown, Emma J.; Hill, Mary Angelique; Giroux, Stacey A.

    2004-01-01

    Cocaine is a major problem in the rural South, but knowledge is limited regarding the impact on African American populations. Purpose: This study of 18-39-year-old black drug users assessed perceptions of contributing factors to drug use and possible interventions. The study design was qualitative-descriptive, utilizing 4 focus groups with 5 rural…

  4. Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor.

    PubMed

    Angelucci, Francesco; Ricci, Valerio; Pomponi, Massimiliano; Conte, Gianluigi; Mathé, Aleksander A; Attilio Tonali, Pietro; Bria, Pietro

    2007-11-01

    Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users.

  5. Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects.

    PubMed

    Pan, Bin; Zhong, Peng; Sun, Dalong; Liu, Qing-song

    2011-08-03

    Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposure in vivo facilitates long-term potentiation (LTP) in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for cocaine-induced reduction of GABAergic inhibition. The present study investigated the downstream signaling mechanisms and functional consequences of I-LTD in the VTA in the rat. Extracellular signal-regulated kinase (ERK) signaling has been implicated in long-term synaptic plasticity, associative learning, and drug addiction. We tested the hypothesis that VTA ERK activity is required for I-LTD and cocaine-induced long-term synaptic plasticity and behavioral effects. We show that the activation of receptors required for I-LTD increased ERK1/2 phosphorylation and inhibitors of ERK activation blocked I-LTD. We further demonstrate that ERK mediates cocaine-induced reduction of GABAergic inhibition and facilitation of LTP induction. Finally, we show that cocaine conditioned place preference (CPP) training (15 mg/kg; four pairings) increased ERK1/2 phosphorylation in the VTA, while bilateral intra-VTA injections of a CB(1) antagonist or an inhibitor of ERK activation attenuated ERK1/2 phosphorylation and the acquisition, but not the expression, of CPP to cocaine. Our study has identified the CB(1) and ERK signaling cascade as a key mediator of several forms of cocaine-induced synaptic plasticity and provided evidence linking long-term synaptic plasticity in the VTA to rewarding effects of cocaine.

  6. Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: implications for addiction.

    PubMed

    Shuman, Tristan; Cai, Denise J; Sage, Jennifer R; Anagnostaras, Stephan G

    2012-12-01

    Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75 mg/kg) as well as its interactions with cocaine (15 mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75 mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.

  7. Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

    PubMed

    Lazer, E S; Hite, G J; Nieforth, K A; Stratford, E S

    1979-07-01

    1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.

  8. Opiates or cocaine: mortality from acute reactions in six major Spanish cities. State Information System on Drug Abuse (SEIT) Working Group.

    PubMed Central

    Sánchez, J; Rodríguez, B; de la Fuente, L; Barrio, G; Vicente, J; Roca, J; Royuela, L

    1995-01-01

    STUDY OBJECTIVE--To describe temporal and geographical variations in mortality from acute reactions to opiates or cocaine and the demographic and toxicological characteristics of persons who died from these in major Spanish cities between 1983 and 1991. DESIGN--Descriptive study. Data were obtained retrospectively from pathologists' reports. SETTING--Cities of Madrid, Barcelona, Valencia, Seville, Zaragoza, and Bilbao. SUBJECTS--Deaths from acute reactions to opiates or cocaine were defined as those in which pathologists' reports did not indicate any other cause of death and in which evidence was found of recent consumption of these drugs. MAIN RESULTS--The mortality rate from acute reactions to opiate/cocaine per 100,000 population in the six cities as a whole rose from 1.2 in 1983 to 8.2 in 1991. Average annual rates for the whole period ranged from 1.7 in Seville to 4.9 in Barcelona. The male/female rates ratio was 5.9:1. The mean age of persons who died rose from 25.1 years in 1983 to 28 years in 1991. In more than 90% of the cases in whom toxicological tests were undertaken opiates were detected, and the proportion in which benzodiazepines or cocaine were detected increased during the period studied. CONCLUSIONS--Between 1983 and 1991 mortality from acute reactions to opiates/cocaine rose dramatically in major Spanish cities and significant differences in mortality between cities were found. Deaths were concentrated among men and young people. Acute drug reactions became one of the leading causes of death in persons 15-39 years of age, representing 11.1% of mortality from all causes in 1988 for this age group. Future studies should examine the relationship between the temporal and geographical variations in this type of mortality and various personal, environmental and social factors. PMID:7707007

  9. Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys.

    PubMed

    Smith, Douglas A; Negus, S Stevens; Poklis, Justin L; Blough, Bruce E; Banks, Matthew L

    2016-04-06

    Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Pre-clinical drug discrimination procedures are useful for interrogating structure-activity relationships of abuse-related drug effects; however, in vivo structure-activity relationship comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP or methcathinone (methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest that hydrophobicity may be an important

  10. Longitudinal changes of amygdala and default mode activation in adolescents prenatally exposed to cocaine

    PubMed Central

    Li, Zhihao; Coles, Claire D.; Lynch, Mary Ellen; Luo, Yuejia; Hu, Xiaoping

    2015-01-01

    Prenatal cocaine exposure (PCE) is associated with long-term and negative effect on arousal regulation. Recent neuroimaging studies have examined brain mechanisms related to arousal dysregulation with cross-sectional experimental designs; but longitudinal changes in the brain, reflecting group differences in neurodevelopment, have never been directly examined. To directly assess the interaction of PCE and neurodevelopment, the present study used a longitudinal design to analyze functional magnetic resonance imaging (fMRI) data collected from 33 adolescents (21 with PCE and 12 non-exposed controls) while they performed the same working memory task with emotional distracters at two points in time. The mean age of participants was 14.3 years at time_1 and 16.7 years at time_2. With confounding factors statistically controlled, the fMRI data revealed significant exposure-by-time interaction in the activations of the amygdala and default mode network (DMN). For the control adolescents, brain activations associated with emotional arousal (amygdala) and cognitive effort (DMN) were both reduced at time_2 as compared to that at time_1. However, these activation reductions were not observed in the PCE group, indicating persistently high levels of emotional arousal and cognitive effort. In addition, correlations between longitudinal changes in the brain and in behavior have shown that adolescents with persistently high emotional arousal were more likely in need of high cognitive effort; and their cognitive performance was more likely to be affected by distractive challenges. The present results complement and extend previous findings from cross-sectional studies with further evidence supporting the view of PCE associated long-term teratogenic effects on arousal regulation. PMID:26577285

  11. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24440755

  13. Epigenetically modified nucleotides in chronic heroin and cocaine treated mice.

    PubMed

    Chao, Mu-Rong; Fragou, Domniki; Zanos, Panos; Hu, Chiung-Wen; Bailey, Alexis; Kouidou, Sofia; Kovatsi, Leda

    2014-09-17

    Epigenetic changes include the addition of a methyl group to the 5' carbon of the cytosine ring, known as DNA methylation, which results in the generation of the fifth DNA base, namely 5-methylcytosine. During active or passive demethylation, an intermediate modified base is formed, 5-hydroxymethylcytosine. We have currently quantified 5-methylcytosine and 5-hydroxymethylcytosine in the liver and brain of mice treated with cocaine or heroin, using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Our results show that global 5-methylcytosine levels are not affected by heroin or cocaine administration, neither in the liver nor in the brain. However, 5-hydroxymethylcytosine levels are reduced in the liver following cocaine administration, while they are not affected by cocaine in the brain or by heroin administration in the liver and the brain. Elucidation of the epigenetic phenomena that takes place with respect to drug abuse and addiction, via quantitative analysis of different modified bases, may enable a better understanding of the underlying mechanisms and may lead to more personalized and effective treatment options.

  14. Hormones, nicotine, and cocaine: clinical studies.

    PubMed

    Mello, Nancy K

    2010-06-01

    Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (<20 min), ratings of "high" and "rush" began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed.

  15. Tobacco abuse and physical activity among medical students

    PubMed Central

    2009-01-01

    Objective This lifestyle is mainly determined during childhood and connected with poor public prophylactic health policy. The aim of this study was to estimate physical activity and level of tobacco abuse, as well as knowledge about health behaviours, among medical students. Methods Questionnaires were completed by Polish (243) and foreign medical students (80). Results It was stated that about 20% of the students smoked cigarettes. Female students from Norway took up smoking significantly more often than other participants, whereas there were more smokers among those from Poland. There was a significantly larger percentage of smoking males from Norway than among male Polish students. The same students presented a low level of physical activity. The smallest level of physical activity was characteristic of the Polish women. Conclusion This situation requires an intensification of activities aimed at supporting pro-health lifestyles and the elimination of unfavourable effects, especially among medical students. PMID:20156733

  16. Identifying Drug (Cocaine) Intake Events from Acute Physiological Response in the Presence of Free-living Physical Activity.

    PubMed

    Hossain, Syed Monowar; Ali, Amin Ahsan; Rahman, Mahbubur; Ertin, Emre; Epstein, David; Kennedy, Ashley; Preston, Kenzie; Umbricht, Annie; Chen, Yixin; Kumar, Santosh

    2014-01-01

    A variety of health and behavioral states can potentially be inferred from physiological measurements that can now be collected in the natural free-living environment. The major challenge, however, is to develop computational models for automated detection of health events that can work reliably in the natural field environment. In this paper, we develop a physiologically-informed model to automatically detect drug (cocaine) use events in the free-living environment of participants from their electrocardiogram (ECG) measurements. The key to reliably detecting drug use events in the field is to incorporate the knowledge of autonomic nervous system (ANS) behavior in the model development so as to decompose the activation effect of cocaine from the natural recovery behavior of the parasympathetic nervous system (after an episode of physical activity). We collect 89 days of data from 9 active drug users in two residential lab environments and 922 days of data from 42 active drug users in the field environment, for a total of 11,283 hours. We develop a model that tracks the natural recovery by the parasympathetic nervous system and then estimates the dampening caused to the recovery by the activation of the sympathetic nervous system due to cocaine. We develop efficient methods to screen and clean the ECG time series data and extract candidate windows to assess for potential drug use. We then apply our model on the recovery segments from these windows. Our model achieves 100% true positive rate while keeping the false positive rate to 0.87/day over (9+ hours/day of) lab data and to 1.13/day over (11+ hours/day of) field data.

  17. 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

  18. Novel approaches to the treatment of cocaine addiction.

    PubMed

    Sofuoglu, Mehmet; Kosten, Thomas R

    2005-01-01

    Cocaine addiction continues to be an important public health problem with over 1.7 million users in the US alone. Although there are no approved pharmacotherapies for cocaine addiction, a number of medications have been tested with some promising results. In this review, we summarise some of the emerging targets for cocaine pharmacotherapy including dopaminergic and GABA medications, adrenoceptor antagonists, vasodilators and immunotherapies. The brain dopamine system plays a significant role in mediating the rewarding effects of cocaine. Among dopaminergic agents tested for cocaine pharmacotherapy, disulfiram has decreased cocaine use in a number of studies. Amantadine, another medication with dopaminergic effects, may also be effective in cocaine users with high withdrawal severity. GABA is the main inhibitory neurotransmitter in the brain, and accumulating evidence suggests that the GABA system modulates the dopaminergic system and cocaine effects. Two anticonvulsant medications with GABAergic effects, tiagabine and topiramate, have yielded positive findings in clinical trials. Baclofen, a GABA(B) receptor agonist, is also promising, especially in those with more severe cocaine use. Some of the physiological and behavioural effects of cocaine are mediated by activation of the adrenergic system. In cocaine users, propranolol, a beta-adrenoceptor antagonist, had promising effects in individuals with more severe cocaine withdrawal symptoms. Cerebral vasodilators are another potential target for cocaine pharmacotherapy. Cocaine users have reduced cerebral blood flow and cortical perfusion deficits. Treatment with the vasodilators amiloride or isradipine has reduced perfusion abnormalities found in cocaine users. The functional significance of these improvements needs to be further investigated. All these proposed pharmacotherapies for cocaine addiction act on neural pathways. In contrast, immunotherapies for cocaine addiction are based on the blockade of cocaine

  19. Antagonism of metabotropic glutamate 1 receptors attenuates behavioral effects of cocaine and methamphetamine in squirrel monkeys.

    PubMed

    Achat-Mendes, Cindy; Platt, Donna M; Spealman, Roger D

    2012-10-01

    Within the group I family of metabotropic glutamate receptors (mGluRs), substantial evidence points to a role for mGluR5 mechanisms in cocaine's abuse-related behavioral effects, but less is understood about the contribution of mGluR1, which also belongs to the group I mGluR family. The selective mGluR1 antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] was used to investigate the role of mGluR1 in the behavioral effects of cocaine and methamphetamine. In drug discrimination experiments, squirrel monkeys were trained to discriminate cocaine from saline by using a two-lever, food-reinforced operant procedure. JNJ16259685 (0.56 mg/kg) pretreatments significantly attenuated cocaine's discriminative stimulus effects and the cocaine-like discriminative stimulus effects of methamphetamine. In monkeys trained to self-administer cocaine or methamphetamine under a second-order schedule of intravenous drug injection, JNJ16259685 (0.56 mg/kg) significantly reduced drug-reinforced responding, resulting in a downward displacement of dose-response functions. In reinstatement studies, intravenous priming with cocaine accompanied by restoration of a cocaine-paired stimulus reinstated extinguished cocaine-seeking behavior, which was significantly attenuated by JNJ16259685 (0.56 mg/kg). Finally, in experiments involving food rather than drug self-administration, cocaine and methamphetamine increased the rate of responding, and the rate-increasing effects of both psychostimulants were significantly attenuated by JNJ16259685 (0.3 mg/kg). At the doses tested, JNJ16259685 did not significantly suppress food-reinforced behavior (drug discrimination or fixed-interval schedule of food delivery), but did significantly reduce species-typical locomotor activity in observational studies. To the extent that the psychostimulant-antagonist effects of JNJ16259685 are independent of motor function suppression, further research is warranted to

  20. Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction.

    PubMed

    Zheng, Fang; Zhan, Chang-Guo

    2008-03-07

    (-)-Cocaine is a widely abused drug and there is currently no available anti-cocaine therapeutic. Promising agents, such as anti-cocaine catalytic antibodies and high-activity mutants of human butyrylcholinesterase (BChE), for therapeutic treatment of cocaine overdose have been developed through structure-and-mechanism-based design and discovery. In particular, a unique computational design strategy based on the modeling and simulation of the rate-determining transition state has been developed and used to design and discover desirable high-activity mutants of BChE. One of the discovered high-activity mutants of BChE has a approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the structure-and-mechanism-based design and discovery effort demonstrates that the unique computational design approach based on transition state modeling and simulation is promising for rational enzyme redesign and drug discovery. The general approach of the structure-and-mechanism-based design and discovery may be used to design high-activity mutants of any enzyme or catalytic antibody.

  1. Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus-Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia.

    PubMed

    Dalvi, Pranjali N; Gupta, Vijayalaxmi G; Griffin, Brooke R; O'Brien-Ladner, Amy; Dhillon, Navneet K

    2015-09-01

    Our previous study supports an additive effect of cocaine to human immunodeficiency virus infection in the development of pulmonary arteriopathy through enhancement of proliferation of pulmonary smooth muscle cells (SMCs), while also suggesting involvement of platelet-derived growth factor receptor (PDGFR) activation in the absence of further increase in PDGF-BB ligand. Redox-related signaling pathways have been shown to regulate tyrosine kinase receptors independent of ligand binding, so we hypothesized that simultaneous treatment of SMCs with transactivator of transcription (Tat) and cocaine may be able to indirectly activate PDGFR through modulation of reactive oxygen species (ROS) without the need for PDGF binding. We found that blocking the binding of ligand using suramin or monoclonal IMC-3G3 antibody significantly reduced ligand-induced autophosphorylation of Y1009 without affecting ligand-independent transphosphorylation of Y934 residue on PDGFRβ in human pulmonary arterial SMCs treated with both cocaine and Tat. Combined treatment of human pulmonary arterial SMCs with cocaine and Tat resulted in augmented production of superoxide radicals and hydrogen peroxide when compared with either treatment alone. Inhibition of this ROS generation prevented cocaine- and Tat-mediated Src activation and transphosphorylation of PDGFRβ at Y934 without any changes in phosphorylation of Y1009, in addition to attenuation of smooth muscle hyperplasia. Furthermore, pretreatment with an Src inhibitor, PP2, also suppressed cocaine- and Tat-mediated enhanced Y934 phosphorylation and smooth muscle proliferation. Finally, we report total abrogation of cocaine- and Tat-mediated synergistic increase in cell proliferation on inhibition of both ligand-dependent and ROS/Src-mediated ligand-independent phosphorylation of PDGFRβ.

  2. Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics.

    PubMed

    Caffino, Lucia; Giannotti, Giuseppe; Malpighi, Chiara; Racagni, Giorgio; Fumagalli, Fabio

    2015-10-01

    Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alters the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non-functional spines. Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network.

  3. Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation

    PubMed Central

    Prasad, Anil; Kulkarni, Rutuja; Jiang, Shuxian; Groopman, Jerome E.

    2017-01-01

    DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated ‘signalosome’ complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co-localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine’s contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts. PMID:28094782

  4. Retrotransposition of long interspersed element 1 induced by methamphetamine or cocaine.

    PubMed

    Okudaira, Noriyuki; Ishizaka, Yukihito; Nishio, Hajime

    2014-09-12

    Long interspersed element 1 (L1) is a retroelement constituting ∼17% of the human genome. A single human cell has 80-100 copies of L1 capable of retrotransposition (L1-RTP), ∼10% of which are "hot L1" copies, meaning they are primed for "jumping" within the genome. Recent studies demonstrated induction of L1 activity by drugs of abuse or low molecular weight compounds, but little is known about the underlying mechanism. The aim of this study was to identify the mechanism and effects of methamphetamine (METH) and cocaine on L1-RTP. Our results revealed that METH and cocaine induced L1-RTP in neuronal cell lines. This effect was found to be reverse transcriptase-dependent. However, METH and cocaine did not induce double-strand breaks. RNA interference experiments combined with add-back of siRNA-resistant cDNAs revealed that the induction of L1-RTP by METH or cocaine depends on the activation of cAMP response element-binding protein (CREB). METH or cocaine recruited the L1-encoded open reading frame 1 (ORF1) to chromatin in a CREB-dependent manner. These data suggest that the cellular cascades underlying METH- and cocaine-induced L1-RTP are different from those behind L1-RTP triggered by DNA damage; CREB is involved in drug-induced L1-RTP. L1-RTP caused by drugs of abuse is a novel type of genomic instability, and analysis of this phenomenon might be a novel approach to studying substance-use disorders.

  5. Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria.

    PubMed

    Cunha-Oliveira, Teresa; Silva, Lisbeth; Silva, Ana Maria; Moreno, António J; Oliveira, Catarina R; Santos, Maria S

    2013-06-07

    Mitochondrial function and energy metabolism are affected in brains of human cocaine abusers. Cocaine is known to induce mitochondrial dysfunction in cardiac and hepatic tissues, but its effects on brain bioenergetics are less documented. Furthermore, the combination of cocaine and opioids (speedball) was also shown to induce mitochondrial dysfunction. In this work, we compared the effects of cocaine and/or morphine on the bioenergetics of isolated brain and liver mitochondria, to understand their specific effects in each tissue. Upon energization with complex I substrates, cocaine decreased state-3 respiration in brain (but not in liver) mitochondria and decreased uncoupled respiration and mitochondrial potential in both tissues, through a direct effect on complex I. Morphine presented only slight effects on brain and liver mitochondria, and the combination cocaine+morphine had similar effects to cocaine alone, except for a greater decrease in state-3 respiration. Brain and liver mitochondrial respirations were differentially affected, and liver mitochondria were more prone to proton leak caused by the drugs or their combination. This was possibly related with a different dependence on complex I in mitochondrial populations from these tissues. In summary, cocaine and cocaine+morphine induce mitochondrial complex I dysfunction in isolated brain and liver mitochondria, with specific effects in each tissue.

  6. 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

  7. 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.

  8. Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART)

    PubMed Central

    Yeoh, Jiann Wei; James, Morgan H.; Graham, Brett A.; Dayas, Christopher V.

    2014-01-01

    Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is mediated in part through projections from hypothalamic peptide transmitter systems such as cocaine- and amphetamine-regulated transcript (CART). Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behavior in an animal model of contingent cocaine self-administration. Despite this work, few studies have assessed how the basic physiological properties of PVT neurons are influenced by exposure to drugs such as cocaine. Further, our previous work did not assess how infusions of CART, which we found to decrease cocaine-seeking, altered the activity of PVT neurons. In the current study we address these issues by recording from anterior PVT (aPVT) neurons in acutely prepared brain slices from cocaine-treated (15 mg/ml, n = 8) and saline-treated (control) animals (n = 8). The excitability of aPVT neurons was assessed by injecting a series of depolarizing and hyperpolarizing current steps and characterizing the resulting action potential (AP) discharge properties. This analysis indicated that the majority of aPVT neurons exhibit tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF) patterns. Interestingly, cocaine exposure significantly increased the proportion of aPVT neurons that exhibited TF. We then investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. Application of CART significantly suppressed excitatory synaptic drive to PVT neurons in both cocaine-treated and control recordings. This finding is consistent with our previous behavioral data, which showed that CART signaling in the PVT negatively regulates drug-seeking behavior. Together, these studies suggest that cocaine

  9. A fatally mistaken fruit juice drink: an unordinary way of cocaine intoxication.

    PubMed

    García-Repetto, R; Giménez, M P; Martinez, M C; Soria, M L

    2010-11-01

    Cocaine is one of the drugs of abuse more frequently consumed in Spain. Furthermore, Spain due to its geographical position is used by trafficker's organizations as the port of entrance of cocaine in the European Union. We present here a case of a fatal intoxication caused by a mistake in the cocaine distribution net in our country. Cocaine was concealed in a tropical juice only sold by the Internet.

  10. Levetiracetam has opposite effects on alcohol- and cocaine-related behaviors in C57BL/6J mice.

    PubMed

    Robinson, J Elliott; Chen, Meng; Stamatakis, Alice M; Krouse, Michael C; Howard, Elaina C; Faccidomo, Sara; Hodge, Clyde W; Fish, Eric W; Malanga, C J

    2013-06-01

    The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial self-stimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose-response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol- and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders.

  11. Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS

    PubMed Central

    Dahal, Santosh; Chitti, Sai V. P.; Nair, Madhavan P. N.; Saxena, Shailendra K.

    2015-01-01

    Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection

  12. Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine.

    PubMed

    Hikida, Takatoshi; Kitabatake, Yasuji; Pastan, Ira; Nakanishi, Shigetada

    2003-05-13

    Drug addiction poses serious social, medical, and economic problems, but effective treatments for drug addiction are still limited. Cocaine and morphine elevate dopamine levels in the nucleus accumbens (NAc), and the overwhelming actions of dopamine are implicated in reinforcement and addiction of abusive drugs. In our previous studies, we reported the regulatory role of acetylcholine (ACh) in the NAc function by selectively ablating the NAc cholinergic neurons with use of immunotoxin-mediated cell targeting. These studies indicated that ACh and dopamine acted convergently but oppositely on the NAc circuit and that cholinergic cell ablation enhanced long-lasting behavioral changes of cocaine addiction. In this investigation, we showed that immunotoxin-mediated ablation of the NAc cholinergic neurons enhanced not only the sensitivity to morphine in conditioned place preference but also negative reinforcement of morphine withdrawal in conditioned place aversion. Remarkably, acetylcholinesterase (AChE) inhibitors that act on the brain AChE suppressed both cocaine- and morphine-induced conditioned place preference and blocked the induction and persistence of cocaine-evoked hyperlocomotion. Importantly, this inhibition was abolished by ablation of the NAc cholinergic neurons. These results demonstrate that centrally active AChE inhibitors prevent long-lasting behavioral abnormalities associated with cocaine and morphine addictions by potentiating the actions of ACh released from the NAc cholinergic neurons. Centrally active AChE inhibitors could thus be approached as novel and potential therapeutic agents for drug addiction.

  13. Morphine, cocaine and antidepressant induced motivational activity and midbrain dopaminergic neurotransmission.

    PubMed

    Deslandes, Paul N; Pache, David M; Buckland, Paul; Sewell, Robert D E

    2002-10-25

    Positive motivational properties of opioids, stimulants and serotonin selective reuptake inhibitors have been reported following place preference conditioning. The possibility that these effects are associated with changes in dopamine concentration in the nucleus accumbens or striatum was investigated. Male Wistar rats were place conditioned in a three compartment model to vehicle or drug (morphine 2.5 mg/kg, cocaine 5 mg/kg, sertraline 5 mg/kg or paroxetine 15 mg/kg) alternately for 8 days using a 30 min pre-treatment time. Control animals received saline only. Nucleus accumbens and striatal tissue were dissected 72 h after final drug dose, and the concentration of dopamine and its metabolites determined using high performance liquid chromatography (HPLC). Striatal dopamine D1-like receptor density was also determined through radioligand binding. Significant place preference (P<0.05) was observed with morphine, cocaine and sertraline. Morphine treated subjects showed a significant decrease (P<0.05) in striatal dopamine concentration, whilst cocaine and sertraline treatment resulted in a significant increase in striatal dopamine levels. Nucleus accumbens concentrations of dopamine, and striatal dopamine D1-like receptor density remained unchanged. The changes in striatal dopamine concentrations are consistent with withdrawal from opioid and stimulant compounds, and suggest that place preference conditioning may, in part, result from negative motivational or aversive effects.

  14. Cocaine and Pregnancy

    MedlinePlus

    ... my baby’s body too? Yes. Cocaine crosses the placenta and enters the developing baby. Cocaine can be ... Later in pregnancy, cocaine use can cause the placenta to pull away from the wall of the ...

  15. Alterations in brain neurotrophic and glial factors following early age chronic methylphenidate and cocaine administration.

    PubMed

    Simchon-Tenenbaum, Yaarit; Weizman, Abraham; Rehavi, Moshe

    2015-04-01

    Attention deficit hyperactivity disorder (ADHD) overdiagnosis and a pharmacological attempt to increase cognitive performance, are the major causes for the frequent (ab)use of psychostimulants in non-ADHD individuals. Methylphenidate is a non-addictive psychostimulant, although its mode of action resembles that of cocaine, a well-known addictive and abused drug. Neuronal- and glial-derived growth factors play a major role in the development, maintenance and survival of neurons in the central nervous system. We hypothesized that methylphenidate and cocaine treatment affect the expression of such growth factors. Beginning on postnatal day (PND) 14, male Sprague Dawley rats were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70 and 90). On PND 56, rats treated with cocaine or methylphenidate from PND 14 through PND 35 exhibited increased hippocampal glial-cell derived neurotrophic factor (GDNF) mRNA levels, after 21 withdrawal days, compared to the saline-treated rats. We found a significant association between cocaine and methylphenidate treatments and age progression in the prefrontal protein expression of brain derived neurotrophic factor (BDNF). Neither treatments affected the behavioral parameters, although acute cocaine administration was associated with increased locomotor activity. It is possible that the increased hippocampal GDNF mRNA levels, may be relevant to the reduced rate of drug seeking behavior in ADHD adolescence that were maintained from childhood on methylphenidate. BDNF protein level increase with age, as well as following stimulant treatments at early age may be relevant to the neurobiology and pharmacotherapy of ADHD.

  16. Vaccines against stimulants: cocaine and MA.

    PubMed

    Kosten, Thomas; Domingo, Coreen; Orson, Frank; Kinsey, Berma

    2014-02-01

    While the worldwide prevalence of cocaine use remains significant, medications, or small molecule approaches, to treat drug addictions have met with limited success. Anti-addiction vaccines, on the other hand, have demonstrated great potential for treating drug abuse using a distinctly different mechanism of eliciting an antibody response that blocks the pharmacological effects of drugs. We provide a review of vaccine-based approaches to treating stimulant addictions; specifically and cocaine addictions. This selective review article focuses on the one cocaine vaccine that has been into clinical trials and presents new data related to pre-clinical development of a methamphetamine (MA) vaccine. We also review the mechanism of action for vaccine induced antibodies to abused drugs, which involves kinetic slowing of brain entry as well as simple blocking properties. We present pre-clinical innovations for MA vaccines including hapten design, linkage to carrier proteins and new adjuvants beyond alum. We provide some new information on hapten structures and linkers and variations in protein carriers. We consider a carrier, outer membrance polysaccharide coat protein (OMPC), that provides some self-adjuvant through lipopolysaccharide components and provide new results with a monophosopholipid adjuvant for the more standard carrier proteins with cocaine and MA. The review then covers the clinical trials with the cocaine vaccine TA-CD. The clinical prospects for advances in this field over the next few years include a multi-site cocaine vaccine clinical trial to be reported in 2013 and phase 1 clinical trials of a MA vaccine in 2014.

  17. Hormones, Nicotine and Cocaine: Clinical Studies

    PubMed Central

    Mello, Nancy K.

    2009-01-01

    Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels, and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (two min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine’s sustained positive effects (< 20 min), ratings of “High” and “Rush” began to decrease within one or two puffs of a high nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse, and implications for treatment of these addictive disorders is discussed. PMID:19835877

  18. Dyadic social interaction as an alternative reward to cocaine.

    PubMed

    Zernig, Gerald; Kummer, Kai K; Prast, Janine M

    2013-09-12

    Individuals suffering from substance use disorders often show severely impaired social interaction, preferring drugs of abuse to the contact with others. Their impaired social interaction is doubly harmful for them as (1) therapy itself is based and dependent on social interaction and as (2) social interaction is not available to them as an "alternative", i.e., non-drug reward, decreasing their motivation to stop drug use. We therefore developed an animal experimental model to investigate the neurobiology of dyadic social interaction- vs. cocaine reward. We took care to avoid: (a) engaging sexual attraction-related aspects of such a social interaction and (b) hierarchical difference as confounding stimuli. The cocaine- or social interaction stimulus was offered - in a mutually exclusive setting - within the confines of a conditioned place preference (CPP) apparatus. In our paradigm, only four 15-min episodes of social interaction proved sufficient to (i) switch the rats' preference from cocaine-associated contextual stimuli to social interaction CPP and (ii) inhibit the subsequent reacquisition/reexpression of cocaine CPP. This behavioral effect was paralleled by a reversal of brain activation (i.e., EGR1 expression) in the nucleus accumbens, the central and basolateral amygdala, and the ventral tegmental area. Of relevance for the psychotherapy of addictive disorders, the most rewarding sensory component of the composite stimulus "social interaction" was touch. To test our hypothesis that motivation is encoded in neuron ensembles dedicated to specific reward scenarios, we are currently (1) mapping the neural circuits involved in cocaine- vs. social-interaction reward and (2) adapting our paradigm for C57BL/6 mice to make use of the plethora of transgenic models available in this species.

  19. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

    SciTech Connect

    Asensio, S.; Goldstein, R.; Asensio, S.; Romero, M.J.; Romero, F.J.; Wong, C.T.; Alia-Klein, N.; Tomasi, D.; Wang, G.-J.; Telang, F..; Volkow, N.D.; Goldstein, R.Z.

    2010-05-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [{sup 11}C]raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.

  20. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

    PubMed Central

    Asensio, Samuel; Romero, Maria J.; Romero, Francisco J.; Wong, Christopher; Alia-Klein, Nelly; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Volkow, Nora D.; Goldstein, Rita Z.

    2009-01-01

    Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to non-drug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [11C]raclopride and positron emission tomography and response to monetary reward was measured (an average of 3 years later) with functional magnetic resonance imaging in seven cocaine addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a non-drug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine addicted individuals. PMID:20034014

  1. High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.

    PubMed

    Khroyan, Taline V; Yasuda, Dennis; Toll, Lawrence; Polgar, Willma E; Zaveri, Nurulain T

    2015-10-15

    Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5-30mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with AT-1001 (1-10mg/kg) or AT-1012 (3-10mg/kg) blocked CPP induced by 5mg/kg cocaine, but not by 30mg/kg cocaine. Lower doses of AT-1001 (0.3-1mg/kg) and AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.

  2. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement.

    PubMed

    Wang, Lei; Lv, Zhigang; Hu, Zhaoyang; Sheng, Jian; Hui, Bin; Sun, Jie; Ma, Lan

    2010-03-01

    The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIalpha, but not CaMKIIbeta, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIalpha, but not CaMKIIbeta, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIalpha, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement.

  3. Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats.

    PubMed

    Krawczyk, Michal; deBacker, Julian; Mason, Xenos; Jones, Andrea A; Dumont, Eric C

    2014-06-03

    Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.

  4. Sex differences in the effects of social and physical environment on novelty-induced exploratory behavior and cocaine-stimulated locomotor activity in adolescent rats.

    PubMed

    Zakharova, Elena; Starosciak, Amy; Wade, Dean; Izenwasser, Sari

    2012-04-21

    Many factors influence the rewarding effects of drugs such as cocaine. The present study was done to determine whether social and environmental factors alter behavior in adolescent male and female rats. On postnatal day (PND) 23, rats were housed in one of several same-sex conditions. Both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone (1 rat/cage) in an environment that either was impoverished (with no toys; II) or enriched (with toys; IE). Standard housing for these studies was social and impoverished, which was 2 rats/cage with no toys (SI2). Other rats were housed 2/cage with toys (SE2), or 3/cage with (SE3) or without (SI3) toys. On PND 37, novelty-induced locomotor activity was measured for 30min. On PND 44-46, locomotor activity in response to an injection of 5mg/kg cocaine was measured for 60min each day. For male rats, only social conditions altered novelty-induced activity. Males housed in groups of three had the most activity, compared to pair-housed and isolated rats. For females, social and environmental enrichment interacted to alter novelty-induced activity. In contrast to males, isolated females had increased activity, compared to group-housed females. Further, isolated females in impoverished environments had more activity than isolated females in enriched environments and group-housed females in impoverished environments. The effect of environmental enrichment on cocaine-stimulated locomotor activity was altered depending upon the number of rats living in a cage for males. For females, only social conditions altered cocaine-stimulated behavior, with activity increasing with the number of rats in the cage, regardless of environmental enrichment. These data show that social and environmental enrichment differentially alter novelty-induced and cocaine-stimulated locomotor activity in adolescent male and female rats.

  5. Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat.

    PubMed

    Blanco-Calvo, Eduardo; Rivera, Patricia; Arrabal, Sergio; Vargas, Antonio; Pavón, Francisco Javier; Serrano, Antonia; Castilla-Ortega, Estela; Galeano, Pablo; Rubio, Leticia; Suárez, Juan; Rodriguez de Fonseca, Fernando

    2014-01-01

    Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2'-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned locomotion

  6. Effects of cocaine on maternal behavior and neurochemistry.

    PubMed

    Nephew, Benjamin C; Febo, Marcelo

    2012-03-01

    Drug addiction is a chronic relapsing disorder that involves drug seeking and abuse despite the negative social and health consequences. While the potential effects of cocaine on child development have been extensively studied over the last 30 years, few researchers have focused on the effects of cocaine on maternal behavior, which includes offspring care and maternal aggression towards an unfamiliar individual. In humans, maternal cocaine use can lead to child neglect, abuse, and disrupt the mother-child bond. While it has been argued the developmental effects of maternal cocaine use on children were initially overstated, it is clear that disruptions of typical maternal behavior (i.e. postpartum depression, anxiety disorders) are detrimental to the physical and emotional health of offspring. Cocaine use in mothers is commonly associated with psychological disorders, including depression and anxiety, and it is postulated that many of the negative effects of maternal cocaine use on offspring are mediated through changes in maternal behavior. This review will summarize research on cocaine and maternal behavior in animal and human studies, discuss potential mechanisms, and suggest therapeutic strategies for treating cocaine-affected maternal behavior which may improve the physical and behavioral health of both mother and child. The primary objective is to stimulate future communication, cooperation, and collaboration between researchers who use animals and humans to study cocaine and maternal behavior.

  7. Peripartum cocaine use and adverse pregnancy outcome.

    PubMed

    Little, Bertis B.; Snell, Laura M.; Trimmer, Kenneth J.; Ramin, Susan M.; Ghali, Fred; Blakely, Craig A.; Garret, Andrea

    1999-09-01

    The objective of the study was to analyze possible adverse effects of peripartum cocaine use on maternal and fetal outcomes. Informed consent was given by 720 (97%) of 740 women who delivered consecutively at a large urban public hospital to test an umbilical cord blood sample for the presence of non-medically administered drugs of abuse and alcohol and to be interviewed for the study. Samples were tested for the presence of a cocaine metabolite (benzoylecgonine-BZE) by radioimmunoassay. The presence of other substances of abuse (alcohol, methamphetamine, opiates) resulted in exclusion from the sample of 143 subjects. Thus, in this cohort analysis, drug-free controls (N = 469) were compared to those positive for cocaine only (N = 108). Peripartum exposure to cocaine only, and no other substances of abuse, was associated with an increased frequency of abruptio placentae (1.9% vs 0% for control, P < 0.004), thick meconium stained amniotic fluid (3.9% vs 0.7% for controls, P < 0.006), premature rupture of membranes (P < 0.02), genitourinary anomalies (OR = 3.6, P < 0.05), abdominal wall defects (OR = 4.4, P < 0.01) and increased frequency of low birth weight (OR = 2.0, P < 0.02). These are important findings because previous studies have been complicated by the confounding effects of other substances of abuse. Am. J. Hum. Biol. 11:598-602, 1999. Copyright 1999 Wiley-Liss, Inc.

  8. dcc Haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking.

    PubMed

    Reynolds, Lauren M; Gifuni, Anthony J; McCrea, E Tess; Shizgal, Peter; Flores, Cecilia

    2016-02-01

    Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence.

  9. 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 M1- and M3-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 (D1R and D2R 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 D1R 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 D1R and D2R 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.

  10. Cocaine-induced very late stent thrombosis.

    PubMed

    Shah, Priyank; Vasudev, Rahul; Abuarqoub, Ahmad Hisham; Shamoon, Fayez

    2016-10-12

    Cocaine misuse is a known cause of acute coronary syndrome (ACS). Management of these patients has always been a challenge due to medication compliance and eventual risk of stent thrombosis. However, even cocaine misusers who are compliant with dual antiplatelet therapy have been reported to have stent thrombosis. All cases of cocaine-induced stent thrombosis reported in the literature have occurred within first year of stent placement (acute, subacute or late). We report a first case of very late stent thrombosis in a 54-year-old active cocaine misuser who presented with ST segment elevation myocardial infarction, which was successfully managed with percutaneous transluminal coronary angioplasty. A review of all the reported cases of cocaine-induced stent thrombosis is also discussed. Given the high mortality associated with stent thrombosis, treatment option for cocaine misusers presenting with ACS should be conservative when possible. If percutaneous coronary intervention is needed, bare metal stent should be preferred.

  11. Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

    SciTech Connect

    Goldstein, R.Z.; Goldstein, R.Z.; Woicik, P.A.; Maloney, T.; Tomasi, D.; Alia-Klein, N.; Shan, J.; Honorario, J.; Samaras, d.; Wang, R.; Telang, F.; Wang, G.-J.; Volkow, N.D.

    2010-09-21

    Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

  12. An Unusual Case of Baclofen Abuse

    PubMed Central

    Das, Soumitra; Palappalllil, Dhanya Sasidharan; Purushothaman, Sumesh Thoppil; Rajan, Varun

    2016-01-01

    Baclofen was initially used for the treatment of spastic conditions. Last decade has seen its emergence as a treatment of profound interest in alcohol dependence, opiates and cocaine abuse, and tobacco addiction. However, the published literature on baclofen abuse is sparse. Here, we report a patient with baclofen abuse. PMID:27833235

  13. SA 4503 attenuates cocaine-induced hyperactivity and enhances methamphetamine substitution for a cocaine discriminative stimulus.

    PubMed

    Rodvelt, Kelli R; Lever, Susan Z; Lever, John R; Blount, Lucas R; Fan, Kuo-Hsien; Miller, Dennis K

    2011-02-01

    Cocaine exhibits preferential (~15-fold) affinity for σ₁ over σ₂ sigma receptors, and previous research has shown an interaction of σ₁ receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants.

  14. Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products.

    PubMed

    Karlsen, Morten; Liu, Huiling; Johansen, Jon Eigill; Hoff, Bård Helge

    2015-03-25

    The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products.

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

    SciTech Connect

    Som, P.; Wang, G.J.; Oster, Z.H.; Knapp, F.F. Jr.; Yonekura, Y.; Fujibayashi, Y.; Yamamoto, K.; Kubota, K.

    1992-12-31

    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. 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.

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

    SciTech Connect

    Som, P.; Wang, G.J. ); Oster, Z.H. ); Knapp, F.F. Jr. ); Yonekura, Y. . Faculty of Medicine); Fujibayashi, Y. . Hospital); Yamamoto, K. . Medical School); Kubota, K. (Tohoku Univ., Sendai

    1992-01-01

    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. 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.

  17. Cocaine induces apoptosis in primary cultured rat aortic vascular smooth muscle cells: possible relationship to aortic dissection, atherosclerosis, and hypertension.

    PubMed

    Su, Jialin; Li, Jianfeng; Li, Wenyan; Altura, Bella; Altura, Burton

    2004-01-01

    Cocaine abuse is known to induce many adverse cardiovascular effects, including hypertension, atherosclerosis, and aortic dissection. A major physiological event leading to these pathophysiological actions of cocaine could be apoptosis. This study was designed to investigate if primary cultured rat aortic vascular smooth muscle cells (VSMCs) can undergo apoptosis when treated with cocaine. After treatment with cocaine (10(-6) to 10(-4) M), morphological analysis of aortic VSMCs using confocal fluoresence microscopy showed that the percentage of apoptotic aortic VSMCs increased after cocaine (10(-6) to 10(-4) M) treatment for 12, 24, and 48 h. These results demonstrate that aortic VSMCs can undergo rapid apoptosis in response to cocaine in a concentration-dependent manner. Cocaine-induced apoptosis may thus play a major role in cocaine abuse-induced aortic dissection, atherosclerosis, and hypertension.

  18. Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP

    PubMed Central

    Chiodi, Valentina; Mallozzi, Cinzia; Ferrante, Antonella; Chen, Jiang F; Lombroso, Paul J; Di Stasi, Anna Maria Michela; Popoli, Patrizia; Domenici, Maria Rosaria

    2014-01-01

    The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine. PMID:23989619

  19. Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP.

    PubMed

    Chiodi, Valentina; Mallozzi, Cinzia; Ferrante, Antonella; Chen, Jiang F; Lombroso, Paul J; Di Stasi, Anna Maria Michela; Popoli, Patrizia; Domenici, Maria Rosaria

    2014-02-01

    The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.

  20. Differential effects of the dopamine D3 receptor antagonist PG01037 on cocaine and methamphetamine self-administration in rhesus monkeys.

    PubMed

    John, William S; Newman, Amy Hauck; Nader, Michael A

    2015-05-01

    The dopamine D3 receptor (D3R) has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. This study extended the assessment of the highly selective D3R antagonist PG01037 on cocaine and methamphetamine (MA) self-administration to include a food-drug choice procedure. Eight male rhesus monkeys (n=4/group) served as subjects in which complete cocaine and MA dose-response curves were determined daily in each session. When choice was stable, monkeys received acute and five-day treatment of PG01037 (1.0-5.6 mg/kg, i.v.). Acute administration of PG01037 was effective in reallocating choice from cocaine to food and decreasing cocaine intake, however, tolerance developed by day 5 of treatment. Up to doses that disrupted responding, MA choice and intake were not affected by PG01037 treatment. PG01037 decreased total reinforcers earned per session and the behavioral potency was significantly greater on MA-food choice compared to cocaine-food choice. Furthermore, the acute efficacy of PG01037 was correlated with the sensitivity of the D3/D2R agonist quinpirole to elicit yawning. These data suggest (1) that efficacy of D3R compounds in decreasing drug choice is greater in subjects with lower D3R, perhaps suggesting that it is percent occupancy that is the critical variable in determining efficacy and (2) differences in D3R activity in chronic cocaine vs. MA users. Although tolerance developed to the effects of PG01037 treatment on cocaine choice, tolerance did not develop to the disruptive effects on food-maintained responding. These findings suggest that combination treatments that decrease cocaine-induced elevations in DA may enhance the efficacy of D3R antagonists on cocaine self-administration.

  1. Cocaine-induced diffuse alveolar hemorrhage: A case report and review of the literature.

    PubMed

    Dushay, Kevin M; Evans, Samuel K; Ghimire, Subash; Liu, Joy

    2016-08-01

    Cocaine is one of the most commonly abused drugs in the United States. Ingestion of cocaine may result in a wide array of disease processes due to its stimulant properties, contaminants, or to downstream effects, such as myo- cardial infarction, stroke, or cardiac arrest. Pulmonary complaints are common in patients seeking treatment for cocaine-associated medical problems and include acute eosinophilic pneumonia, pneumothorax, pneumomediastium, diffuse alveolar hemorrhage (DAH), pulmonary hypertension and granulomatosis. We present a case of DAH due to cocaine abuse and rapid resolution with mechanical ventilation and supportive care. [Full article available at http://rimed.org/rimedicaljournal-2016-08.asp, free with no login].

  2. Intravenous methylphenidate abuse. Prototype for prescription drug abuse.

    PubMed

    Parran, T V; Jasinski, D R

    1991-04-01

    Data are presented from a case series of 22 patients who abused methylphenidate hydrochloride (Ritalin-SR). The abuse pattern and symptoms of toxicity were similar to that seen with cocaine hydrochloride and amphetamine sulfate addiction; yet, the morbidity and mortality seen in this case series were greater than usual for a group of patients involved in intravenous drug abuse. We describe the characteristics of the methylphenidate abuse syndrome in terms of the pharmacology of methylphenidate, the constituents of the Ritalin-SR preparation, and the disease of chemical dependence. We propose solutions to the problem of methylphenidate abuse.

  3. Prenatal cocaine exposure alters functional activation in the ventral prefrontal cortex and its structural connectivity with the amygdala.

    PubMed

    Li, Zhihao; Santhanam, Priya; Coles, Claire D; Ellen Lynch, Mary; Hamann, Stephan; Peltier, Scott; Hu, Xiaoping

    2013-07-30

    Prenatal cocaine exposure (PCE) is associated with arousal dysregulation, and alterations of amygdala activity in response to emotional arousal have previously been reported. However, voluntary regulation of emotional affect, enabling appropriate neural response to different streams of stimuli, must also engage prefrontal regions, yet the impact of PCE on these prefrontal mechanisms has not been investigated. Recent neuroimaging studies have shown the involvement of ventral prefrontal cortex (vPFC) in the modulation of amygdala reactivity and the mediation of effective emotional regulation. Based on these findings, using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the present study compared functional activations of the vPFC as well as its structural connectivity with the amygdala between groups of PCE and control adolescents. In a working memory task with emotional distracters, the PCE adolescents exhibited less capability of increasing their vPFC activation in response to increased memory load, which corresponded with their less suppressed amygdala activation. Reduced structural connectivity between the vPFC and the amygdala was also observed from DTI measurement in the PCE group. In addition, correlations between amygdala activation and (i) vPFC activation, as well as (ii) amygdala-vPFC structural connectivity, were observed in the control but not in the PCE group. These data complement previous findings of the impact of PCE on the activity of the amygdala and extend our understanding of the neurobiological mechanisms underlying the effect of PCE on arousal dysregulation reported in human and animal studies.

  4. Sleep Regulates Incubation of Cocaine Craving

    PubMed Central

    Chen, Bo; Wang, Yao; Liu, Xiaodong; Liu, Zheng

    2015-01-01

    After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine self-administration, rats exhibited persistent reduction in nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats during their active (dark) phase of the day, which selectively decreased the fragmentation of REM sleep during their inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depicting the progressive intensification of cocaine seeking after withdrawal. In contrast, experimentally increasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substrate that can be engaged by sleep to regulate cocaine craving and relapse, and demonstrate sleep-based therapeutic opportunities for cocaine addiction. SIGNIFICANCE STATEMENT Sleep abnormalities are common symptoms in chronic drug users long after drug withdrawal. These withdrawal-associated sleep symptoms, particularly reduction in total sleep time and deteriorating sleep quality, have been

  5. Cocaine-induced dystonic reaction: an unlikely presentation of child neglect.

    PubMed

    Pinto, Jamie M; Babu, Kavita; Jenny, Carole

    2013-09-01

    Child neglect can be difficult to recognize. Parental substance abuse may place a child at increased risk of neglect. This report reviews 2 cases of dystonic reaction in children after accidental exposure to cocaine in their home environments. The reports are followed by a review of proposed physiologic mechanisms for cocaine-induced dystonia and a discussion on neurological symptoms that may develop after cocaine exposure. Pediatric emergency physicians should consider cocaine exposure when a child of any age presents with abnormal movements. Dystonic reaction is an uncommon, but reported, complication of cocaine exposure in the absence of other risk factors and may be the first presentation of child neglect.

  6. Signs of Painkiller Abuse and Addiction

    MedlinePlus

    ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... loved one, get them from a friend, or buy them from a dealer. Some people might even ...

  7. Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex

    PubMed Central

    Sun, Wei-Lun; Zelek-Molik, Agnieszka; McGinty, Jacqueline F.

    2013-01-01

    Rationale Dephosphorylation of extracellular signal-regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) in the dorsomedial prefrontal cortex (dmPFC) at the end of short access (ShA) cocaine self-administration is implicated in cocaine-seeking. However, what receptors and phosphatases mediate this effect and whether ERK/CREB and related phospho-proteins in the dmPFC react similarly during early withdrawal from long access (LgA) cocaine self-administration are unknown. Objectives The effects of ShA vs. LgA cocaine self-administration on the phosphorylation of protein phosphatase 2A (PP2A) and striatal-enriched protein tyrosine phosphatase (STEP), as well as GluN and GluA receptor subtype expression in the dmPFC during early withdrawal were compared. Methods Rats self-administered cocaine or received saline during 2-hr or 6-hr daily sessions for 10-11 days. Two hr after the final session, the dmPFC was dissected out and processed for immunoblotting. Results Similar to previous findings after ShA cocaine, phospho-ERK and phospho-CREB in the dmPFC were decreased after LgA cocaine. Cocaine elevated phospho-PP2A (de-activation) and decreased phosphor-STEP (activation) in both ShA and LgA cocaine rats. GluN1, GluN2B and phospho-GluN2B Tyr1472 in the dmPFC were decreased after ShA and LgA cocaine. Further, a significant reduction of GluA2, GluA1 and phospho-GluA1 Ser845 was found only in LgA rats. Conclusions Activation of phospho-STEP may underlie ERK and CREB dephosphorylation in the dmPFC as well as internalization and degradation of GluN complexes during early withdrawal from both ShA and LgA cocaine self-administration whereas differential alteration of AMPA receptor subunits after ShA and LgA cocaine self-administration depends on cocaine intake. PMID:23624776

  8. Influence of Cocaine History on the Behavioral Effects of Dopamine D3 Receptor-Selective Compounds in Monkeys

    PubMed Central

    Blaylock, B L; Gould, R W; Banala, A; Grundt, P; Luedtke, R R; Newman, A H; Nader, M A

    2011-01-01

    Although dopamine D3 receptors have been associated with cocaine abuse, little is known about the consequences of chronic cocaine on functional activity of D3 receptor-preferring compounds. This study examined the behavioral effects of D3 receptor-selective 4-phenylpiperazines with differing in vitro functional profiles in adult male rhesus monkeys with a history of cocaine self-administration and controls. In vitro assays found that PG 619 (N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) was a potent D3 antagonist in the mitogenesis assay, but a fully efficacious agonist in the adenylyl cyclase assay, NGB 2904 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide HCl) was a selective D3 antagonist, whereas CJB 090 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) exhibited a partial agonist profile in both in vitro assays. In behavioral studies, the D3 preferential agonist quinpirole (0.03–1.0 mg/kg, i.v.) dose-dependently elicited yawns in both groups of monkeys. PG 619 and CJB 090 elicited yawns only in monkeys with an extensive history of cocaine, whereas NGB 2904 did not elicit yawns, but did antagonize quinpirole and PG 619-elicited yawning in cocaine-history monkeys. In another experiment, doses of PG 619 that elicited yawns did not alter response rates in monkeys self-administering cocaine (0.03–0.3 mg/kg per injection). Following saline extinction, cocaine (0.1 mg/kg) and quinpirole (0.1 mg/kg), but not PG 619 (0.1 mg/kg), reinstated cocaine-seeking behavior. When given before a cocaine prime, PG 619 decreased cocaine-elicited reinstatement. These findings suggest that (1) an incongruence between in vitro and in vivo assays, and (2) a history of cocaine self-administration can affect in vivo efficacy of D3 receptor-preferring compounds PG 619 and CJB 090, which appear to be dependent on the behavioral assay. PMID:21289600

  9. A Methanol Extract of Brugmansia arborea Affects the Reinforcing and Motor Effects of Morphine and Cocaine in Mice

    PubMed Central

    Bracci, Antonio; Daza-Losada, Manuel; Aguilar, Maria; Miñarro, José; Rodríguez-Arias, Marta

    2013-01-01

    Previous reports have shown that several of the effects of morphine, including the development of tolerance and physical withdrawal symptoms, are reduced by extracts of Brugmansia arborea (L.) Lagerheim (Solanaceae) (B. arborea). In the present study we evaluate the action of the methanol extract of B. arborea (7.5–60 mg/kg) on the motor and reinforcing effects of morphine (20 and 40 mg/kg) and cocaine (25 mg/kg) using the conditioned place preference (CPP) procedure. At the doses employed, B. arborea did not affect motor activity or induce any effect on CPP. The extract partially counteracted morphine-induced motor activity and completely blocked the CPP induced by 20 mg/kg morphine. On the other hand, B. arborea blocked cocaine-induced hyperactivity but did not block cocaine-induced CPP. Reinstatement of extinguished preference with a priming dose of morphine or cocaine was also inhibited by B. arborea. The complex mechanism of action of B. arborea, which affects the dopaminergic and the cholinergic systems, seems to provide a neurobiological substrate for the effects observed. Considered as a whole, these results point to B. arborea as a useful tool for the treatment of morphine or cocaine abuse. PMID:23533488

  10. Time course of cocaine in rabbit hair.

    PubMed

    Jurado, C; Rodriguez-Vicente, C; Menéndez, M; Repetto, M

    1997-01-17

    The accurate interpretation of analytical results from hair testing for drugs of abuse continues to be a complex and difficult problem since many questions still remain unanswered. In this paper an animal model was developed to ascertain the time course for the appearance and disappearance of cocaine and its metabolite benzoylecgonine (BE) in hair. Female Fauve Bourgogne red-haired rabbits (n = 6) were intraperitoneally administered a single dose of cocaine at 5 mg/kg. Animal hair was shaved just before drug administration and the newly grown back hair was subsequently shaved and collected daily over a period of two weeks. Samples were analyzed for cocaine and BE by gas chromatography-mass spectrometry (GC-MS). The profiles were quite similar for parent drug and metabolite. Cocaine and BE appeared in the first sampling (day 1), with peak concentration appearing that same day. 1.01 ng/mg and 0.51 ng/mg for cocaine and BE, respectively. Levels declined rapidly on day 2, remaining detectable for ten days after drug administration. This study demonstrates that the initial incorporation of cocaine compounds in rabbit hair is very rapid (24 h). A small fraction of the drug is detected ten days after exposure, at a time when concentrations in other biological specimens (blood or urine) are not detectable.

  11. 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.

  12. 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

  13. Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

    SciTech Connect

    Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira; Aiamkitsumrit, Benjamas; Fassnacht, Ryan; Kashanchi, Fatah; Ochem, Alex; Simon, Gary L.; Karn, Jonathan; Hauser, Kurt F.; Tyagi, Mudit

    2015-09-15

    Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. - Highlights: • Cocaine induces the initiation phase of HIV transcription by activating NF-ĸB. • Cocaine induced NF-ĸB phosphorylation promotes its interaction with P300. • Cocaine enhances the elongation phase of HIV transcription by stimulating MSK1. • Cocaine activated MSK1 catalyzes the phosphorylation of histone H3 at its Ser10. • Cocaine induced H3S10 phosphorylation facilitates the recruitment of P-TEFb at LTR.

  14. Exposure to the Selective κ-Opioid Receptor Agonist Salvinorin A Modulates the Behavioral and Molecular Effects of Cocaine in Rats

    PubMed Central

    Chartoff, Elena H; Potter, David; Damez-Werno, Diane; Cohen, Bruce M; Carlezon, William A

    2008-01-01

    Stress and chronic exposure to drugs of abuse can trigger addictive and depressive disorders. Both stimuli increase activity of dynorphin, a neuropeptide that acts at κ-opioid receptors (KORs). In humans, KOR agonists cause dysphoria, raising the possibility that dynorphin modulates the depressive-like effects of stress and chronic drug use. We examined if KOR activation alters sensitivity to stimulant drugs by assessing the effects of the selective KOR agonist, salvinorin A (SalvA), on cocaine-induced locomotor activity and c-Fos expression. Acute administration of SalvA blocked the locomotor-stimulant effects of cocaine, whereas repeated SalvA together with concomitant exposure to activity testing chambers potentiated the locomotor response to a cocaine challenge. In contrast, repeated SalvA administered in home cages rather than the activity chambers failed to potentiate the locomotor response to a cocaine challenge. One potential explanation for these findings is that activation of KORs disrupts context conditioning: acute locomotor responses to SalvA alone did not fully habituate with repeated testing in the activity chambers. The effects of SalvA on locomotor activity paralleled its effects on cocaine-induced c-Fos expression in the dorsal striatum: acute SalvA attenuated cocaine-induced c-Fos, whereas repeated SalvA potentiated it when administered in the activity chambers but not the home cage. Acute SalvA also blocked the locomotor stimulant effects of the DI receptor agonist SKF 82958, whereas repeated SalvA potentiated these effects when administered in the activity chambers. These findings suggest that SalvA regulates the stimulant effects of cocaine through interactions with DI receptor-mediated signaling in the dorsal striatum. PMID:18185499

  15. Pharmacological manipulation of glucocorticoid receptors differentially affects cocaine self-administration in environmentally enriched and isolated rats

    PubMed Central

    Hofford, Rebecca S.; Prendergast, Mark A.; Bardo, Michael T.

    2015-01-01

    Social isolation rearing (isolated condition, IC) is used as a model of early life stress in rodents. Rats raised in this condition are often compared to rats raised in an environmentally enriched condition (EC). However, EC rats are repeatedly exposed to forced novelty, another classic stressor in rodents. These studies explored the relationship between cocaine self-administration and glucocorticoid receptor (GR) activation and measured total levels of GR protein in reward-related brain regions (medial prefrontal cortex, orbitofrontal cortex, nucleus accumbens, amygdala) in rats chronically exposed to these conditions. For experiment 1, rats were housed in EC or IC and were then trained to self-administer cocaine. Rats raised in these housing conditions were tested for their cocaine responding after pretreatment with the GR antagonist, RU486, or the GR agonist, corticosterone (CORT). For experiment 2, levels of GR from EC and IC rats were measured in brain regions implicated in drug abuse using Western blot analysis. Pretreatment with RU486 (20 mg/kg) decreased responding for a low unit dose of cocaine (0.03 mg/kg/infusion) in EC rats only. IC rats were unaffected by RU486 pretreatment, but earned significantly more cocaine than EC rats after pretreatment with CORT (10 mg/kg). No difference in GR expression was found between EC and IC rats in any brain area examined. These results, along with previous literature, suggest that enrichment enhances responsivity of the HPA axis related to cocaine reinforcement, but this effect is unlikely due simply to differential baseline GR expression in areas implicated in drug abuse. PMID:25655510

  16. Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.

    PubMed

    Banks, Matthew L; Negus, S Stevens

    2017-04-01

    Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT2C receptor activation nor 5-HT2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT2C agonists and 5-HT2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

  17. Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression.

    PubMed

    Barr, Jeffrey L; Forster, Gina L; Unterwald, Ellen M

    2014-08-01

    Dopaminergic neurotransmission in the nucleus accumbens is important for various reward-related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In this study, in vivo microdialysis in freely moving adult male Sprague-Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus-mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N-methyl-d-aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A : NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal-nucleus accumbens communication, in part through changes in glutamate receptor composition. A behaviorally sensitizing regimen of cocaine (20 mg/kg, ip 7 days) also sensitized ventral hippocampus (hipp)-mediated dopaminergic transmission within the nucleus accumbens (Nac) to NMDA stimulation (bolts). This was associated with reduced ventral hippocampal NR2A:NR2B subunit ratio, suggesting that repeated exposure to cocaine produces changes in hippocampal NMDA receptor composition that lead to enhanced ventral hippocampus-nucleus accumbens communication.

  18. Abuse Liability Profile of Three Substituted Tryptamines

    PubMed Central

    Forster, Michael J.; Janowsky, Aaron; Eshleman, Amy J.

    2011-01-01

    The abuse liability profile of three synthetic hallucinogens, N,N-diisopropyltryptamine (DIPT), 5-N,N-diethyl-5-methoxytryptamine (5-MeO-DET), and 5-methoxy-α-methyltryptamine (5-MeO-AMT), was tested in rats trained to discriminate hallucinogenic and psychostimulant compounds, including cocaine, methamphetamine, 3,4-methylenedioxymethylamphetamine (MDMA), lysergic acid diethylamide (LSD), (−)-2,5-dimethoxy-4-methylamphetamine (DOM), and dimethyltryptamine (DMT). Because abused hallucinogens act at 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A receptors, and abused psychostimulants act at monoamine transporters, binding and functional activities of DIPT, 5-MeO-DET, and 5-MeO-AMT at these sites were also tested. DIPT fully substituted in rats trained to discriminate DMT (ED50 = 1.71 mg/kg) and DOM (ED50 = 1.94 mg/kg), but produced only 68% LSD-appropriate responding. 5-MeO-DET fully substituted for DMT (ED50 = 0.41 mg/kg) and produced 59% MDMA-appropriate responding. 5-MeO-AMT did not fully substitute for any of the training drugs, but produced 67% LSD-appropriate responding. None of the compounds produced substitution in rats trained to discriminate cocaine or methamphetamine. All three compounds showed activity at 5-HT1A and 5-HT2A receptors as well as blockade of reuptake by the serotonin transporter. In addition, 5-MeO-AMT produced low levels of serotonin release and low potency blockade of dopamine uptake. DIPT, 5-MeO-DET, and 5-MeO-AMT produced behavioral and receptor effects similar to those of abused hallucinogens, but were not similar to those of psychostimulants. DIPT and 5-MeO-DET may have abuse liability similar to known hallucinogens and may be hazardous because high doses produced activity and lethality. PMID:21474568

  19. Positive affective vocalizations during cocaine and sucrose self-administration: a model for spontaneous drug desire in rats.

    PubMed

    Browning, Jenny R; Browning, Douglas A; Maxwell, Alexis O; Dong, Yan; Jansen, Heiko T; Panksepp, Jaak; Sorg, Barbara A

    2011-01-01

    Ultrasonic vocalizations in the 50 kHz range (50 kHz USVs) are emitted by rodents upon activation of positive affective states and appear to be a direct measure of internal emotional and motivational urges to seek rewarding stimuli such as drugs of abuse. Since these behavioral responses do not rely on training for expression, they can be viewed as a "spontaneous" measure of affective state. The goal of the present study was to monitor spontaneous USVs throughout a widely-used cocaine self-administration and reinstatement model of addiction and relapse. To gain insight into the changes in affective state across the different phases of a standard self-administration experiment, we measured 50 kHz USVs in rats during cocaine self-administration and reinstatement, and compared these to sucrose self-administration and reinstatement. During cocaine self-administration, the number of 50 kHz USVs increased over acquisition of self-administration and decreased during extinction. Furthermore, the number of USVs on the first day of acquisition in the cocaine experiment was positively correlated with how rapidly cocaine self-administration was acquired. These findings suggest that the initial affective response to cocaine may be a sensitive predictor of the motivational efficacy of rewarding stimuli and therefore the susceptibility to acquire self-administration of cocaine. Cue- and cocaine-induced reinstatement elevated 50 kHz USVs above extinction levels. Rats trained for sucrose self-administration showed no elevation in USVs during acquisition when USVs were considered over the entire 2 h session, but they did show an elevation in USVs during acquisition when considered over only the first 5 min of the session. As with cocaine-induced reinstatement, sucrose-induced reinstatement produced significantly more USVs compared to the prior extinction day. Taken together, USVs may serve as a sensitive and dynamic non-invasive measure that spontaneously (i.e. without any

  20. Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.

    PubMed

    Martín-García, Elena; Bourgoin, Lucie; Cathala, Adeline; Kasanetz, Fernando; Mondesir, Miguel; Gutiérrez-Rodriguez, Ana; Reguero, Leire; Fiancette, Jean-François; Grandes, Pedro; Spampinato, Umberto; Maldonado, Rafael; Piazza, Pier Vincenzo; Marsicano, Giovanni; Deroche-Gamonet, Véronique

    2016-08-01

    The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

  1. Concentrations of cocaine and benzoylecgonine in femoral blood from cocaine-related deaths compared with venous blood from impaired drivers.

    PubMed

    Jones, Alan Wayne; Holmgren, Anita

    2014-01-01

    The concentrations of cocaine and its major metabolite benzoylecgonine (BZE) were determined in femoral blood from 132 cocaine-related deaths and compared with venous blood from 988 apprehended drivers. Cocaine and BZE were determined by solid-phase extraction and isotope dilution gas chromatography-mass spectrometry with limits of quantitation of 0.02 mg/L for both substances. Significantly more men (95-98%) than women (2-5%) abused cocaine, although their mean age was about the same (29-30 years). Mean age (±SD) of cocaine-related deaths was 29 ± 7 years, which was not significantly different from 30 ± 8 years in traffic cases (P > 0.05). The median concentration of cocaine in blood in 61 fatalities was 0.10 mg/L compared with 0.06 mg/L in traffic cases (P < 0.001). In drug intoxication deaths, the median concentration of cocaine was 0.13 mg/L (N = 25), which was not significantly different from 0.09 mg/L (N = 36) in other causes of death. Cocaine-related deaths mostly involved mixed drug intoxications including co-ingestion of heroin, cannabis, amphetamines as well as legal drugs, such as benzodiazepines and/or ethanol. The concentrations of cocaine in blood from living and deceased persons overlapped, which makes it infeasible to predict toxicity from the analytical toxicology results alone.

  2. Serotonin Syndrome in the Setting of Lamotrigine, Aripiprazole, and Cocaine Use

    PubMed Central

    Kotwal, Anupam; Cutrona, Sarah L.

    2015-01-01

    Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin. We describe a case of serotonin syndrome that occurred after ingestion of higher than prescribed doses of lamotrigine and aripiprazole, in addition to cocaine abuse. The diagnosis was established based on Hunter toxicity criteria and severity was classified as mild. The features of this syndrome resolved shortly after discontinuation of the offending agents. Serotonin syndrome is characterized by mental status changes, autonomic hyperactivity, and neuromuscular abnormalities along a spectrum ranging from mild to severe. Serotonin syndrome in our patient was most likely caused by the pharmacokinetic and pharmacodynamic interactions between lamotrigine, aripiprazole, and cocaine leading to increased CNS serotonergic activity. PMID:26339247

  3. Cocaine inhibition of GABA(A) current: role of dephosphorylation.

    PubMed

    Ye, Jiang-Hong; Ren, Jun

    2006-01-01

    Acute cocaine toxicity is frequently associated with seizures. The mechanisms underlying the convulsant effect of cocaine are not well understood. Previously, we have shown that cocaine depresses whole-cell current evoked by gamma-aminobutyric acid (GABA) in hippocampal neurons freshly isolated from rats. Cocaine's effect was voltage-independent and concentration-dependent. In the present study, using whole-cell patch-clamp recording on rat neurons freshly isolated from hippocampus, we examined the intracellular mechanisms involved in cocaine's action. Increasing intracellular Ca(2+) concentration ([Ca]i) from 0.01 to 5 microM strongly increased the depressant effect of cocaine. By contrast, 1-[N, O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a specific antagonist of Ca/calmodulin-dependent protein kinase (CaMKII), attenuated or enhanced cocaine's action in different neurons: in three out of nine neurons dialysed with 5 microM KN-62,1 mM cocaine depressed GABA current by only 33%, but in another three out of nine neurons, cocaine depressed GABA current by as much as 83%. Chelerythrine (a specific CaCa(2+)/phospholipid-dependent protein kinase C [PKC] antagonist) had minimal effect on cocaine's action. We suggest that cocaine induces an increase in [Ca]i, which stimulates phosphatase activity and thus leads to dephosphorylation of GABA receptors. This dephosphorylation-mediated disinhibitory action may play a role in cocaine-induced convulsant states.

  4. Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential.

    PubMed

    Bentzley, Brandon S; Aston-Jones, Gary

    2016-03-03

    Preclinical evidence indicates that inactivation of subthalamic nucleus (STN) may be effective for treating cocaine addiction, and therapies that target STN, e.g. deep brain stimulation, are available indicating that this may have clinical promise. Here, we assessed the therapeutic potential of STN inactivation using a translationally relevant economic approach that quantitatively describes drug-taking behavior, and tested these results with drug-seeking tasks. Economic demand for cocaine was assessed in rats (n = 11) using a within-session threshold procedure in which cocaine price (responses/mg cocaine) was sequentially increased throughout the session. Cocaine demand was assessed in this manner immediately after bilateral microinfusions into STN of either vehicle (artificial cerebrospinal fluid) or the GABAA receptor agonist muscimol. A separate group of animals (n = 8) was tested for changes in cocaine seeking either during extinction or in response to cocaine-associated cues. Muscimol-induced inhibition of STN significantly attenuated cocaine consumption at high prices, drug seeking during extinction and cued reinstatement of cocaine seeking. In contrast, STN inhibition did not reduce cocaine consumption at low prices or locomotor activity. Thus, STN inactivation reduced economic demand for cocaine and multiple measures of drug seeking during extinction. In view of the association between economic demand and addiction severity in both rat and human, these results indicate that STN inactivation has substantial clinical potential for treatment of cocaine addiction.

  5. 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.

  6. Management of a cocaine-induced palatal perforation with a nasal septal button.

    PubMed

    Trimarchi, Matteo; Sykopetrites, Vittoria; Bussi, Mario

    2016-01-01

    A cocaine-induced midline destructive lesion (CIMDL) is a rare consequence of cocaine insufflation that involves the nose, sinuses, and occasionally the palate. Palatal perforations compromise swallowing, mastication, and speech. An obturator prosthesis can be used to overcome these complications. In selected cases, a nasal septal button is a good alternative for the sealing of a palatal perforation, especially when surgery is not indicated, such as in cases of persistent cocaine abuse. Abstinence from cocaine is the most effective long-term management option for patients with a CIMDL, and surgical correction of the defect should be postponed until the patient stops sniffing cocaine and the lesion becomes stable. We describe the case of a 39-year-old cocaine abuser whose oronasal communication was plugged with a nasal septal button, which resulted in an immediate alleviation of his oronasal reflux.

  7. Mind Over Matter: Cocaine

    MedlinePlus

    ... Over Matter Teaching Guide and Series / Cocaine Print Mind Over Matter: Cocaine Order Free Publication in: English ... how drugs affect the brain and nervous system. Mind Over Matter is produced by the National Institute ...

  8. Cocaine and Cardiovascular Events.

    ERIC Educational Resources Information Center

    Cantwell, John D.; Rose, Fred D.

    1986-01-01

    The case of a 21-year-old man who suffered a myocardial infarction after using cocaine and amphetamines is reported. A brief literature review provides evidence of cocaine's potential cardiovascular effects. (Author/MT)

  9. Chronic opiate treatment enhances both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal.

    PubMed

    He, Shaunteng; Grasing, Kenneth

    2004-08-16

    After chronic exposure to psychostimulants or opiates, self-administration or conditioned place preference with either class is increased (sensitized). Cross-sensitization of conditioned place preference, i.e., enhancement of psychostimulant-induced preferences after exposure to opiates, has also been described, but increases in cocaine self-administration after morphine pretreatment have not been reported. The present study evaluated effects of chronic morphine treatment on cocaine reinforcement. Opiate dependence was established in Wistar rats by administration of morphine as a constant infusion that was gradually increased to a dose of 50mg/kg per day over a 1-week period. Immediately after discontinuation of chronic morphine treatment, animals were allowed to acquire cocaine self-administration under a simple fixed-ratio schedule (FR-1), and were subsequently advanced to a progressive ratio schedule. Acquisition of cocaine self-administration under the FR-1 did not differ in saline- and morphine-pretreated animals. For cocaine self-administration under a progressive ratio schedule measured at 5 or more days after the onset of opiate withdrawal, chronic pretreatment with morphine increased the number of ratios completed, augmented final response requirements, and produced a more stable pattern of cocaine self-administration. Responding was also increased in morphine-pretreated animals during an initial extinction session. These results show that chronic opiate treatment can enhance both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal. A similar effect may occur in human patients who discontinue methadone or other forms of replacement therapy for opiate abuse, and may contribute to relapse involving use of cocaine or other psychostimulants.

  10. Early methylphenidate exposure enhances cocaine self-administration but not cocaine-induced conditioned place preference in young adult rats

    PubMed Central

    Crawford, Cynthia A.; Baella, Shelley A.; Farley, Cristal M.; Herbert, Matthew S.; Horn, Leslie R.; Campbell, Rachel H.; Zavala, Arturo R.

    2010-01-01

    Rationale Previous studies in rodents show that early exposure to methylphenidate alters later responsiveness to drugs of abuse. An interesting feature of these studies is that early methylphenidate treatment decreases the rewarding value of cocaine when measured by conditioned place preference (CPP), but the same treatment increases cocaine self-administration. Objective The goal of the present study was to examine the effects of early methylphenidate exposure on cocaine-induced responding using both reward paradigms. Methods Rats were treated with methylphenidate (0, 2, or 5 mg/kg) from postnatal day (PD) 11 to PD 20 and then cocaine-induced CPP or cocaine self-administration was measured in separate groups of rats in adulthood. The CPP procedure included eight days of acquisition training, eight days of extinction training, and a reinstatement test. Rats were conditioned with 0, 10 or 20 mg/kg cocaine. Reinstatement was assessed after a priming dose of cocaine (10 mg/kg). For the self-administration experiment, a jugular catheter was implanted and rats were trained to press a lever reinforced with cocaine (0.25 or 0.75 mg/kg/infusion) on a fixed ratio (FR) 1 schedule. Rats were gradually moved from an FR1 to an FR10 schedule and, after criterion was reached, rats were placed on a progressive ratio schedule for five days. Results Cocaine produced robust rewarding effects as determined by both the CPP and self-administration experiments; however, early methylphenidate exposure only enhanced the reinforcing effects of cocaine on the self-administration paradigm. Interestingly, this methylphenidate enhancement was only seen in male rats. Conclusions These data suggest that in males methylphenidate enhances the reinforcing value of cocaine, but not cocaine-associated cues. PMID:20848087

  11. Opponent process properties of self-administered cocaine.

    PubMed

    Ettenberg, Aaron

    2004-01-01

    Over the past decade, data collected in our laboratory have demonstrated that self-administered cocaine produces Opponent-Process-like behavioral effects. Animals running a straight alley once each day for IV cocaine develop over trials an approach-avoidance conflict about re-entering the goal box. This conflict behavior is characterized by a stop in forward locomotion (usually at the very mouth of the goal box) followed by a turn and 'retreat' back toward the goal box. The results of a series of studies conducted over the past decade collectively suggest that the behavioral ambivalence exemplified by rats running the alley for IV cocaine stems from concurrent and opponent positive (rewarding) and negative (anxiogenic) properties of the drug--both of which are associated with the goal box. These opponent properties of cocaine have been shown to result from temporally distinct affective states. Using a conditioned place preference test, we have been able to demonstrate that while the initial immediate effects of IV cocaine are reinforcing, the state present 15 min post-injection is aversive. In our most recent work, the co-administration of IV cocaine with either oral ethanol or IV heroin was found to greatly diminish the development and occurrence of retreat behaviors in the runway. It may therefore be that the high incidence of co-abuse of cocaine with either ethanol or heroin, stems from the users' motivation to alleviate some of the negative side effects of cocaine. It would seem then that the Opponent Process Theory has provided a useful conceptual framework for the study of the behavioral consequences of self-administered cocaine including the notion that both positive and negative reinforcement mechanisms are involved in the development and maintenance of cocaine abuse.

  12. Substance abuse and child maltreatment.

    PubMed

    Wells, Kathryn

    2009-04-01

    Pediatricians and other medical providers caring for children need to be aware of the dynamics in the significant relationship between substance abuse and child maltreatment. A caregiver's use and abuse of alcohol, marijuana, heroin, cocaine, methamphetamine, and other drugs place the child at risk in multiple ways. Members of the medical community need to understand these risks because the medical community plays a unique and important role in identifying and caring for these children. Substance abuse includes the abuse of legal drugs as well as the use of illegal drugs. The abuse of legal substances may be just as detrimental to parental functioning as abuse of illicit substances. Many substance abusers are also polysubstance users and the compounded effect of the abuse of multiple substances may be difficult to measure. Often other interrelated social features, such as untreated mental illness, trauma history, and domestic violence, affect these families.

  13. Wheel-running mitigates psychomotor sensitization initiation but not post-sensitization conditioned activity and conditioned place preference induced by cocaine in mice.

    PubMed

    Geuzaine, Annabelle; Tirelli, Ezio

    2014-04-01

    Previous literature suggests that physical exercise allowed by an unlimited access to a running wheel for several weeks can mitigate chronic neurobehavioral responsiveness to several addictive drugs in rodents. Here, the potential preventive effects of unlimited wheel-running on the initiation of psychomotor sensitization and the acquisition and extinction of conditioned place preference (CPP) induced by 10 mg/kg cocaine in C56BL/6J mice were assessed in two independent experiments. To this end, half of the mice were singly housed with a running wheel at 28 days of age for 10 weeks prior to psychopharmacological tests, during which housing conditions did not change, and the other half of mice were housed without running wheel. In Experiment 1, prior to initiating sensitization, psychomotor activity on the two first drug-free once-daily sessions was not affected by wheel-running. This was also found for the acute psychomotor-activating effect of cocaine on the first sensitization session. Psychomotor sensitization readily developed over the 9 following once-daily sessions in mice housed without wheel, whereas it was inhibited in mice housed with a wheel. However, that difference did not transfer to post-sensitization conditioned activity. In contrast with the sensitization results, mice housed with a wheel still expressed a clear-cut CPP which did not extinguish differently from that of the other group, a result in disaccord with previous studies reporting either an attenuating or an increasing effect of wheel-running on cocaine-induced conditioned reward. The available results together indicate that interactions between wheel-running and cocaine effects are far from being satisfactorily characterized.

  14. Microinjection of the D2 agonist quinpirole into the A10 dopamine region blocks amphetamine-, but not cocaine-stimulated motor activity.

    PubMed

    Steketee, J D; Kalivas, P W

    1992-05-01

    Dopamine neurons in the ventral mesencephalon are under the inhibitory influence of dopamine D2 and gamma-aminobutyric acidB receptors. In a previous report, we demonstrated that intra-A10 injections of baclofen, a gamma-aminobutyric acidB agonist, could inhibit the motor-stimulant response to cocaine and amphetamine. In order to further extend these results, we examined the effects of injection of the D2 agonist quinpirole into the A10 region on cocaine- and amphetamine-stimulated motor activity. The results of this study showed that intra-A10 quinpirole dose-dependently decreased locomotor activity. In addition, an intra-A10 injection of 0.3 nmol/microliter quinpirole, a dose chosen for its near threshold effect, could block the motor-stimulant response to a low dose of amphetamine (0.5 mg/kg) and attenuate the response to moderate doses (1.0 and 2.0 mg/kg). Cocaine-stimulated motor activity, at all doses tested (7.5, 15.0 and 30.0 mg/kg), was not altered by intra-A10 quinpirole pretreatment. In vivo microdialysis revealed that quinpirole was unable to block the amphetamine-induced increase in extracellular dopamine concentrations within the nucleus accumbens, despite blocking the motor-stimulant response. It is suggested that the different mechanisms of action of cocaine and amphetamine, uptake blocker vs. releaser or longloop vs. shortloop feedback inhibition of A10 dopamine neurons, respectively, may account for the differential effects that quinpirole had in blocking the motor-stimulant response to these psychostimulants.

  15. 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

  16. Recreational drugs of abuse.

    PubMed

    Albertson, Timothy E

    2014-02-01

    The use of recreational drugs of abuse continues to expand without limitations to national boundaries, social status, race, or education. Beyond the prevalence of illicit drug use and dependence, their contribution to the global burden of disease and death are large and troubling. All medical providers should be aware of the evolving drugs of abuse and their medical and social consequences. In addition to heroin and stimulants such as cocaine and methamphetamine, new designer stimulants called "bath salts" and cannabinoids called "spice," along with the abuse of prescription drugs and volatile substances, are now widely recognized problems in many societies. The wide variety and continuingly expanding clinical manifestations of toxicity of recreational drugs of abuse is not widely appreciated by clinicians. This edition attempts to summarize six major classes of drugs of abuse and their clinical effects with special emphasis on their immunological and respiratory effects.

  17. Acute Cocaine Induces Fast Activation of D1 Receptor and Progressive Deactivation of D2 Receptor Strial Neurons: In Vivo Optical Microprobe [Ca(superscript)2+]subscript)i Imaging

    SciTech Connect

    Du, C.; Luo, Z.; Volkow, N.D.; Heintz, N.; Pan, Y.; Du, C.

    2011-09-14

    Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine's reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca{sup 2+}]{sub i} ) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R- versus D2R-expressing neurons in striatum. Acute cocaine (8 mg/kg, i.p.) rapidly increased [Ca{sup 2+}]{sub i} in D1R-expressing neurons (10.6 {+-} 3.2%) in striatum within 8.3 {+-} 2.3 min after cocaine administration after which the increases plateaued; these fast [Ca{sup 2+}]{sub i} increases were blocked by pretreatment with a D1R antagonist (SCH23390). In contrast, cocaine induced progressive decreases in [Ca{sup 2+}]{sub i} in D2R-expressing neurons (10.4 {+-} 5.8%) continuously throughout the 30 min that followed cocaine administration; these slower [Ca{sup 2+}]{sub i} decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R-expressing neurons (direct-pathway) enhances cocaine reward, whereas activation of D2R expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine's rewarding effects entail both its fast stimulation ofD1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer-lasting deactivation of indirect-pathway neurons). We also provide direct in vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration.

  18. Cocaine-induced vasculitis with cutaneous manifestation: A recurrent episode after 2 years

    PubMed Central

    Swe, Thein; Pervil-Ulysse, Mona; Baqui, AAM A.

    2016-01-01

    Cocaine is a popular recreational drug in the United States, and up to 70% of the seized cocaine contains levamisole which is an antihelminthic that can cause cutaneous vasculitis with necrosis and positive antineutrophil cytoplasmic antibodies (ANCAs). Here, we report a unique case of recurrent cocaine-induced vasculitis in a patient who smokes cocaine for more than 20 years. A 38-year-old woman complained of painful erythematous rash in her right arm and right thigh which appeared some hours after smoking cocaine. Physical examination revealed tender, erythematous base, retiform purpura with necrosis and bullae. Serological test showed high atypical perinuclear ANCA titer of 1:320 and antimyeloperoxidase antibody level of 20.4 U/mL. Cocaine-induced vasculitis should be one of the differential diagnoses in cocaine abusers who present with painful rash and areas of necrosis. Early diagnosis is important since it is an emerging public health concern. PMID:28217616

  19. Time-dependent changes in nicotine behavioral responsivity during early withdrawal from chronic cocaine administration and attenuation of cocaine sensitization by mecamylamine.

    PubMed

    Szabo, Steven T; Fowler, J C; Froeliger, Brett; Lee, Tong H

    2014-04-01

    Cocaine abuse is associated with a high prevalence of nicotine dependence. In animals, nicotinic antagonists have been reported to block the development of cocaine behavioral sensitization and to attenuate cocaine place preference or self-administration. In the present study, we have determined: (1) changes in the locomotor responses to nicotine challenge during the first week of withdrawal from daily cocaine pretreatment; and (2) effects of the non-selective nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine given during the first 5 days of cocaine withdrawal on the maintenance of cocaine behavioral sensitization. Male Sprague-Dawley rats were pretreated with daily saline (SI) or cocaine (CI) injections for 14 days. In Experiment 1, separate animals in the SI and CI groups received a single nicotine challenge on day 1, 3, or 7 of withdrawal from their respective pretreatments. The CI group displayed enhanced locomotor responses to nicotine as compared to SI controls on days 3 and 7 of withdrawal, but not day 1. In Experiment 2, SI and CI animals were treated once a day with either saline or mecamylamine during the first 5 days of withdrawal, and were subsequently challenged with single cocaine injections on both withdrawal days 7 and 14. Mecamylamine treatment significantly attenuated expression of cocaine behavioral sensitization on both withdrawal days 7 and 14. Time-dependent changes in nicotinic responses occur during the first week of cocaine withdrawal, and intact nAChR neurotransmission during this period may be necessary for maintenance of cocaine behavioral sensitization.

  20. Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter

    NASA Astrophysics Data System (ADS)

    Hauck Newman, Amy; Katz, Jonathan L.

    The dopamine transporter (DAT) has been a primary target for cocaine abuse/addiction medication discovery. However predicted addiction liability and limited clinical evaluation has provided a formidable challenge for development of these agents for human use. The unique and atypical pharmacological profile of the benztropine (BZT) class of dopamine uptake inhibitors, in preclinical models of cocaine effects and abuse, has encouraged further development of these agents. Moreover, in vivo studies have challenged the original DAT hypothesis and demonstrated that DAT occupancy and subsequent increases in dopamine produced by BZT analogues are significantly delayed and long lasting, as compared to cocaine. These important and distinctive elements are critical to the lack of abuse liability among BZT analogues, and improve their potential for development as treatments for cocaine abuse and possibly other neuropsychiatric disorders.

  1. Active-learning Strategies for Legal Topics and Substance Abuse in a Pharmacy Curriculum.

    PubMed

    Steinhardt, Sarah J; Clark, John E; Kelly, William N; Hill, Angela M

    2017-02-25

    Objective. To implement active-learning strategies to engage students in learning, applying, and teaching legal and substance abuse topics. Design. Medication Safety course student groups created films on a National Patient Safety Goal (NPSG) using a movie genre and presented them in film festival format. Pharmacogenomics course student groups taught ethical, legal, and social implications (ELSI) topics through presentation of short stories about comic book characters with genetic mutations. Students in the Drugs of Abuse course composed and performed dances depicting the mechanism of action of a drug in an in-class rave dance format. Assessment. Course evaluations revealed student engagement with subject material and enjoyment of the creative applications, critical thinking, and collaborative aspects of the activities. Students performed well on examination questions and graded assignments. Conclusion. These active-learning strategies facilitated students' abilities to learn, apply, and teach material in medication safety, pharmacogenomics, and substance abuse courses.

  2. Active-learning Strategies for Legal Topics and Substance Abuse in a Pharmacy Curriculum

    PubMed Central

    Clark, John E.; Kelly, William N.; Hill, Angela M.

    2017-01-01

    Objective. To implement active-learning strategies to engage students in learning, applying, and teaching legal and substance abuse topics. Design. Medication Safety course student groups created films on a National Patient Safety Goal (NPSG) using a movie genre and presented them in film festival format. Pharmacogenomics course student groups taught ethical, legal, and social implications (ELSI) topics through presentation of short stories about comic book characters with genetic mutations. Students in the Drugs of Abuse course composed and performed dances depicting the mechanism of action of a drug in an in-class rave dance format. Assessment. Course evaluations revealed student engagement with subject material and enjoyment of the creative applications, critical thinking, and collaborative aspects of the activities. Students performed well on examination questions and graded assignments. Conclusion. These active-learning strategies facilitated students’ abilities to learn, apply, and teach material in medication safety, pharmacogenomics, and substance abuse courses. PMID:28289294

  3. Crack users show high rates of antisocial personality disorder, engagement in illegal activities and other psychosocial problems.

    PubMed

    Paim Kessler, Felix Henrique; Barbosa Terra, Mauro; Faller, Sibele; Ravy Stolf, Anderson; Carolina Peuker, Ana; Benzano, Daniela; Pechansky, Flavio

    2012-01-01

    The aim of this study was to compare three groups of Brazilian psychoactive substance (PAS) abuse patients (crack cocaine users, cocaine snorters, and non-cocaine PAS users) in terms of psychiatric comorbidities and severity of psychosocial problems. A cross-sectional, multi-center study was conducted at five Brazilian research centers. A total of 738 current PAS abusers seeking specialized treatment (outpatient and inpatient clinics) were assessed using the sixth version of the Addiction Severity Index (ASI-6): 293 patients using crack cocaine were compared with 126 using powder cocaine and 319 using non-cocaine PAS (mostly alcohol and marijuana). Psychiatric comorbidities were assessed in a smaller sample (290 cases), originating from three of the centers, using the Mini International Neuropsychiatric Interview Plus (MINI-Plus). Crack and powder cocaine users were significantly younger than non-cocaine PAS users (31.1 ± 8.1 and 32.9 ± 8.8 vs. 42.4 ± 12, respectively; p < .001). Crack users presented a higher rate of antisocial personality disorder (25%) than powder cocaine (9%) and non-cocaine PAS users (9%), even when adjusted for confounding factors (Pr = 2.6; 95% CI 1.10-6.40). According to ASI-6 summary scores, crack users presented a significantly higher rate of occupational, family, and legal problems and reported more illegal and violent activities such as burglary and theft (23%) and threatening or assaulting (32%) than non-cocaine PAS users. Our findings, combined with the recent increase observed in the prevalence of crack use in Brazil, highlight the severity of psychiatric symptoms and psychosocial problems related to this powerful drug and corroborate the already suggested association between crack/cocaine, violence, and legal problems. Treatment programs for crack users should routinely consider the possibility of associated psychiatric comorbidities, such as antisocial personality disorder, which may affect treatment outcomes.

  4. Long-acting cocaine hydrolase for addiction therapy

    PubMed Central

    Chen, Xiabin; Xue, Liu; Hou, Shurong; Jin, Zhenyu; Zhang, Ting; Zheng, Fang; Zhan, Chang-Guo

    2016-01-01

    Cocaine abuse is a world-wide public health and social problem without a US Food and Drug Administration-approved medication. An ideal anticocaine medication would accelerate cocaine metabolism, producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Our recent studies have led to the discovery of the desirable, highly efficient cocaine hydrolases (CocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of the CNS. Preclinical and clinical data have demonstrated that these CocHs are safe for use in humans and are effective for accelerating cocaine metabolism. However, the actual therapeutic use of a CocH in cocaine addiction treatment is limited by its short biological half-life (e.g., 8 h or shorter in rats). Here we demonstrate a novel CocH form, a catalytic antibody analog, which is a fragment crystallizable (Fc)-fused CocH dimer (CocH-Fc) constructed by using CocH to replace the Fab region of human IgG1. The CocH-Fc not only has a high catalytic efficiency against cocaine but also, like an antibody, has a considerably longer biological half-life (e.g., ∼107 h in rats). A single dose of CocH-Fc was able to accelerate cocaine metabolism in rats even after 20 d and thus block cocaine-induced hyperactivity and toxicity for a long period. Given the general observation that the biological half-life of a protein drug is significantly longer in humans than in rodents, the CocH-Fc reported in this study could allow dosing once every 2–4 wk, or longer, for treatment of cocaine addiction in humans. PMID:26712009

  5. 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.

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

    SciTech Connect

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

    1992-01-01

    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. 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.

  7. Measuring collaboration and integration activities in criminal justice and substance abuse treatment agencies.

    PubMed

    Fletcher, Bennett; Lehman, Wayne; Wexler, Harry; Melnick, Gerald; Taxman, Faye; Young, Douglas

    2009-08-01

    Individuals with substance abuse problems who are involved in the criminal justice system frequently need community-based drug and alcohol abuse treatment and other services. To reduce the risk of relapse to illicit drugs and criminal recidivism, criminal justice agencies may need to establish collaborations with substance abuse treatment and other community-based service providers. Although there are many variations of interorganizational relationships, the nature of these interagency collaborations among justice agencies and treatment providers has received little systematic study. As a first step,we present an instrument to measure interagency collaboration and integration activities using items in the National Criminal Justice Treatment Practices Surveys conducted as part of the Criminal Justice Drug Abuse Treatment Studies(CJ-DATS). Collaboration and integration activities related to drug-involved offenders were examined between substance abuse treatment providers, correctional agencies, and the judiciary. The measurement scale reliably identified two levels of collaboration: less structured, informal networking and coordination and more structured and formalized levels of cooperation and collaboration. An illustration of the use of the systems integration tool is presented.

  8. Activation of mGluR7s inhibits cocaine-induced reinstatement of drug-seeking behavior by a nucleus accumbens glutamate-mGluR2/3 mechanism in rats.

    PubMed

    Li, Xia; Li, Jie; Gardner, Eliot L; Xi, Zheng-Xiong

    2010-09-01

    The metabotropic glutamate receptor 7 (mGluR7) has been reported to be involved in cocaine and alcohol self-administration. However, the role of mGluR7 in relapse to drug seeking is unknown. Using a rat relapse model, we found that systemic administration of AMN082, a selective mGluR7 allosteric agonist, dose-dependently inhibits cocaine-induced reinstatement of drug-seeking behavior. Intracranial microinjections of AMN082 into the nucleus accumbens (NAc) or ventral pallidum, but not the dorsal striatum, also inhibited cocaine-primed reinstatement, an effect that was blocked by local co-administration of MMPIP, a selective mGluR7 antagonist. In vivo microdialysis demonstrated that cocaine priming significantly increased extracellular dopamine in the NAc, ventral pallidum and dorsal striatum, while increasing extracellular glutamate in the NAc only. AMN082 alone failed to alter extracellular dopamine, but produced a slow-onset long-lasting increase in extracellular glutamate in the NAc only. Pre-treatment with AMN082 dose-dependently blocked both cocaine-enhanced NAc glutamate and cocaine-induced reinstatement, an effect that was blocked by MMPIP or LY341497 (a selective mGluR2/3 antagonist). These data suggest that mGluR7 activation inhibits cocaine-induced reinstatement of drug-seeking behavior by a glutamate-mGluR2/3 mechanism in the NAc. The present findings support the potential use of mGluR7 agonists for the treatment of cocaine addiction.

  9. Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism.

    PubMed

    McCutcheon, James E; Loweth, Jessica A; Ford, Kerstin A; Marinelli, Michela; Wolf, Marina E; Tseng, Kuei Y

    2011-10-12

    Following prolonged withdrawal from extended access cocaine self-administration in adult rats, high conductance Ca2+ -ermeable AMPA receptors (CP-AMPARs) accumulate in nucleus accumbens (NAc) synapses and mediate the expression of "incubated" cue-induced cocaine craving. Using patch-clamp recordings from NAc slices prepared after extended access cocaine self-administration and >45 d of withdrawal, we found that group I metabotropic glutamate receptor (mGluR) stimulation using 3,5-dihydroxyphenylglycine (DHPG; 50 μm) rapidly eliminates the postsynaptic CP-AMPAR contribution to NAc synaptic transmission. This is accompanied by facilitation of Ca2+ -impermeable AMPAR (CI-AMPAR)-mediated transmission, suggesting that DHPG may promote an exchange between CP-AMPARs and CI-AMPARs. In saline controls, DHPG also reduced excitatory transmission but this occurred through a CB1 receptor-dependent presynaptic mechanism rather than an effect on postsynaptic AMPARs. Blockade of CB1 receptors had no significant effect on the alterations in AMPAR transmission produced by DHPG in the cocaine group. Interestingly, the effect of DHPG in the cocaine group was mediated by mGluR1 whereas its effect in the saline group was mediated by mGluR5. These results indicate that regulation of synaptic transmission in the NAc is profoundly altered after extended access cocaine self-administration and prolonged withdrawal. Furthermore, they suggest that activation of mGluR1 may represent a potential strategy for reducing cue-induced cocaine craving in abstinent cocaine addicts.

  10. Parental Substance Abuse and the Nature of Child Maltreatment.

    ERIC Educational Resources Information Center

    Famularo, Richard; And Others

    1992-01-01

    Randomly selected juvenile court records (n=190) of cases of child maltreatment found that 67 percent involved parents who were substance abusers. Specific associations were found between (1) alcohol abuse and physical maltreatment, and (2) cocaine abuse and sexual maltreatment. (Author/DB)

  11. Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

    PubMed

    Leri, Francesco; Zhou, Yan; Goddard, Benjamin; Cummins, Erin; Kreek, Mary Jeanne

    2006-07-01

    Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

  12. Skf 525-A induces cocaine N-demethylase, ethoxyresorufin O-deethylase, and pentoxyresorufin O-dealkylase activities by induction of cytochrome p-450 2B in female B6C3F1 mice.

    PubMed

    Jeong, Tae Cheon; Chang, Hyeun Wook; Lee, Eung Seok; Jeon, Tae Won; Jeong, Hye Gwang; Holsapple, Michael P

    2004-12-01

    Studies demonstrated that cocaine-induced immunosuppression is mediated by metabolites of cocaine. Although SKF 525-A inhibited cocaine N-demethylation in liver S9 fractions isolated from female B6C3F1 mice, our study showed that pretreatment of mice with SKF 525-A potentiated cocaine-induced suppression of the antibody response to sheep red blood cells. An increase in formaldehyde generation was subsequently shown following incubation of cocaine with the S9 fractions prepared from SKF 525-A-treated mice, indicating the possibility of cytochrome P-450 (CYP) induction. Therefore, the inductive effects of SKF 525-A on CYP enzyme activities and proteins were investigated in female B6C3F1 mice to elucidate the potentiation of cocaine-induced immunosuppression by SKF 525-A. When SKF 525-A was administered at 10, 20, or 40 mg/kg/d intraperitoneally for 7 consecutive days, both ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase activities were induced dose-dependently. Furthermore, the induction of enzymatic activity was time dependent. Meanwhile, when the type of isozyme induced by SKF 525-A was analyzed by Western immunoblotting with monospecific anti-CYP 1A and anti-CYP 2B antibodies, only the CYP 2B appeared to be induced. From in vitro inhibition studies with monoclonal antibodies, it was confirmed that the induced activity of ethoxyresorufin O-deethylase by SKF 525-A was due to increased levels of CYP 2B proteins. Our present results provide an explanation for the potentiation of cocaine-induced immunosuppression by repeated exposure to SKF 525-A. Our results also indicate that ethoxyresorufin O-deethylase, a selective substrate for CYP 1A, may also be catalyzed by CYP 2B.

  13. 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.

  14. 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

  15. 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.

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

    PubMed

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

    2016-08-30

    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.

  17. fMRI of Cocaine Self-Administration in Macaques Reveals Functional Inhibition of Basal Ganglia

    PubMed Central

    Mandeville, Joseph B; Choi, Ji-Kyung; Jarraya, Bechir; Rosen, Bruce R; Jenkins, Bruce G; Vanduffel, Wim

    2011-01-01

    Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion. PMID:21307843

  18. Enhanced morphine- and cocaine-induced behavioral sensitization in alcohol-preferring AA rats.

    PubMed

    Honkanen, A; Mikkola, J; Korpi, E R; Hyytiä, P; Seppälä, T; Ahtee, L

    1999-03-01

    Locomotor stimulation and behavioral sensitization induced by acute and repeated treatment with alcohol, cocaine or morphine were studied in the alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-Alcohol) rats and non-selected Wistar rats. Daily treatment with alcohol (ethanol, 0.4 or 1.0 g/kg, IP) for 6 days had no effect on locomotor activity either in the AA or ANA rats. Acute cocaine (5, 10 or 20 mg/kg, IP) produced a locomotor stimulation in the animals of all lines studied, and there was no difference in this effect between the AA and ANA rats. During a 4-day repeated cocaine treatment, the AA rats became sensitized with the 10 mg/kg dose, while the ANA rats did not show any sensitization with this dose. With the 20 mg/kg cocaine dose, in addition to locomotor stimulation, the rats of all lines studied showed stereotyped behavior, which response was enhanced during repeated treatment. Morphine-induced locomotor stimulation was larger in the AA rats than in the ANA or Wistar rats both with 1.0 and 3.0 mg/kg doses and only the AA rats were sensitized during 4-day treatment with the 1 mg/kg dose. With the 3.0 mg/kg morphine dose, only the AA rats showed a weak sensitization evident only during the initial 30 min after morphine injection. As the drug-induced behavioral sensitization is an important factor in the development of drug addiction, it is possible that mechanisms underlying the enhanced susceptibility of the AA rats to morphine- and cocaine-induced sensitization contribute to the high intake of alcohol and other abused drugs by these animals.

  19. Cocaine- or stress-induced metaplasticity of LTP in the dorsal and ventral hippocampus.

    PubMed

    Keralapurath, Madhusudhanan M; Clark, Jason K; Hammond, Sherri; Wagner, John J

    2014-05-01

    Despite the well documented role of the hippocampus in various modes of drug reinstatement behavior, the persisting effects of in vivo cocaine exposure on hippocampal synaptic plasticity are not sufficiently understood. In this report we investigated the effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of hippocampus along its septotemporal axis. Male Sprague-Dawley rats experienced a behavioral protocol, in which locomotor activity was monitored in response to various conditioning treatments. LTP was measured in ex vivo slice preparations taken 1-2 weeks after the last behavioral session from the ventral (vH) and dorsal (dH) sectors of hippocampus. Unexpectedly, experiencing the minor intermittent stimuli of the behavioral protocol caused stress-induced metaplastic changes in both vH (increased LTP) and dH (decreased LTP) in the saline conditioned rats relative to behaviorally naïve controls. These stress effects in the vH and dH were blocked by conditioning with either mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) antagonists, respectively. Stress-induced metaplasticity in the vH was also prevented by prior administration of the kappa opioid antagonist nor-binaltorphimine. Cocaine conditioning induced locomotor sensitization and significantly increased LTP in the vH without causing significant change in LTP in the dH. Cocaine-induced metaplasticity in the vH was prevented by co-administration of the dopamine D2-like antagonist eticlopride during cocaine conditioning, but not by co-administration of the D1/5 antagonist SCH 23390. Our results suggest that the functional connectivity of hippocampus is altered by metaplastic triggers such as exposure to drugs of abuse and/or stressors, thereby shifting the efferent output of hippocampus from dH (cortical) toward vH (limbic) influenced circuits.

  20. Variations in the stimulus salience of cocaine reward influences drug-associated contextual memory.

    PubMed

    Liddie, Shervin; Itzhak, Yossef

    2016-03-01

    Drugs of abuse act as reinforcers because they influence learning and memory processes resulting in long-term memory of drug reward. We have previously shown that mice conditioned by fixed daily dose of cocaine (Fix-C) or daily escalating doses of cocaine (Esc-C) resulted in short- and long-term persistence of drug memory, respectively, suggesting different mechanisms in acquisition of cocaine memory. The present study was undertaken to investigate the differential contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the formation of Fix-C and Esc-C memory in C57BL/6J mice. Training by Esc-C resulted in marked elevation in hippocampal expression of Grin2b mRNA and NR2B protein levels compared with training by Fix-C. The NR2B-containing NMDAR antagonist ifenprodil had similar attenuating effects on acquisition and reconsolidation of Fix-C and Esc-C memory. However, the NMDAR antagonist MK-801 had differential effects: (1) higher doses of MK-801 were required for post-retrieval disruption of reconsolidation of Esc-C memory than Fix-C memory; and (2) pre-retrieval MK-801 inhibited extinction of Fix-C memory but it had no effect on Esc-C memory. In addition, blockade of NMDAR downstream signaling pathways also showed differential regulation of Fix-C and Esc-C memory. Inhibition of neuronal nitric oxide synthase attenuated acquisition and disrupted reconsolidation of Fix-C but not Esc-C memory. In contrast, the mitogen-activating extracellular kinase inhibitor SL327 attenuated reconsolidation of Esc-C but not Fix-C memory. These results suggest that NMDAR downstream signaling molecules associated with consolidation and reconsolidation of cocaine-associated memory may vary upon changes in the salience of cocaine reward during conditioning.

  1. Combined Effects of Simultaneous Exposure to Caffeine and Cocaine in the Mouse Striatum.

    PubMed

    Muñiz, Javier A; Gomez, Gimena; González, Betina; Rivero-Echeto, María Celeste; Cadet, Jean Lud; García-Rill, Edgar; Urbano, Francisco J; Bisagno, Veronica

    2016-05-01

    Caffeine is the world's most popular psychoactive drug and is also an active adulterant found in many drugs of abuse, including seized cocaine samples. Despite several studies which examine the effects of caffeine or cocaine administered as single agents, little data are available for these agents when given in combination. The purpose of the present study was to determine if combined intake of both psychostimulants can lead to maladaptive changes in striatal function. Mice were injected with a binge regimen (intermittent treatment for 13 days) of caffeine (3 × 5 mg/kg), cocaine (3 × 10 mg/kg), or combined administration. We found that chronic caffeine potentiated locomotion induced by cocaine and that both caffeine-treated groups showed sensitization. Striatal tissue was obtained 24 h and 7 days after last injection (withdrawal) for immunohistochemistry and mRNA expression. Our results show that combined intake of both psychostimulants can increase GFAP immunoreactivity in the striatum at both times post treatment. Gene expression analysis, targeted at dopamine, adenosine, and glutamate receptor subunit genes, revealed significant transcript down-regulation in the dorsal striatum of AMPA, NMDA, D1 and D2 receptor subunit mRNA expression in the group that received combined treatment, but not after individual administration. At withdrawal, we found increased D1 receptor mRNA expression along with increased A1, AMPA, NMDA, and metabotropic subunit expression. A2A mRNA showed decreased expression after both times in all experimental groups. Our study provides evidence that there are striatal alterations mediated by combined caffeine and cocaine administration, and highlights negative outcomes of chronic intake of both psychostimulants.

  2. Exposure to chronic mild stress prevents kappa opioid-mediated reinstatement of cocaine and nicotine place preference.

    PubMed

    Al-Hasani, Ream; McCall, Jordan G; Bruchas, Michael R

    2013-01-01

    Stress increases the risk of drug abuse, causes relapse to drug seeking, and potentiates the rewarding properties of both nicotine and cocaine. Understanding the mechanisms by which stress regulates the rewarding properties of drugs of abuse provides valuable insight into potential treatments for drug abuse. Prior reports have demonstrated that stress causes dynorphin release, activating kappa opioid receptors (KOR) in monoamine circuits resulting in both potentiation and reinstatement of cocaine and nicotine conditioned place preference. Here we report that kappa opioid-dependent reinstatement of cocaine and nicotine place preference is reduced when the mice are exposed to a randomized chronic mild stress (CMS) regime prior to training in a conditioned place preference-reinstatement paradigm. The CMS schedule involves seven different stressors (removal of nesting for 24 h, 5 min forced swim stress at 15°C, 8 h food and water deprivation, damp bedding overnight, white noise, cage tilt, and disrupted home cage lighting) rotated over a 3-week period. This response is KOR-selective, as CMS does not protect against cocaine or nicotine drug-primed reinstatement. This protection from reinstatement is also observed following sub-chronic social defeat stress, where each mouse is placed in an aggressor mouse home cage for a period of 20 min over 5 days. In contrast, a single acute stressor resulted in a potentiation of KOR-induced reinstatement, as previously reported. Prior studies have shown that stress alters sensitivity to opioids and prior stress can influence the pharmacodynamics of the opioid receptor system. Together, these findings suggest that exposure to different forms of stress may cause a dysregulation of kappa opioid circuitry and that changes resulting from mild stress can have protective and adaptive effects against drug relapse.

  3. Lesture Less And Listen More...A Laboratory, Activity Oriented Unit On Drug Abuse

    ERIC Educational Resources Information Center

    Spaulding, Jerry; Munch, Theodore W.

    1973-01-01

    Describes a drug unit which uses videotape interviews to: (1) motivate adolescents to develop positive attitudes toward drug abuse; (2) increase student participation in classroom activities; (3) use appropriate science exercises to further understandings; and (4) permit students to work on things of personal interest. (Author/CJ)

  4. Cocaine and the heart

    PubMed Central

    Egred, M; Davis, G

    2005-01-01

    Cocaine is the second commonest illicit drug used and the most frequent cause of drug related deaths. Its use is associated with both acute and chronic complications that may involve any system, the most common being the cardiovascular system. Cocaine misuse has a major effect in young adult drug users with resulting loss of productivity and undue morbidity with cocaine related cardiac and cerebrovascular effects. Many cocaine users have little or no idea of the risks associated with its use. Patients, health care professionals, and the public should be educated about the dangers and the considerable risks of cocaine use. This review concentrates on the cardiovascular effects of cocaine and their management. PMID:16143686

  5. 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).

  6. Cocaine-Induced Vasculitis

    PubMed Central

    Berman, Mark; Paran, Daphna; Elkayam, Ori

    2016-01-01

    The use of cocaine continues to grow worldwide. One of the possible side-effects of cocaine is vasculitis. Two distinct vasculitic syndromes have been described due to cocaine. One is cocaine-induced midline destructive lesion, secondary to a direct vasoconstrictor effect of cocaine, inducing ischemic necrosis of the septal cartilage and perforation of the nasal septum, mimicking findings of granulomatosis with polyangiitis in the upper airways. The other is ANCA-associated vasculitis, attributed to the levamisole component that contaminates about 70% of the cocaine. This type of vasculitis may be myeloperoxidase (MPO) and proteinase 3 (PR3) positive, and its main manifestations are typical cutaneous findings, arthralgia, otolaryngologic involvement, and agranulocytosis. A high degree of suspicion and awareness is needed in order properly to diagnose and treat these patients. PMID:27824551

  7. Prevention of the incubation of cocaine seeking by aerobic exercise in female rats

    PubMed Central

    Zlebnik, Natalie E.; Carroll, Marilyn E.

    2015-01-01

    BACKGROUND Recent research has demonstrated that aerobic exercise can attenuate craving for drugs of abuse and reduce escalation and reinstatement of drug-seeking behavior in animal models. The present study examined the effects of aerobic exercise on the development of the incubation of cocaine-seeking behavior or the progressive increase in cocaine seeking over a protracted withdrawal period from cocaine self-administration. METHODS Female rats were trained to self-administer cocaine (0.4 mg/kg/inf) during daily 6-h sessions for 10 days. Subsequently, access to cocaine and cocaine-paired cues was discontinued during a 3- or 30-day withdrawal period when rats had access to either a locked or unlocked running wheel. At the end of the withdrawal period, rats were reintroduced to the operant conditioning chamber and reexposed to cocaine-paired cues to examine cocaine-seeking behavior under extinction conditions. RESULTS Rats with access to a locked running wheel during 30 days of withdrawal had significantly greater cue-induced cocaine-seeking behavior than rats that had access to an unlocked running wheel for 30 days. Further, there was robust incubation of cocaine seeking in rats with access to a locked running wheel as cocaine seeking was notably elevated at 30 vs. 3 days of withdrawal. However, cocaine-seeking behavior did not differ between rats with access to an unlocked running wheel for 30 vs. 3 days, indicating that incubation of cocaine seeking was suppressed following access to exercise for 30 days. CONCLUSION Aerobic exercise during extended withdrawal from cocaine self-administration decreased incubation of cue-induced cocaine-seeking behavior and may reduce vulnerability to relapse. PMID:26159456

  8. Vaccines against drug abuse.

    PubMed

    Shen, X Y; Orson, F M; Kosten, T R

    2012-01-01

    The currently available medications for the treatment of drug abuse have had only limited success. Anti-addiction vaccines, aimed at eliciting antibodies that block the pharmacological effects of drugs, have great potential for treating drug abuse. We review the status of two vaccines that are undergoing clinical trials (for cocaine and nicotine addiction) and two that are still in preclinical development (for methamphetamine and heroin addiction). We also outline the challenges and ethical concerns associated with the development of anti-addiction vaccines and their use as future therapeutics.

  9. 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

  10. Correlation between cocaine prices and purity with trends in emergency department visits in a major metropolitan area.

    PubMed

    Zhu, He; Wilson, Fernando A; Stimpson, Jim P; Pagán, José A

    2014-10-01

    Illicit drug use not only causes acute and chronic adverse health outcomes but also results in a significant burden to health care providers. The objective of this study is to examine the relationship between cocaine prices and purity with emergency department (ED) visits for the Chicago-Naperville-Joliet metropolitan area. Our primary outcome was number of cocaine-related ED visits per quarter provided by the Drug Abuse Warning Network. The predictor variables of cocaine purity and price were provided by the System to Retrieve Information from Drug Evidence database. Autoregressive integrated moving average (ARIMA) regressions were used to estimate the effects of cocaine price and purity on cocaine-related ED visits. Although cocaine prices did not change substantially over time, cocaine purity decreased by over 30 % between 2006 and 2010. ARIMA regression results suggest that cocaine-related ED visits were not significantly associated with powder or crack cocaine prices; however, a decrease in powder cocaine purity was associated with 2,081 fewer ED visits overall from 2007 to 2010. The cocaine trade continues to be a major public health and law enforcement threat to large metropolitan cities like Chicago. Regular monitoring of cocaine purity levels may provide early warning of impending changes in cocaine-related ED visits for law enforcement and health care providers.

  11. Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice.

    PubMed

    Kelley, Brian M; Rowan, James D

    2004-01-01

    Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first

  12. Medical consequences of cocaine.

    PubMed Central

    Gray, J. D.

    1993-01-01

    Cocaine use among middle-class North Americans increased dramatically during the 1980s. Medical complications involve almost every organ system and are produced by intense vasoconstriction. Managing cocaine-induced disease requires careful identification and the use of alpha-adrenergic blocking agents, in addition to standard therapy and referral to specialists to manage cocaine withdrawal. Images p1976-a p1980-a PMID:8106032

  13. Cocaine Enhances HIV-1–Induced CD4+ T-Cell Apoptosis

    PubMed Central

    Pandhare, Jui; Addai, Amma B.; Mantri, Chinmay K.; Hager, Cynthia; Smith, Rita M.; Barnett, Louis; Villalta, Fernando; Kalams, Spyros A.; Dash, Chandravanu

    2015-01-01

    Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1–associated CD4+ T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4+ T cells from HIV-1–negative and HIV-1–positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4+ T cells with cocaine (up to 100 μmol/L concentrations) did not induce apoptosis, but 200 to 1000 μmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4+ T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4+ T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4+ T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1–infected drug abusers. PMID:24486327

  14. Differential regulation of MeCP2 and PP1 in passive or voluntary administration of cocaine or food.

    PubMed

    Bodetto, Sarah Pol; Romieu, Pascal; Sartori, Maxime; Tesone-Coelho, Carolina; Majchrzak, Monique; Barbelivien, Alexandra; Zwiller, Jean; Anglard, Patrick

    2014-12-01

    Cocaine exposure induces changes in the expression of numerous genes, in part through epigenetic modifications. We have initially shown that cocaine increases the expression of the chromatin remodeling protein methyl-CpG binding protein 2 (MeCP2) and characterized the protein phosphatase-1Cβ (PP1Cβ) gene, as repressed by passive i.p. cocaine injections through a Mecp2-mediated mechanism involving de novo DNA methylation. Both proteins being involved in learning and memory processes, we investigated whether voluntary cocaine administration would similarly affect their expression using an operant self-administration paradigm. Passive and voluntary i.v. cocaine intake was found to induce Mecp2 and to repress PP1Cβ in the prefrontal cortex and the caudate putamen. This observation is consistent with the role of Mecp2 acting as a transcriptional repressor of PP1Cβ and shows that passive intake was sufficient to alter their expression. Surprisingly, striking differences were observed under the same conditions in food-restricted rats tested for food pellet delivery. In the prefrontal cortex and throughout the striatum, both proteins were induced by food operant conditioning, but remained unaffected by passive food delivery. Although cocaine and food activate a common reward circuit, changes observed in the expression of other genes such as reelin and GAD67 provide new insights into molecular mechanisms differentiating neuroadaptations triggered by each reinforcer. The identification of hitherto unknown genes differentially regulated by drugs of abuse and a natural reinforcer should improve our understanding of how two rewarding stimuli differ in their ability to drive behavior.

  15. 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.

  16. Mesolimbic leptin signaling negatively regulates cocaine-conditioned reward

    PubMed Central

    Shen, M; Jiang, C; Liu, P; Wang, F; Ma, L

    2016-01-01

    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 Leprflox/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. PMID:27922639

  17. 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

  18. Effects of chronic buspirone treatment on cocaine self-administration.

    PubMed

    Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J; Bergman, Jack

    2013-02-01

    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.

  19. Cocaine withdrawal in Planaria.

    PubMed

    Raffa, R B; Valdez, J M

    2001-10-26

    Cocaine-exposed planarians displayed abstinence-induced withdrawal behavior when placed into cocaine-free, but not cocaine-containing, water. The effect, manifested and quantified using a new spontaneous locomotor velocity metric, was dose-dependently related to cocaine exposure (8x10(-9) to 8x10(-5) M). Ultraviolet light (254 nm=7.83x10(-19) J), which was previously shown to interfere with drug-receptor interactions in Planaria, enhanced the abstinence-induced decreased locomotor velocity.

  20. Voucher-based reinforcement of cocaine abstinence in treatment-resistant methadone patients: effects of reinforcement magnitude.

    PubMed

    Silverman, K; Chutuape, M A; Bigelow, G E; Stitzer, M L

    1999-09-01

    Voucher-based reinforcement of cocaine abstinence has been one of the most effective means of treating cocaine abuse in methadone patients, but it has not been effective in all patients. This study was designed to determine if we could promote cocaine abstinence in a population of treatment-resistant cocaine abusing methadone patients by increasing the magnitude of voucher-based abstinence reinforcement. Participants were 29 methadone patients who previously failed to achieve sustained cocaine abstinence when exposed to an intervention in which they could earn up to $1155 in vouchers (exchangeable for goods/services) for providing cocaine-free urines. Each patient was exposed in counterbalanced order to three 9-week voucher conditions that varied in magnitude of voucher reinforcement. Patients were exposed to a zero, low and high magnitude condition in which they could earn up to $0, $382, or $3480 in vouchers for providing cocaine-free urines. Analyses for 22 patients exposed to all three conditions showed that increasing voucher magnitude significantly increased patients' longest duration of sustained cocaine abstinence (P<0.001) and percent of cocaine-free urines (P<0.001), and significantly decreased patients' reports of cocaine injections (P=0.024). Almost half (45%) of the patients in the high magnitude condition achieved >/=4 weeks of sustained cocaine abstinence, whereas only one patient in the low and none in the zero magnitude condition achieved more than 2 weeks. Reinforcement magnitude was a critical determinant of the effectiveness of this abstinence reinforcement intervention.

  1. Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.

    PubMed

    Wang, Huikun; Treadway, Tyler; Covey, Daniel P; Cheer, Joseph F; Lupica, Carl R

    2015-09-29

    Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.

  2. Cocaine Use and Splenic Rupture: A Rare Yet Serious Association

    PubMed Central

    Karthik, Nishrutha; Gnanapandithan, Karthik

    2016-01-01

    Cocaine abuse is frequent in patients visiting the emergency department. The knowledge of the cardiovascular complications of cocaine is excellent among physicians. However the awareness regarding its abdominal complications, the most important of which include gastroduodenal perforation, bowel ischemia and splenic rupture is less adequate. We report a 58-year-old with cocaine use who presents with upper abdominal pain and a rapidly worsening clinical status. He was found to have atraumatic splenic rupture causing a hemoperitoneum that was managed by intervention radiology guided splenic artery embolization. Splenic hemorrhage and rupture need timely recognition, as they are difficult to diagnose clinically and can be potentially fatal. In the encounter of patients with cocaine use who present with chest or upper abdominal pain, clinicians should consider imaging to look for splenic rupture as it is often masked or overlooked due to the complicated clinical picture. PMID:27777711

  3. Periadolescent nicotine exposure causes heterologous sensitization to cocaine reinforcement.

    PubMed

    McMillen, Brian A; Davis, Barbara J; Williams, Helen L; Soderstrom, Ken

    2005-02-21

    There is increasing concern that abuse of tobacco during periadolescence increases the potential for later abuse of other drugs. To test this hypothesis, Sprague-Dawley rats received once-daily injections of either water or 0.4 mg/kg nicotine from postnatal day 35 through 44. Beginning on postnatal day 80, animals were tested in a 12-day cocaine-induced conditioned place preference (CPP) paradigm. Prior nicotine treatment enhanced the dose-response to cocaine. CPP training with 3.0 mg/kg i.p. cocaine increased time in drug-paired chambers by 50% in control rats and 94% in nicotine-exposed animals. Thus, periadolescent nicotine exposure produced long-term sensitization to an indirect-acting dopamine agonist.

  4. Effects of prenatal cocaine on hearing, vision, growth, and behavior.

    PubMed

    Church, M W; Crossland, W J; Holmes, P A; Overbeck, G W; Tilak, J P

    1998-06-21

    The illicit use of cocaine has increased dramatically over the last 10-12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of "cocaine babies." According to some estimates, these children make up more than half of the drug-associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre- and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.

  5. Structural analysis of thermostabilizing mutations of cocaine esterase

    SciTech Connect

    Narasimhan, Diwahar; Nance, Mark R.; Gao, Daquan; Ko, Mei-Chuan; Macdonald, Joanne; Tamburi, Patricia; Yoon, Dan; Landry, Donald M.; Woods, James H.; Zhan, Chang-Guo; Tesmer, John J.G.; Sunahara, Roger K.

    2010-09-03

    Cocaine is considered to be the most addictive of all substances of abuse and mediates its effects by inhibiting monoamine transporters, primarily the dopamine transporters. There are currently no small molecules that can be used to combat its toxic and addictive properties, in part because of the difficulty of developing compounds that inhibit cocaine binding without having intrinsic effects on dopamine transport. Most of the effective cocaine inhibitors also display addictive properties. We have recently reported the use of cocaine esterase (CocE) to accelerate the removal of systemic c