Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence.

PubMed

Haller, Gabe; Kapoor, Manav; Budde, John; Xuei, Xiaoling; Edenberg, Howard; Nurnberger, John; Kramer, John; Brooks, Andy; Tischfield, Jay; Almasy, Laura; Agrawal, Arpana; Bucholz, Kathleen; Rice, John; Saccone, Nancy; Bierut, Laura; Goate, Alison

2014-02-01

Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actually with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 × 10(-4)) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 × 10(-4)) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276; H329Y) shows association with both cocaine dependence symptoms (P = 7.4 × 10(-5), β = 2.04) and alcohol dependence symptoms (P = 2.6 × 10(-4), β = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006). These are the first results to implicate rare variants in CHRNB3 or CHRNA3 in risk for alcohol dependence or cocaine dependence.

Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence

PubMed Central

Haller, Gabe; Kapoor, Manav; Budde, John; Xuei, Xiaoling; Edenberg, Howard; Nurnberger, John; Kramer, John; Brooks, Andy; Tischfield, Jay; Almasy, Laura; Agrawal, Arpana; Bucholz, Kathleen; Rice, John; Saccone, Nancy; Bierut, Laura; Goate, Alison

2014-01-01

Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actually with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 × 10−4) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 × 10−4) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276; H329Y) shows association with both cocaine dependence symptoms (P = 7.4 × 10−5, β = 2.04) and alcohol dependence symptoms (P = 2.6 × 10−4, β = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006). These are the first results to implicate rare variants in CHRNB3 or CHRNA3 in risk for alcohol dependence or cocaine dependence. PMID:24057674

Prenatal coke: what's behind the smoke? Prenatal cocaine/alcohol exposure and school-age outcomes: the SCHOO-BE experience.

PubMed

Delaney-Black, V; Covington, C; Templin, T; Ager, J; Martier, S; Compton, S; Sokol, R

1998-06-21

Despite media reports and educators' concerns, little substantive data have been published to document or refute the emerging reports that children prenatally exposed to cocaine have serious behavioral problems in school. Recent pilot data from this institution have indeed demonstrated teacher-reported problem behaviors following prenatal cocaine exposure after controlling for the effects of prenatal alcohol use and cigarette exposure. Imperative in the study of prenatal exposure and child outcome is an acknowledgement of the influence of other control factors such as postnatal environment, secondary exposures, and parenting issues. We report preliminary evaluation from a large ongoing historical prospective study of prenatal cocaine exposure on school-age outcomes. The primary aim of this NIDA-funded study is to determine if a relationship exists between prenatal cocaine/alcohol exposures and school behavior and, if so, to determine if the relationship is characterized by a dose-response relationship. A secondary aim evaluates the relationship between prenatal cocaine/alcohol exposures and school achievement. Both relationships will be assessed in a black, urban sample of first grade students using multivariate statistical techniques for confounding as well as mediating and moderating prenatal and postnatal variables. A third aim is to evaluate the relationship between a general standardized classroom behavioral measure and a tool designed to tap the effects thought to be specific to prenatal cocaine exposure. This interdisciplinary research team can address these aims because of the existence of a unique, prospectively collected perinatal Database, funded in part by NIAAA and NICHD. The database includes repeated measures of cocaine, alcohol, and other substances for over 3,500 births since 1986. Information from this database is combined with information from the database of one of the largest public school systems in the nation. The final sample will be

Cocaine

MedlinePlus

... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter ... The Brain & the Actions of Cocaine, Opioids and Marijuana The first in a 5-part series, offers ...

Stress system changes associated with marijuana dependence may increase craving for alcohol and cocaine

PubMed Central

Fox, Helen C.; Tuit, Keri L.; Sinha, Rajita

2013-01-01

Objective To date, little research exists defining bio-behavioral adaptations associated with both marijuana abuse and risk of craving and relapse to other drugs of abuse during early abstinence. Method Fifty-nine treatment-seeking individuals dependent on alcohol and cocaine were recruited. Thirty of these individuals were also marijuana (MJ) dependent; 29 were not. Twenty-six socially drinking healthy controls were also recruited. All participants were exposed to three 5-min guided imagery conditions (stress, alcohol/cocaine cue and relaxing), presented randomly, one per day across three consecutive days. Measures of craving, anxiety, heart rate, blood pressure, plasma adrenocorticotrophic hormone and cortisol were collected at baseline and subsequent recovery time points. Results The MJ-dependent group showed increased basal anxiety ratings and cardiovascular output alongside enhanced alcohol craving and cocaine craving, and dampened cardiovascular response to stress and cue. They also demonstrated elevated cue-induced anxiety and stress-induced cortisol and adrenocorticotrophic hormone levels, which were not observed in the non-MJ-dependent group or controls. Cue-related alcohol craving and anxiety were both predictive of a shorter number of days to marijuana relapse following discharge from inpatient treatment. Conclusions Findings provide some support for drug cross-sensitization in terms of motivational processes associated with stress-related and cue-related craving and relapse. PMID:23280514

Crack-cocaine users have less family cohesion than alcohol users.

PubMed

Marchi, Nino C; Scherer, Juliana N; Pachado, Mayra P; Guimarães, Luciano S; Siegmund, Gerson; de Castro, Melina N; Halpern, Silvia; Benzano, Daniela; Formigoni, Maria L; Cruz, Marcelo; Pechansky, Flavio; Kessler, Felix H

2017-01-01

Many studies correlate characteristics of family functioning and the development of drug addiction. This study sought to evaluate and compare the family environment styles of two groups of psychoactive substance users: 1) alcohol-only users and 2) crack-cocaine users. Three hundred and sixty-four users of alcohol, crack-cocaine, and other drugs, recruited from research centers in four Brazilian capitals participated in this study. Subjects were evaluated through the Family Environment Scale and the Addiction Severity Index, 6th version (ASI-6). ASI-6 t-scores were compared by analysis of variance (ANOVA) and post-hoc tests. A final model was obtained using a logistic regression analysis. All analyses were adjusted for partner, age, and psychiatric t-score. We found a significant difference between groups in the cohesion subscale (p = 0.044). The post-hoc test revealed a difference of 1.06 points (95%CI 0.11-2.01) between groups 1 (6.45±0.28) and 2 (5.38±0.20). No significant between-group differences were observed in the other subscales. However, categorical analyses of variables regarding family dynamic showed that crack users more often reported that sometimes people in their family hit each other (30.4% vs. 13.2%, p = 0.007) and that people in their family frequently compared each other regarding work and/or school achievement (57.2% vs. 42.6%, p = 0.041). These results suggest that families of crack-cocaine users are less cohesive than families of alcohol users. This type of family environment may affect treatment outcome, and should thus be adequately approached.

The effects of perceived quality on the behavioural economics of alcohol, amphetamine, cannabis, cocaine, and ecstasy purchases.

PubMed

Cole, Jon C; Goudie, Andrew J; Field, Matt; Loverseed, Anne-Claire; Charlton, Sarah; Sumnall, Harry R

2008-04-01

Previous research has indicated that non-dependent polydrug users are willing to pay more money to buy good quality drugs as their income increased. This study sought to examine whether altering the perceived quality of controlled drugs would affect drug purchases if the monetary price remained fixed. A random sample of 80 polydrug users were recruited. All participants were administered an anonymous questionnaire consisting of the Drug Abuse Screening Test for Adolescents (DAST-A), the Severity of Dependence Scale for cannabis (SDS), the Alcohol Use Disorders Identification Test (AUDIT), the Hospital Anxiety and Depression Scale (HADS), and questions about their drug use. Participants then completed a simulation of controlled drug purchases where the price of alcohol, amphetamine, cannabis, cocaine, and ecstasy remained the same but their perceived quality changed (i.e. unit price increased as the perceived quality decreased). The demand for alcohol was quality inelastic and alcohol quality had no effects on the purchase of any other controlled drug. Demand for cannabis was quality elastic and alcohol substituted for cannabis as its unit price increased. Demand for cocaine was quality elastic and alcohol, cannabis, and ecstasy substituted for cocaine as its unit price increased. Demand for ecstasy was quality elastic and alcohol and cocaine both substituted for ecstasy as its unit price increased. These results suggest that perceived quality influences the demand for controlled drugs and that monitoring the perceived quality of controlled drugs may provide a warning of potential public health problems in the near future.

Personality risk factors for cocaine abuse.

PubMed

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

1989-07-01

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

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.

Mediators of Telephone-Based Continuing Care for Alcohol and Cocaine Dependence

ERIC Educational Resources Information Center

Mensinger, Janell Lynn; Lynch, Kevin G.; Tenhave, Thomas R.; McKay, James R.

2007-01-01

A previous randomized trial with 224 alcohol and/or cocaine addicts who had completed an initial phase of treatment indicated that 12 weeks of telephone-based continuing care yielded higher abstinence rates over 24 months than did group counseling continuing care. The current study examined mediators of this treatment effect. Results suggested…

Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat.

PubMed

de Guglielmo, Giordano; Cippitelli, Andrea; Somaini, Lorenzo; Gerra, Gilberto; Li, Hongwu; Stopponi, Serena; Ubaldi, Massimo; Kallupi, Marsida; Ciccocioppo, Roberto

2013-07-01

Pregabalin (Lyrica™) is a structural analog of γ-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse.

PubMed

Vengeliene, Valentina; Cannella, Nazzareno; Takahashi, Tatiane; Spanagel, Rainer

2016-09-01

The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway. An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse-the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue-induced reinstatement of alcohol- and cocaine-seeking behaviour. Our results show that relapse-like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine-seeking behaviour was also abolished by administration of Ro61-8048. Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic/NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts.

Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.

PubMed

Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie

2017-09-01

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse. © 2016 Society for the Study of Addiction.

Cost-Effectiveness of Peer-Delivered Interventions for Cocaine and Alcohol Abuse among Women: A Randomized Controlled Trial

PubMed Central

Prah Ruger, Jennifer; Abdallah, Arbi Ben; Luekens, Craig; Cottler, Linda

2012-01-01

Aims To determine whether the additional interventions to standard care are cost-effective in addressing cocaine and alcohol abuse at 4 months (4 M) and 12 months (12 M) from baseline. Method We conducted a cost-effectiveness analysis of a randomized controlled trial with three arms: (1) NIDA's Standard intervention (SI); (2) SI plus a Well Woman Exam (WWE); and, (3) SI, WWE, plus four Educational Sessions (4ES). Results To obtain an additional cocaine abstainer, WWE compared to SI cost $7,223 at 4 M and $3,611 at 12 M. Per additional alcohol abstainer, WWE compared to SI cost $3,611 and $7,223 at 4 M and 12 M, respectively. At 12 M, 4ES was dominated (more costly and less effective) by WWE for abstinence outcomes. Conclusions To our knowledge, this is the first cost-effectiveness analysis simultaneously examining cocaine and alcohol abuse in women. Depending on primary outcomes sought and priorities of policy makers, peer-delivered interventions can be a cost-effective way to address the needs of this growing, underserved population. Trial Registration ClinicalTrials.gov NCT01235091 PMID:22448255

Perceptions of Risk as Predictors of Alcohol, Marijuana, and Cocaine Use among College Students.

ERIC Educational Resources Information Center

Gonzalez, Gerardo M.; Haney, Michael L.

1990-01-01

Examined relationship of perception of risk regarding the use of alcohol, marijuana, and cocaine to use of these substances by college students (N=242). Determined perceptions of risk significantly predicted usage patterns and attitudes toward the use of various drugs. (Author/ABL)

Reductions in alcohol and cocaine use following a group coping intervention for HIV-positive adults with childhood sexual abuse histories.

PubMed

Meade, Christina S; Drabkin, Anya S; Hansen, Nathan B; Wilson, Patrick A; Kochman, Arlene; Sikkema, Kathleen J

2010-11-01

Few interventions exist to reduce alcohol and non-injection drug use among people living with HIV/AIDS. This study tested the effects of a coping group intervention for HIV-positive adults with childhood sexual abuse histories on alcohol, cocaine and marijuana use. Participants were assigned randomly to the experimental coping group or a time-matched comparison support group. Both interventions were delivered in a group format over 15 weekly 90-minute sessions. A diverse sample of 247 HIV-positive men and women with childhood sexual abuse were recruited from AIDS service organizations and community health centers in New York City. Substance use was assessed pre- and post-intervention and every 4 months during a 12-month follow-up period. Using an intent-to-treat analysis, longitudinal changes in substance use by condition were assessed using generalized estimating equations. At baseline, 42% of participants drank alcohol, 26% used cocaine and 26% used marijuana. Relative to participants in the support group, those in the coping group had greater reductions in quantity of alcohol use (Wald χ²(₄)=10.77, P = 0.029) and any cocaine use (Wald χ²(₄) = 9.81, P = 0.044) overtime. Many HIV patients, particularly those with childhood sexual abuse histories, continue to abuse substances. This group intervention that addressed coping with HIV and sexual trauma was effective in reducing alcohol and cocaine use, with effects sustained at 12-month follow-up. Integrating mental health treatment into HIV prevention may improve outcomes. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age‐related loss of slow wave, stage 3 sleep

PubMed Central

Bjurstrom, Martin F.; Olmstead, Richard

2016-01-01

Abstract Background and aims Sleep disturbance is a prominent complaint in cocaine and alcohol dependence. This controlled study evaluated differences of polysomnographic (PSG) sleep in cocaine‐ and alcohol‐dependent subjects, and examined whether substance dependence interacts with age to alter slow wave sleep and rapid eye movement (REM) sleep. Design Cross‐sectional comparison. Setting Los Angeles and San Diego, CA, USA. Participants Abstinent cocaine‐dependent subjects (n = 32), abstinent alcohol‐dependent subjects (n = 73) and controls (n = 108); mean age 40.3 years recruited 2005–12. Measurements PSG measures of sleep continuity and sleep architecture primary outcomes of Stage 3 sleep and REM sleep. Covariates included age, ethnicity, education, smoking, body mass index and depressive symptoms. Findings Compared with controls, both groups of substance dependent subjects showed loss of Stage 3 sleep (P < 0.001). A substance dependence × age interaction was found in which both cocaine‐ and alcohol‐dependent groups showed loss of Stage 3 sleep at an earlier age than controls (P < 0.05 for all), and cocaine‐dependent subjects showed loss of Stage 3 sleep at an earlier age than alcoholics (P < 0.05). Compared with controls, REM sleep was increased in both substance‐dependent groups (P < 0.001), and cocaine and alcohol dependence were associated with earlier age‐related increase in REM sleep (P < 0.05 for all). Conclusions Cocaine and alcohol dependence appear to be associated with marked disturbances of sleep architecture, including increased rapid eye movement sleep and accelerated age‐related loss of slow wave, Stage 3 sleep. PMID:26749502

Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence.

PubMed

Kendler, Kenneth S; Myers, John; Prescott, Carol A

2007-11-01

Although genetic risk factors have been found to contribute to dependence on both licit and illicit psychoactive substances, we know little of how these risk factors interrelate. To clarify the structure of genetic and environmental risk factors for symptoms of dependence on cannabis, cocaine, alcohol, caffeine, and nicotine in males and females. Lifetime history by structured clinical interview. General community. Four thousand eight hundred sixty-five members of male-male and female-female pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measure Lifetime symptoms of abuse of and dependence on cannabis, cocaine, alcohol, caffeine, and nicotine. Controlling for greater symptom prevalence in males, genetic and environmental parameters could be equated across sexes. Two models explained the data well. The best-fit exploratory model contained 2 genetic factors and 1 individual environmental factor contributing to all substances. The first genetic factor loaded strongly on cocaine and cannabis dependence; the second, on alcohol and nicotine dependence. Nicotine and caffeine had high substance-specific genetic effects. A confirmatory model, which also fit well, contained 1 illicit drug genetic factor--loading only on cannabis and cocaine--and 1 licit drug genetic factor loading on alcohol, caffeine, and nicotine. However, these factors were highly intercorrelated (r = + 0.82). Large substance-specific genetic effects remained for nicotine and caffeine. The pattern of genetic and environmental risk factors for psychoactive substance dependence was similar in males and females. Genetic risk factors for dependence on common psychoactive substances cannot be explained by a single factor. Rather, 2 genetic factors-one predisposing largely to illicit drug dependence, the other primarily to licit drug dependence-are needed. Furthermore, a large proportion of the genetic influences on nicotine and particularly caffeine dependence

The Neuropsychology of Cocaine Addiction: Recent Cocaine Use Masks Impairment

PubMed Central

Woicik, Patricia A; Moeller, Scott J; Alia-Klein, Nelly; Maloney, Thomas; Lukasik, Tanya M; Yeliosof, Olga; Wang, Gene-Jack; Volkow, Nora D; Goldstein, Rita Z

2009-01-01

Individuals with current cocaine use disorders (CUD) form a heterogeneous group, making sensitive neuropsychological (NP) comparisons with healthy individuals difficult. The current study examined the effects on NP functioning of four factors that commonly vary among CUD: urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Sixty-four cocaine abusers were matched to healthy comparison subjects on gender and race; the groups also did not differ in measures of general intellectual functioning. All subjects were administered an extensive NP battery measuring attention, executive function, memory, facial and emotion recognition, and motor function. Compared with healthy control subjects, CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. The current findings replicate a previously reported statistically significant, but relatively mild NP impairment in CUD as compared with matched healthy control individuals and further suggest that frequent/recent cocaine may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition, without negatively impacting mood in individuals addicted to cocaine. PMID:18496524

The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.

PubMed

Kaag, A M; Schulte, M H J; Jansen, J M; van Wingen, G; Homberg, J; van den Brink, W; Wiers, R W; Schmaal, L; Goudriaan, A E; Reneman, L

2018-06-01

Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use. In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine. Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively. These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Heroin and cocaine abusers have higher discount rates for delayed rewards than alcoholics or non-drug-using controls.

PubMed

Kirby, Kris N; Petry, Nancy M

2004-04-01

To test a prediction of the discounting model of impulsiveness that discount rates would be positively associated with addiction. The delay-discount rate refers to the rate of reduction in the present value of a future reward as the delay to that reward increases. We estimated participants' discount rates on the basis of their pattern of choices between smaller immediate rewards ($11-80) and larger, delayed rewards ($25-85; at delays from 1 week to 6 months) in a questionnaire format. Participants had a one-in-six chance of winning a reward that they chose on one randomly selected trial. Heroin (n = 27), cocaine (n = 41) and alcohol (n = 33) abusers and non-drug-using controls (n = 44) were recruited from advertisements. They were tested in a drug abuse research clinic at a medical school. On average, the cocaine and heroin groups had higher rates than controls (both P < 0.001), but alcoholics did not (P = 0.44). Abstinence was associated with lower rates for heroin abusers (P = 0.03), but not for cocaine or alcohol abusers (both P > 0.50). These data suggest that discount rates vary with the preferred drug of abuse, and that high discount rates should be considered in the development of substance abuse prevention and treatment efforts.

Prenatal and postnatal cocaine exposure predict teen cocaine use

PubMed Central

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

2015-01-01

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

Demand Curves for Hypothetical Cocaine in Cocaine-Dependent Individuals

PubMed Central

Bruner, Natalie R.; Johnson, Matthew W.

2013-01-01

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

Demand curves for hypothetical cocaine in cocaine-dependent individuals.

PubMed

Bruner, Natalie R; Johnson, Matthew W

2014-03-01

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

Prenatal and postnatal cocaine exposure predict teen cocaine use.

PubMed

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

2011-01-01

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

Longer treatment with alternative non-drug reinforcement fails to reduce resurgence of cocaine or alcohol seeking in rats.

PubMed

Nall, Rusty W; Craig, Andrew R; Browning, Kaitlyn O; Shahan, Timothy A

2018-04-02

Provision of alternative non-drug reinforcement is among the most effective methods for treating substance use disorders. However, when alternative reinforcers become unavailable during treatment interruptions or upon cessation of treatment, relapse often occurs. Relapse following the loss of alternative reinforcement is known as resurgence. One factor that could reduce resurgence is longer duration of treatment with alternative reinforcement, but the available data are mixed. Further, the effects of length of treatment have previously only been examined with food seeking. The present experiments directly examined if duration of treatment impacted the magnitude of resurgence of cocaine or alcohol seeking in rats. First, rats were trained to self-administer cocaine (Experiment 1) or alcohol (Experiment 2) by performing a target behavior. Second, target behavior was extinguished and performing an alternative behavior produced an alternative non-drug (i.e., food) reinforcer. Finally, resurgence was assessed following removal of alternative reinforcement after either 5 or 20 sessions of treatment. Treatment duration did not differentially affect resurgence of cocaine seeking in Experiment 1 or Alcohol seeking in Experiment 2. These results suggest that extended treatment with alternative non-drug reinforcement may not decrease propensity to relapse. Further, these results may have implications for treatment of substance use disorders and for theories of resurgence. Copyright © 2017 Elsevier B.V. All rights reserved.

Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana.

PubMed

Rivkin, Michael J; Davis, Peter E; Lemaster, Jennifer L; Cabral, Howard J; Warfield, Simon K; Mulkern, Robert V; Robson, Caroline D; Rose-Jacobs, Ruth; Frank, Deborah A

2008-04-01

The objective of this study was to use volumetric MRI to study brain volumes in 10- to 14-year-old children with and without intrauterine exposure to cocaine, alcohol, cigarettes, or marijuana. Volumetric MRI was performed on 35 children (mean age: 12.3 years; 14 with intrauterine exposure to cocaine, 21 with no intrauterine exposure to cocaine) to determine the effect of prenatal drug exposure on volumes of cortical gray matter; white matter; subcortical gray matter; cerebrospinal fluid; and total parenchymal volume. Head circumference was also obtained. Analyses of each individual substance were adjusted for demographic characteristics and the remaining 3 prenatal substance exposures. Regression analyses adjusted for demographic characteristics showed that children with intrauterine exposure to cocaine had lower mean cortical gray matter and total parenchymal volumes and smaller mean head circumference than comparison children. After adjustment for other prenatal exposures, these volumes remained smaller but lost statistical significance. Similar analyses conducted for prenatal ethanol exposure adjusted for demographics showed significant reduction in mean cortical gray matter; total parenchymal volumes; and head circumference, which remained smaller but lost statistical significance after adjustment for the remaining 3 exposures. Notably, prenatal cigarette exposure was associated with significant reductions in cortical gray matter and total parenchymal volumes and head circumference after adjustment for demographics that retained marginal significance after adjustment for the other 3 exposures. Finally, as the number of exposures to prenatal substances grew, cortical gray matter and total parenchymal volumes and head circumference declined significantly with smallest measures found among children exposed to all 4. CONCLUSIONS; These data suggest that intrauterine exposures to cocaine, alcohol, and cigarettes are individually related to reduced head

College students' use of cocaine.

PubMed

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

2006-01-01

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

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

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

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

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

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

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

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

We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series ofmore » PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.« less

Methamphetamine Cured my Cocaine Addiction

PubMed Central

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

2011-01-01

Cocaine dependence is an enduring problem and years of research and drug development has yet to produce an efficacious pharmacotherapy. Recent clinical research suggests that chronic treatment with amphetamine-like medications produces tolerance to cocaine’s reinforcing effects and may offer a viable pharmacotherapy. Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously addicted to cocaine are reviewed. Data obtained from initial screen and informal conversation suggested that all participants considered methamphetamine to have helped them stop using cocaine and eliminate cocaine craving. Methamphetamine also significantly decreased their alcohol consumption but did not alter cannabis or nicotine use. PMID:23066512

Temperament and character traits associated with the use of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens: evidence from a large Brazilian web survey.

PubMed

Schneider, Ricardo; Ottoni, Gustavo L; de Carvalho, Hudson W; Elisabetsky, Elaine; Lara, Diogo R

2015-01-01

To evaluate how personality traits are associated with occasional use, abuse, and dependence of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens in a large availability sample of adults via online questionnaires. The sample consisted of 8,646 individuals (24.7% men and 75.3% women) who completed an anonymous web survey. Involvement with drugs and temperament/character traits were assessed through the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Temperament and Character Inventory - Revised (TCI-R), respectively. Interactions among variables were analyzed using MANOVA with Bonferroni adjustment. Novelty seeking was the trait most associated with increased involvement with alcohol, cannabis, and cocaine. There was a significant association between harm avoidance and benzodiazepine use. Persistence was lower in cannabis-, benzodiazepine-, and cocaine-dependent subjects, as well as in hallucinogen abusers. Self-directedness was reduced in dependents of all drug classes. No strong relationships were found between other temperament or character dimensions and the severity of drug use. Novelty seeking was associated with increased involvement with all drugs studied in this sample, although to a lesser extent with benzodiazepines and hallucinogens. The temperament and character profile for benzodiazepine use was different from that of other drugs due to the relationship with higher harm avoidance and self-transcendence and lower self-directedness.

Snow Control - An RCT protocol for a web-based self-help therapy to reduce cocaine consumption in problematic cocaine users

PubMed Central

2011-01-01

Background Cocaine use has increased in most European countries, including Switzerland, and many states worldwide. The international literature has described treatment models that target the general population. In addition to supplying informative measures at the level of primary and secondary prevention, the literature also offers web-based self-help tools for problematic substance users, which is in line with tertiary prevention. Such programs, however, have been primarily tested on individuals with problematic alcohol and cannabis consumption, but not on cocaine-dependent individuals. Methods/Design This paper presents the protocol of a randomised clinical trial to test the effectiveness of a web-based self-help therapy to reduce cocaine use in problematic cocaine users. The primary outcome is severity of cocaine dependence. Secondary outcome measures include cocaine craving, consumption of cocaine and other substances of abuse in the past month, and changes in depression characteristics. The therapy group will receive a 6-week self-help therapy to reduce cocaine consumption based on methods of Cognitive Behavioural Therapy, principles of Motivational Interviewing and self-control practices. The control group will be presented weekly psycho-educative information with a quiz. The predictive validity of participant characteristics on treatment retention and outcome will be explored. Discussion To the best of our knowledge, this will be the first randomised clinical trial to test the effectiveness of online self-help therapy to reduce or abstain from cocaine use. It will also investigate predictors of outcome and retention. This trial is registered at Current Controlled Trials and is traceable as NTR-ISRCTN93702927. PMID:21943294

Neural correlates of the severity of cocaine, heroin, alcohol, MDMA and cannabis use in polysubstance abusers: a resting-PET brain metabolism study.

PubMed

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

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. 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. 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. 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.

Social Behavior of Offspring Following Prenatal Cocaine Exposure in Rodents: A Comparison with Prenatal Alcohol

PubMed Central

Sobrian, Sonya K.; Holson, R. R.

2011-01-01

Clinical and experimental reports suggest that prenatal cocaine exposure (PCE) alters the offsprings’ social interactions with caregivers and conspecifics. Children exposed to prenatal cocaine show deficits in caregiver attachment and play behavior. In animal models, a developmental pattern of effects that range from deficits in play and social interaction during adolescence, to aggressive reactions during competition in adulthood is seen. This review will focus primarily on the effects of PCE on social behaviors involving conspecifics in animal models. Social relationships are critical to the developing organism; maternally directed interactions are necessary for initial survival. Juvenile rats deprived of play behavior, one of the earliest forms of non-mother directed social behaviors in rodents, show deficits in learning tasks and sexual competence. Social behavior is inherently complex. Because the emergence of appropriate social skills involves the interplay between various conceptual and biological facets of behavior and social information, it may be a particularly sensitive measure of prenatal insult. The social behavior surveyed include social interactions, play behavior/fighting, scent marking, and aggressive behavior in the offspring, as well as aspects of maternal behavior. The goal is to determine if there is a consensus of results in the literature with respect to PCE and social behaviors, and to discuss discrepant findings in terms of exposure models, the paradigms, and dependent variables, as well as housing conditions, and the sex and age of the offspring at testing. As there is increasing evidence that deficits in social behavior may be sequelae of developmental exposure alcohol, we compare changes in social behaviors reported for prenatal alcohol with those reported for prenatal cocaine. Shortcomings in the both literatures are identified and addressed in an effort to improve the translational value of future experimentation. PMID:22144967

Level of In Utero Cocaine Exposure and Neonatal Ultrasound Findings

PubMed Central

Frank, Deborah A.; McCarten, Kathleen M.; Robson, Caroline D.; Mirochnick, Mark; Cabral, Howard; Park, Henry; Zuckerman, Barry

2008-01-01

Objective To assess whether there is an association between the level of in utero cocaine exposure and findings on neonatal cranial ultrasound, controlling for potentially confounding variables. Study Design In a prospective longitudinal study, three cocaine exposure groups were defined by maternal report and infant meconium assay: unexposed, heavier cocaine exposure (>75th percentile self-reported days of use or of meconium benzoylecogonine concentration) or lighter cocaine exposure (all others). Neonatal ultrasounds from 241 well, term infants were read by a single radiologist who was masked to the exposure group. Results Infants with lighter cocaine exposure did not differ from the unexposed infants on any ultrasound findings. After controlling for infant gender, gestational age, and birth weight z scores and for maternal parity, blood pressure in labor, ethnicity, and use of cigarettes, alcohol, and marijuana during pregnancy, the more heavily cocaine-exposed infants were more likely than the unexposed infants to show subependymal hemorrhage in the caudothalamic groove (covariate adjusted odds ratio: 3.88; 95% confidence interval: 1.45, 10.35). Conclusions This is the first study to demonstrate that ultrasound findings suggestive of vascular injury to the neonatal central nervous system are related to the level of prenatal cocaine exposure. Inconsistency in previous research in identifying an association between prenatal cocaine exposure and neonatal cranial ultrasound findings may reflect failure to consider dose effects. PMID:10545554

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

PubMed

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

2012-10-01

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

Main mental disorders in crack-cocaine users treated at Psychosocial Care Centers for Alcohol and Drugs in the city of Recife, Brazil.

PubMed

Castro, Antonio Gomes de; Silva, Diego César Nunes da; Figueiroa, Magda da Silva

2016-01-01

Brazil's Northeast region has the highest crack-cocaine consumption in the country. Crack-cocaine has more intense effects than cocaine powder and can cause greater chemical dependence. Psychosocial Care Centers for Alcohol and Drugs (CAPSad) are public health services that provide treatment for drug dependence. It is common for drug users, and particularly crack-cocaine users, to develop mental disorders. Objective: To evaluate the most common mental disorders in crack-cocaine dependents in treatment at CAPSad in the city of Recife, Brazil. The research database "Between rocks and shots: user profiles, consumption strategies, and social impact of crack cocaine" (CEP/CCS/UFPE no. 206/11) was consulted to establish the areas of crack cocaine consumption in the city of Recife. There were 885 patients in treatment for crack-cocaine use, with a mean age of 29.8±9.4 years. The mean duration of drug use was 6.1±4.6 years. Most of the patients were males (80.3%), had left school at some point between the 1st and 9th grades (45.6%), were unemployed and/or seeking employment (52%) and used drugs daily (56.4%). Cocaine chemical dependence was more significant when correlated with use of crack-cocaine and other drugs such as medications and hallucinogens (p = 0.01). Data from this study showed strong associations between crack-cocaine uses and development of mental disorders, particularly when abuse of multiple substances occurs. Based on these data, there is a clear need for coordination of related public policies for support and social reintegration to provide these people with comprehensive care.

Lifestyle Differences between Young Adult Cocaine Users and Their Nonuser Peers.

ERIC Educational Resources Information Center

Castro, Felipe G.; And Others

1987-01-01

Examined health-related behaviors in 25 young adult cocaine users and 25 matched nonusers. Found cocaine users consumed more coffee and alcohol, and fewer balanced meals, than did nonusers. Users reported less relaxation and daily organization than did nonusers. Suggests that cocaine use is embedded in complex of interrelated unhealthy behaviors;…

The effects of price and perceived quality on the behavioural economics of alcohol, amphetamine, cannabis, cocaine, and ecstasy purchases.

PubMed

Goudie, Andrew J; Sumnall, Harry R; Field, Matt; Clayton, Hannah; Cole, Jon C

2007-07-10

Behavioural economic models of substance use describe the relationship between changes in unit price and consumption. However, these models rarely take account of the perceived quality (i.e. potency) of controlled drugs. Therefore we investigated the effects of both price and quality on the decision to purchase controlled drugs by polysubstance misusers. Forty current polysubstance misusers (29 males, 11 females; mean age 23.8) were recruited into the study. Participants were asked to hypothetically purchase drugs from a price list of alcohol, amphetamine, cannabis, cocaine and ecstasy at different levels of quality and price (i.e. better quality drugs cost more money). The disposable income available for those purchases was systematically varied in order to determine the impact of income on the decision to purchase drugs. Demand for both normal and strong alcohol was income inelastic. Demand for both poor and average quality cannabis and ecstasy was income inelastic, but demand for good quality cannabis and ecstasy was income elastic. The demand for poor quality cocaine was income inelastic, with the demand for both average and good quality cocaine being income elastic. Participants reported too few purchases of amphetamine, which precluded behavioural economic analysis. These results suggest that, like other goods, controlled drugs are purchased based upon the consumer's interpretations of their relative value. Therefore, it is probable that the purchase and subsequent use of controlled drugs by polysubstance misusers will be heavily influenced by the economic environment.

Cocaine use may induce telomere shortening in individuals with HIV infection.

PubMed

Lai, Shenghan; Heaphy, Christopher M; Rizzo, Anthony J; Celentano, David D; Gerstenblith, Gary; Li, Ji; Moore, Richard D; Treisman, Glenn; Chen, Shaoguang; Foster, Parker; Kickler, Thomas; Lai, Hong

2018-06-08

Although cocaine use may induce/accelerate HIV-associated comorbidities in HIV-infected individuals on antiretroviral therapy (ART), and that HIV itself may accelerate aging, the issue of whether cocaine use plays a role in HIV-associated aging in HIV-infected cocaine users has not been reported. The goals of this study were (1) to explore factor(s) associated with peripheral blood leukocyte telomere length, a marker of cellular replicative history, and telomere shortening in HIV-infected individuals, and (2) to assess whether cocaine use plays a role in accelerating telomere shortening in cocaine users with HIV infection. Between June 2010 and December 2016, 147 HIV-infected participants in Baltimore, Maryland, were enrolled in a cross-sectional study investigating factor(s) associated with telomere length. Of these 147, 93 participated in a follow-up study to examine factor(s) associated with telomere shortening. Robust regression model was used to analyze cross-sectional data and the generalized estimating equation approach was used to analyze follow-up data. Cross-sectional analyses demonstrated that (1) both daily alcohol consumption and use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were independently associated with telomere length, and cocaine use modified the associations of daily alcohol use and NNRTI use with telomere length. Longitudinal analyses suggested that both daily alcohol consumption and duration of NNRTI use were independently associated with telomere shortening, and (2) cocaine use induced/accelerated telomere shortening in HIV-infected individuals. Our findings suggest that cocaine use may promote premature aging in HIV-infected individuals who are on ART. Our results emphasize the importance of cocaine abstinence/reduced use, which may retard HIV-associated premature aging. Copyright © 2018 Elsevier Inc. All rights reserved.

Chronic Inhibition of Dopamine β-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

PubMed Central

Gaval-Cruz, Meriem; Liles, Larry Cameron; Iuvone, Paul Michael; Weinshenker, David

2012-01-01

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors. PMID:23209785

Gene x Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

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

Alia-Klein, N.; Alia-Klein, N.; Parvaz, M.A.

Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. The objective is to examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles).more » The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis x MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. The results are: (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls; (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use; and (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.« less

Executive control deficits in substance-dependent individuals: a comparison of alcohol, cocaine, and methamphetamine and of men and women.

PubMed

van der Plas, Ellen A A; Crone, Eveline A; van den Wildenberg, Wery P M; Tranel, Daniel; Bechara, Antoine

2009-08-01

Substance dependence is associated with executive function deficits, but the nature of these executive defects and the effect that different drugs and sex have on these defects have not been fully clarified. Therefore, we compared the performance of alcohol- (n = 33; 18 women), cocaine- (n = 27; 14 women), and methamphetamine-dependent individuals (n = 38; 25 women) with sex-matched healthy comparisons (n = 36; 17 women) on complex decision making as measured with the Iowa Gambling Task, working memory, cognitive flexibility, and response inhibition. Cocaine- and methamphetamine-dependent individuals were impaired on complex decision making, working memory, and cognitive flexibility, but not on response inhibition. The deficits in working memory and cognitive flexibility were milder than the decision-making deficits and did not change as a function of memory load or task switching. Interestingly, decision making was significantly more impaired in women addicted to cocaine or methamphetamine than in men addicted to these drugs. Together, these findings suggest that drug of choice and sex have different effects on executive functioning, which, if replicated, may help tailor intervention.

Early adolescent cocaine use as determined by hair analysis in a prenatal cocaine exposure cohort

PubMed Central

Warner, Tamara Duckworth; Behnke, Marylou; Eyler, Fonda Davis; Szabo, Nancy J.

2010-01-01

Background Preclinical and other research suggest that youth with prenatal cocaine exposure (PCE) may be at high risk for cocaine use due to both altered brain development and exposure to unhealthy environments. Methods Participants are early adolescents who were prospectively enrolled in a longitudinal study of PCE prior to or at birth. Hair samples were collected from the youth at ages 10½ and 12½ (N=263). Samples were analyzed for cocaine and its metabolites using ELISA screening with gas chromatography/mass spectroscopy (GC/MS) confirmation of positive samples. Statistical analyses included comparisons between the hair-positive and hair-negative groups on risk and protective factors chosen a priori as well as hierarchical logistical regression analyses to predict membership in the hair-positive group. Results Hair samples were positive for cocaine use for 14% (n=36) of the tested cohort. Exactly half of the hair-positive preteens had a history of PCE. Group comparisons revealed that hair-negative youth had significantly higher IQ scores at age 10½; the hair-positive youth had greater availability of cigarettes, alcohol, and other drugs in the home; caregivers with more alcohol problems and depressive symptoms; less nurturing home environments; and less positive attachment to their primary caregivers and peers. The caregivers of the hair-positive preteens reported that the youth displayed more externalizing and social problems, and the hair-positive youth endorsed more experimentation with cigarettes, alcohol, and/or other drugs. Mental health problems, peer drug use, exposure to violence, and neighborhood characteristics did not differ between the groups. Regression analyses showed that the availability of drugs in the home had the greatest predictive value for hair-positive group membership while higher IQ, more nurturing home environments, and positive attachment to caregivers or peers exerted some protective effect. Conclusion The results do not support a

Enhanced Choice for Viewing Cocaine Pictures in Cocaine Addiction

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

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

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

Anticonvulsants for cocaine dependence.

PubMed

Minozzi, Silvia; Cinquini, Michela; Amato, Laura; Davoli, Marina; Farrell, Michael F; Pani, Pier Paolo; Vecchi, Simona

2015-04-17

Cocaine dependence is a major public health problem that is characterised by recidivism and a host of medical and psychosocial complications. Although effective pharmacotherapy is available for alcohol and heroin dependence, none is currently available for cocaine dependence, despite two decades of clinical trials primarily involving antidepressant, anticonvulsivant and dopaminergic medications. Extensive consideration has been given to optimal pharmacological approaches to the treatment of individuals with cocaine dependence, and both dopamine antagonists and agonists have been considered. Anticonvulsants have been candidates for use in the treatment of addiction based on the hypothesis that seizure kindling-like mechanisms contribute to addiction. To evaluate the efficacy and safety of anticonvulsants for individuals with cocaine dependence. We searched the Cochrane Drugs and Alcohol Group Trials Register (June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1966 to June 2014), EMBASE (1988 to June 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2014), Web of Science (1991 to June 2014) and the reference lists of eligible articles. All randomised controlled trials and controlled clinical trials that focus on the use of anticonvulsant medications to treat individuals with cocaine dependence. We used the standard methodological procedures expected by The Cochrane Collaboration. We included a total of 20 studies with 2068 participants. We studied the anticonvulsant drugs carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate and vigabatrin. All studies compared anticonvulsants versus placebo. Only one study had one arm by which the anticonvulsant was compared with the antidepressant desipramine. Upon comparison of anticonvulsant versus placebo, we found no significant differences for any of the efficacy and safety measures. Dropouts: risk ratio (RR) 0.95, 95

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

PubMed Central

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

2012-01-01

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

Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues.

PubMed

George, M S; Anton, R F; Bloomer, C; Teneback, C; Drobes, D J; Lorberbaum, J P; Nahas, Z; Vincent, D J

2001-04-01

Functional imaging studies have recently demonstrated that specific brain regions become active in cocaine addicts when they are exposed to cocaine stimuli. To test whether there are regional brain activity differences during alcohol cue exposure between alcoholic subjects and social drinkers, we designed a functional magnetic resonance imaging (fMRI) protocol involving alcohol-specific cues. Ten non-treatment-seeking adult alcoholic subjects (2 women) (mean [SD] age, 29.9 [9.9] years) as well as 10 healthy social drinking controls of similar age (2 women) (mean [SD] age, 29.4 [8.9] years) were recruited, screened, and scanned. In the 1.5-T magnetic resonance imaging scanner, subjects were serially rated for alcohol craving before and after a sip of alcohol, and after a 9-minute randomized presentation of pictures of alcoholic beverages, control nonalcoholic beverages, and 2 different visual control tasks. During picture presentation, changes in regional brain activity were measured with the blood oxygen level-dependent technique. Alcoholic subjects, compared with the social drinking subjects, reported higher overall craving ratings for alcohol. After a sip of alcohol, while viewing alcohol cues compared with viewing other beverage cues, only the alcoholic subjects had increased activity in the left dorsolateral prefrontal cortex and the anterior thalamus. The social drinkers exhibited specific activation only while viewing the control beverage pictures. When exposed to alcohol cues, alcoholic subjects have increased brain activity in the prefrontal cortex and anterior thalamus-brain regions associated with emotion regulation, attention, and appetitive behavior.

Cocaine abuse and its treatment.

PubMed

Resnick, R B; Resnick, E B

1984-12-01

Increasing numbers of individuals with a diagnosis of cocaine abuse (DSM-III, 305.6) are seeking medical and psychiatric care. The majority of users inhale the drug in powdered form, as cocaine is rapidly absorbed by mucous membranes. The patterns of use resemble those for the use of alcohol and marijuana: recreational, intensified, circumstantial, and compulsive. When cocaine is taken intravenously or by freebasing, individuals are much more vulnerable to developing a compulsive pattern of use that could lead to an organic delusional syndrome. Cocaine causes systemic effects that are similar to those of amphetamine, but they have a much shorter duration of action. Blood pressure, heart rate, feelings of "pleasantness" and "stimulation" are increased, and hunger is decreased. Acute tolerance may develop over hours of continuous use, but it disappears after a short period of abstinence (overnight). In psychomotor testing, performance that is impaired by fatigue is restored to baseline levels. Users like cocaine because they feel more alert, energetic, sociable, and sensual. However, these positive feelings are commonly followed by anxiety, depression, irritability, fatigue, and craving more cocaine. Chronic intoxication is always associated with adverse psychosocial sequelae. Treatment initially must be directed toward the patient's stopping all use of cocaine, employing strategies such as contingency contracts, urinalysis, family intervention, the assignment of financial control to others, or hospitalization. Several psychopharmacologic agents are helpful as an adjunct to a comprehensive treatment plan. Overdoses of cocaine are treated by diazepam and propranolol. Antidepressant medications, both TCAs and MAOIs, often help relieve the symptoms of depression that emerge when chronic use of cocaine is discontinued. Classical and operant conditioning contribute to craving for the drug and opportunities to extinguish these factors are valuable in preventing relapse

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

PubMed Central

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

2014-01-01

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

Plants as a source of butyrylcholinesterase variants designed for enhanced cocaine hydrolase activity.

PubMed

Larrimore, Katherine E; Barcus, Matthew; Kannan, Latha; Gao, Yang; Zhan, Chang-Guo; Brimijoin, Stephen; Mor, Tsafrir

2013-03-25

Cocaine addiction affects millions of people with disastrous personal and social consequences. Cocaine is one of the most reinforcing of all drugs of abuse, and even those who undergo rehabilitation and experience long periods of abstinence have more than 80% chance of relapse. Yet there is no FDA-approved treatment to decrease the likelihood of relapse in rehabilitated addicts. Recent studies, however, have demonstrated a promising potential treatment option with the help of the serum enzyme butyrylcholinesterase (BChE), which is capable of breaking down naturally occurring (-)-cocaine before the drug can influence the reward centers of the brain or affect other areas of the body. This activity of wild-type (WT) BChE, however, is relatively low. This prompted the design of variants of BChE which exhibit significantly improved catalytic activity against (-)-cocaine. Plants are a promising means to produce large amounts of these cocaine hydrolase variants of BChE, cheaply, safely with no concerns regarding human pathogens and functionally equivalent to enzymes derived from other sources. Here, in expressing cocaine-hydrolyzing mutants of BChE in Nicotiana benthamiana using the MagnICON virus-assisted transient expression system, and in reporting their initial biochemical analysis, we provide proof-of-principle that plants can express engineered BChE proteins with desired properties. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

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

2013-05-09

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

Probing Active Cocaine Vaccination Performance through Catalytic and Noncatalytic Hapten Design

PubMed Central

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

2013-01-01

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

Comparing Exponential and Exponentiated Models of Drug Demand in Cocaine Users

PubMed Central

Strickland, Justin C.; Lile, Joshua A.; Rush, Craig R.; Stoops, William W.

2016-01-01

Drug purchase tasks provide rapid and efficient measurement of drug demand. Zero values (i.e., prices with zero consumption) present a quantitative challenge when using exponential demand models that exponentiated models may resolve. We aimed to replicate and advance the utility of using an exponentiated model by demonstrating construct validity (i.e., association with real-world drug use) and generalizability across drug commodities. Participants (N = 40 cocaine-using adults) completed Cocaine, Alcohol, and Cigarette Purchase Tasks evaluating hypothetical consumption across changes in price. Exponentiated and exponential models were fit to these data using different treatments of zero consumption values, including retaining zeros or replacing them with 0.1, 0.01, 0.001. Excellent model fits were observed with the exponentiated model. Means and precision fluctuated with different replacement values when using the exponential model, but were consistent for the exponentiated model. The exponentiated model provided the strongest correlation between derived demand intensity (Q0) and self-reported free consumption in all instances (Cocaine r = .88; Alcohol r = .97; Cigarette r = .91). Cocaine demand elasticity was positively correlated with alcohol and cigarette elasticity. Exponentiated parameters were associated with real-world drug use (e.g., weekly cocaine use), whereas these correlations were less consistent for exponential parameters. Our findings show that selection of zero replacement values impact demand parameters and their association with drug-use outcomes when using the exponential model, but not the exponentiated model. This work supports the adoption of the exponentiated demand model by replicating improved fit and consistency, in addition to demonstrating construct validity and generalizability. PMID:27929347

Controlling Cocaine: Supplying Versus Demand Programs

DTIC Science & Technology

1994-01-01

programs are administered to preteens , while cocaine use does not normally start until the late teens and early twenties. 7 A primary activity of...initiation for various drugs. Prevention programs attempt to convince preteens to abstain from marijuana, cigarettes, and alcohol. Therefore, to argue that

Subtypes of cocaine abusers.

PubMed

Weiss, R D; Mirin, S M

1986-09-01

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

Possible addiction transference from cocaine insufflation to oral bupropion in bipolar patient.

PubMed

Costa, Carolina; Araujo, Alberto; Brasil, Marco; Cruz, Marcelo

2015-01-01

Alert for the risk of oral bupropion addiction in patients with cocaine dependence. Single-case study. After a period of cocaine and alcohol abstinence, a 42-year-old patient started taking oral bupropion to relieve the symptoms of cocaine craving. He increased the bupropion dose up to 2250 mg/d without seizures. This case highlights the possibility of oral bupropion addiction after cocaine dependence. To our knowledge, it is the first case in the literature and emphasizes the risk of bupropion's misuse. Therefore, physicians should carefully examine the patient's profile before prescribing it, as well as follow appropriate measures.

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

DTIC Science & Technology

1991-01-01

addicts . Buackground Once considered to be nonaddictive, recent studies show that cocaine is one of the most potent drugs of abuse. Cocaine is a...responsibility for addiction prevention and treatment programs. The agencies we contacted include NIDA, the Alcohol, Drug Abuse, and Mental Health Administration...heroin addicts for Treating Crack are being used to treat many crack addicts . Meanwhile, drug treatment Addicts researchers are experimenting with new

Hapten optimization for cocaine vaccine with improved cocaine recognition.

PubMed

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

2014-09-01

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

Design and synthesis of a fluorescent molecular imprinted polymer for use in an optical fibre-based cocaine sensor

NASA Astrophysics Data System (ADS)

Wren, Stephen P.; Piletsky, Sergey A.; Karim, Kal; Gascoine, Paul; Lacey, Richard; Sun, Tong; Grattan, Kenneth T. V.

2014-05-01

Previously, we have developed chemical sensors using fibre optic-based techniques for the detection of Cocaine, utilising molecularly imprinted polymers (MIPs) containing fluorescein moieties as the signalling groups. Here, we report the computational design of a fluorophore which was incorporated into a MIP for the generation of a novel sensor that offers improved sensitivity for Cocaine with a detection range of 1-100μM. High selectivity for Cocaine over a suite of known Cocaine interferants (25μM) was also demonstrated by measuring changes in the intensity of fluorescence signals received from the sensor.

Comparing exponential and exponentiated models of drug demand in cocaine users.

PubMed

Strickland, Justin C; Lile, Joshua A; Rush, Craig R; Stoops, William W

2016-12-01

Drug purchase tasks provide rapid and efficient measurement of drug demand. Zero values (i.e., prices with zero consumption) present a quantitative challenge when using exponential demand models that exponentiated models may resolve. We aimed to replicate and advance the utility of using an exponentiated model by demonstrating construct validity (i.e., association with real-world drug use) and generalizability across drug commodities. Participants (N = 40 cocaine-using adults) completed Cocaine, Alcohol, and Cigarette Purchase Tasks evaluating hypothetical consumption across changes in price. Exponentiated and exponential models were fit to these data using different treatments of zero consumption values, including retaining zeros or replacing them with 0.1, 0.01, or 0.001. Excellent model fits were observed with the exponentiated model. Means and precision fluctuated with different replacement values when using the exponential model but were consistent for the exponentiated model. The exponentiated model provided the strongest correlation between derived demand intensity (Q0) and self-reported free consumption in all instances (Cocaine r = .88; Alcohol r = .97; Cigarette r = .91). Cocaine demand elasticity was positively correlated with alcohol and cigarette elasticity. Exponentiated parameters were associated with real-world drug use (e.g., weekly cocaine use) whereas these correlations were less consistent for exponential parameters. Our findings show that selection of zero replacement values affects demand parameters and their association with drug-use outcomes when using the exponential model but not the exponentiated model. This work supports the adoption of the exponentiated demand model by replicating improved fit and consistency and demonstrating construct validity and generalizability. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Disability income, cocaine use, and repeated hospitalization among schizophrenic cocaine abusers--a government-sponsored revolving door?

PubMed

Shaner, A; Eckman, T A; Roberts, L J; Wilkins, J N; Tucker, D E; Tsuang, J W; Mintz, J

1995-09-21

Many patients with serious mental illness are addicted to drugs and alcohol. This comorbidity creates additional problems for the patients and for the clinicians, health care systems, and social-service agencies that provide services to this population. One problem is that disability income, which many people with serious mental illness receive to pay for basic needs, may facilitate drug abuse. In this study, we assessed the temporal patterns of cocaine use, psychiatric symptoms, and psychiatric hospitalization in a sample of schizophrenic patients receiving disability income. We evaluated 105 male patients with schizophrenia and cocaine dependence at the time of their admission to the hospital. They had severe mental illness and a long-term dependence on cocaine, with repeated admissions to psychiatric hospitals; many were homeless. The severity of psychiatric symptoms and urinary concentrations of the cocaine metabolite benzoylecgonine were evaluated weekly for 15 weeks. Cocaine use, psychiatric symptoms, and hospital admissions all peaked during the first week of the month, shortly after the arrival of the disability payment, on the first day. The average patient spent nearly half his total income on illegal drugs. Among cocaine-abusing schizophrenic persons, the cyclic pattern of drug use strongly suggests that it is influenced by the monthly receipt of disability payments. The consequences of this cycle include the depletion of funds needed for housing and food, exacerbation of psychiatric symptoms, more frequent psychiatric hospitalization, and a high rate of homelessness. The troubling irony is that income intended to compensate for the disabling effects of severe mental illness may have the opposite effect.

The drug use behaviour of cocaine users.

PubMed

Moosburger, R; Plant, A J; Pierce, J P

1990-01-01

We interviewed 50 current cocaine users with the aim of providing insights into cocaine use in Sydney. The study sample was obtained by one researcher using a chain referral technique. Appointments were made for interview and the interview aimed to determine the quantity, frequency, pattern and circumstances of drug use in the respondents. The study sample included people with a wide range of incomes and occupations; all but one person were employed. Extensive current drug use was reported; 78% smoked tobacco, 98% drank alcohol with 36% having more than two drinks per day, 96% used marijuana with 40% smoking marijuana at least 5 times per week, 65% used amphetamines, 36% used hallucinogens and 10% used heroin. Ten per cent were unable to name one health risk of cocaine. When asked about the image of a cocaine user, 42% thought of a rock star, film industry worker or someone involved in the arts and entertainment world. The information obtained from a study such as this provides important data for targeting of people in anti-drug campaigns.

Multigenerational and Transgenerational Inheritance of Drug Exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine

PubMed Central

Yohn, Nicole L.; Bartolomei, Marisa S.; Blendy, Julie A.

2015-01-01

Familial inheritance of drug abuse is composed of both genetic and environmental factors. Additionally, epigenetic transgenerational inheritance may provide a means by which parental drug use can influence several generations of offspring. Recent evidence suggests that parental drug exposure produces behavioral, biochemical, and neuroanatomical changes in future generations. The focus of this review is to discuss these multigenerational and transgenerational phenotypes in the offspring of animals exposed to drugs of abuse. Specifically, changes found following the administration of alcohol, opioids, cocaine, marijuana, and nicotine will be discussed. In addition, epigenetic modifications to the genome following administration of these drugs will be detailed as well as their potential for transmission to the next generation. PMID:25839742

Examining supply changes in Australia's cocaine market.

PubMed

Hughes, Caitlin E; Chalmers, Jenny; Bright, David A; Matthew-Simmons, Francis; Sindicich, Natasha

2012-05-01

Media attention to cocaine use and supply has increased following some of the largest cocaine seizures in Australia's history. Whether there has been an expansion in supply remains unclear. This paper examines the evidence behind assertions of increased supply in Australia and the scale and nature of any apparent increase, using proxy indicators of cocaine importation, distribution and use. Eight proxies of cocaine importation, distribution and use were adopted, including amount of importation, mode of importation and supply flows to Australia. Each proxy indicator was sourced using publicly available and Australia-wide data, including information on the total weight of border seizures, mode of detection and country of embarkation of individual seizures. Data permitting, trends were examined for up to a 12 year period (1997-1998 to 2009-2010). Since 2006-2007 there was evidence of increased cocaine importation, albeit less than between 1998-1999 and 2001-2002. There were further signs that the 2006-2007 expansion coincided with a diversification of trafficking routes to and through Australia (beyond the traditional site of entry-Sydney) and shifts in the geographic distribution of use. The congruity between indicators suggests that there has been a recent expansion in cocaine supply to and distribution within Australia, but that the more notable shift has concerned the nature of supply, with an apparent growth in importation and distribution beyond New South Wales. The diversification of cocaine supply routes may increase risks of market entrenchment and organised crime throughout Australia. © 2011 Australasian Professional Society on Alcohol and other Drugs.

Non-invasive detection of cocaine dissolved in beverages using displaced Raman spectroscopy.

PubMed

Eliasson, C; Macleod, N A; Matousek, P

2008-01-21

We demonstrate the potential of Raman spectroscopy to detect cocaine concealed inside transparent glass bottles containing alcoholic beverages. A clear Raman signature of cocaine with good signal-to-noise was obtained from a approximately 300 g solution of adulterated cocaine (purity 75%) in a 0.7 L authentic brown bottle of rum with 1 s acquisition time. The detection limit was estimated to be of the order of 9 g of pure cocaine per 0.7 L (approximately 0.04 moles L(-1)) with 1 s acquisition time. The technique holds great promise for the fast, non-invasive, detection of concealed illicit compounds inside beverages using portable Raman instruments, thus permitting drug trafficking to be combated more effectively.

Cocaine

MedlinePlus

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

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

PubMed

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

2010-01-01

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

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

PubMed

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

2017-09-01

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

Cocaine withdrawal

MedlinePlus

... Substance use - cocaine withdrawal; Substance abuse - cocaine withdrawal; Drug abuse - cocaine withdrawal; Detox - cocaine ... Elsevier Saunders; 2016:chap 50. National Institute on Drug Abuse. What is cocaine? Updated May 2016. www.drugabuse. ...

Emotion regulation behavior during a separation procedure in 18-month-old children of mothers using cocaine and other drugs.

PubMed

Molitor, Adriana; Mayes, Linda C; Ward, Anna

2003-01-01

This study examined the association between maternal cocaine use and children's emotional regulation. Using a brief separation procedure, we observed 78 18-month-old at-risk children and their mothers from three defined maternal groups: no drug use; no cocaine use but a positive history for alcohol, tobacco, and/or marijuana; and cocaine use with or without alcohol, tobacco, and/or marijuana. Coded videotaped behavior identified three maternal constructs (separation style, physical engagement, and emotional engagement) and three child constructs (negative reactivity to separation, initial regulatory activity, and follow-up positive emotional engagement). Cocaine-using mothers displayed less emotional engagement than other mothers. Children with cocaine-using mothers displayed less negative reactivity and follow-up positive emotional engagement than their counterparts. Child reactivity was connected to maternal drug use, whereas emotional engagement during reunion was linked to birthweight and maternal behavior. Results suggest a possible impairment or restriction of emotional expression and regulation in the face of stress and/or maternal disengagement that is more common among cocaine-exposed children with their mothers.

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

PubMed

John, William S; Nader, Michael A

2017-01-01

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

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

PubMed Central

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

2012-01-01

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

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…

Sex Differences in Psychiatric Comorbidity and Plasma Biomarkers for Cocaine Addiction in Abstinent Cocaine-Addicted Subjects in Outpatient Settings

PubMed Central

Pedraz, María; Araos, Pedro; García-Marchena, Nuria; Serrano, Antonia; Romero-Sanchiz, Pablo; Suárez, Juan; Castilla-Ortega, Estela; Mayoral-Cleries, Fermín; Ruiz, Juan Jesús; Pastor, Antoni; Barrios, Vicente; Chowen, Julie A.; Argente, Jesús; Torrens, Marta; de la Torre, Rafael; Rodríguez De Fonseca, Fernando; Pavón, Francisco Javier

2015-01-01

effect on POEA and N-arachidonoyl-ethanolamine concentrations. Regarding psychiatric comorbidity in the cocaine group, women had lower incidence rates of comorbid substance use disorders than did men. For example, alcohol use disorders were found in 80% of men and 40% of women. In contrast, the addicted women had increased prevalences of comorbid psychiatric disorders (i.e., mood, anxiety, and psychosis disorders). Additionally, cocaine-addicted subjects showed a relationship between the concentrations of N-stearoyl-ethanolamine and 2-linoleoyl-glycerol and diagnosis of psychiatric comorbidity. These results demonstrate the existence of a sex influence on plasma biomarkers for cocaine addiction and on the presence of comorbid psychopathologies for clinical purposes. PMID:25762940

Toward a Global View of Alcohol, Tobacco, Cannabis, and Cocaine Use: Findings from the WHO World Mental Health Surveys

PubMed Central

Degenhardt, Louisa; Chiu, Wai-Tat; Sampson, Nancy; Kessler, Ronald C; Anthony, James C; Angermeyer, Matthias; Bruffaerts, Ronny; de Girolamo, Giovanni; Gureje, Oye; Huang, Yueqin; Karam, Aimee; Kostyuchenko, Stanislav; Lepine, Jean Pierre; Mora, Maria Elena Medina; Neumark, Yehuda; Ormel, J. Hans; Pinto-Meza, Alejandra; Posada-Villa, José; Stein, Dan J; Takeshima, Tadashi; Wells, J. Elisabeth

2008-01-01

Background Alcohol, tobacco, and illegal drug use cause considerable morbidity and mortality, but good cross-national epidemiological data are limited. This paper describes such data from the first 17 countries participating in the World Health Organization's (WHO's) World Mental Health (WMH) Survey Initiative. Methods and Findings Household surveys with a combined sample size of 85,052 were carried out in the Americas (Colombia, Mexico, United States), Europe (Belgium, France, Germany, Italy, Netherlands, Spain, Ukraine), Middle East and Africa (Israel, Lebanon, Nigeria, South Africa), Asia (Japan, People's Republic of China), and Oceania (New Zealand). The WHO Composite International Diagnostic Interview (CIDI) was used to assess the prevalence and correlates of a wide variety of mental and substance disorders. This paper focuses on lifetime use and age of initiation of tobacco, alcohol, cannabis, and cocaine. Alcohol had been used by most in the Americas, Europe, Japan, and New Zealand, with smaller proportions in the Middle East, Africa, and China. Cannabis use in the US and New Zealand (both 42%) was far higher than in any other country. The US was also an outlier in cocaine use (16%). Males were more likely than females to have used drugs; and a sex–cohort interaction was observed, whereby not only were younger cohorts more likely to use all drugs, but the male–female gap was closing in more recent cohorts. The period of risk for drug initiation also appears to be lengthening longer into adulthood among more recent cohorts. Associations with sociodemographic variables were consistent across countries, as were the curves of incidence of lifetime use. Conclusions Globally, drug use is not distributed evenly and is not simply related to drug policy, since countries with stringent user-level illegal drug policies did not have lower levels of use than countries with liberal ones. Sex differences were consistently documented, but are decreasing in more recent

Outpatient Cocaine Abuse Treatment: Predictors of Success.

ERIC Educational Resources Information Center

Westhuis, David J.; Gwaltney, Lisa; Hayashi, Reiko

2001-01-01

Uses data from the U.S. Army's Alcohol and Drug Abuse Prevention and Control Program to analyze which treatment and demographic variables have an effect on cocaine treatment outcomes. Results suggest the following treatment variables had an effect on outcomes: type of treatment; length of time in treatment; and the length of time since the patient…

Evaluation of the U.S. Army Alcohol and Drug Abuse Prevention and Control Program. Phase 2

DTIC Science & Technology

1994-06-13

24 Alcohol Last Use and Frequency of Use by Track ................ 26 ! Cannabis and Cocaine Last Use By Track...Outcome ...................................... 69 Alcohol Track II Probability Results ........................... 70 Cannabis Track I1 Probability...81 Time By Treatment Modality for Alcohol By Track ................. 82 Time By Treatment Modality for Cannabis and Cocaine ............. 84

Cocaine Dysregulates Opioid Gating of GABA Neurotransmission in the Ventral Pallidum

PubMed Central

Scofield, Michael D.; Rice, Kenner C.; Cheng, Kejun; Roques, Bernard P.

2014-01-01

The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse. PMID:24431463

WITHDRAWN: Carbamazepine for cocaine dependence.

PubMed

Lima Reisser, Anelise A R L; Silva de Lima, Mauricio; Soares, Bernardo Garcia de Oliveira; Farrell, Michael

2009-01-21

Cocaine dependence has become a public health problem, developing a significant number of medical, psychological and social problems. Although there is no consensus regarding how to treat cocaine dependence, effective pharmacotherapy has a potentially major role to play as part of a broader treatment milieu. The anti-convulsant carbamazepine, a tricyclic medication that is widely used to treat a variety of neurological and psychiatric disorders, has been used for treatment of cocaine dependence, although its effectiveness has not been established. To determine whether carbamazepine is effective for the treatment of cocaine dependence. We searched: Cochrane Controlled Trials Register (Cochrane Library issue 1, 1999), MEDLINE (f1966 - October 1997), EMBASE (1980 - October 1997), PsycLIT (1974 - July 1997), Biological Abstracts and LILACS (1982 - 1997); scan of reference list of relevant articles; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. The specialised register of trials of Cochrane Group on Drugs and Alcohol until February 2003. All randomised controlled trials focused on the use of carbamazepine versus placebo on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. The reviewers extracted the data independently, Odds Ratios, weighted mean difference and number needed to treat were estimated. Qualitative assessments of the methodology of eligible studies were carried out using validated checklists. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Where possible analysis was carried out according to the "intention to treat" principles. 5 studies were included (455 participants). No differences regarding positive urine sample for cocaine metabolites. Scores on Spielberg State Anxiety

Cocaine adulteration.

PubMed

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

2017-10-01

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

Psychiatric comorbidity in a sample of cocaine-dependent outpatients seen in the Community of Madrid drug addiction care network.

PubMed

Martínez-Gras, Isabel; Ferre Navarrete, Francisco; Pascual Arriazu, Jesús; Peñas Pascual, José; de Iceta Ruiz de Gauna, Mariano; Fraguas Herráez, David; Rubio Valladolid, Gabriel

2016-03-02

The objective of this study was to estimate the current prevalence of psychiatric disorders in cocaine-dependent patients who attend different treatment centres in the Community of Madrid. A prospective multicentre study was used, and a total of 197 cocaine-dependent subjects were assessed. The assessment instrument used for diagnosis was the Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV). The main findings of this study were a high prevalence of psychiatric comorbidity in cocaine-dependent patients seeking treatment (64.0%). The most common Non Substance Use Disorders found were attention-deficit/hyperactivity Disorders (34.5%) and depressive disorders (13.7%). The most common Substance Use Disorder was alcohol dependence (28.4%). Cocaine-dependent patients who had a depressive disorder and were alcohol dependent presented a more severe clinical profile and a higher degree of psychopathology, measured using different assessment tools, than the patients who were only cocaine dependent. These data suggest that the presence of psychiatric comorbidity could constitute a risk factor associated with the severity of cocaine dependence. The clinical heterogeneity found also indicates the need to search for individualised treatments that more specifically fit the needs of this population.

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

PubMed

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

2013-01-01

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

A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Cooper, Ziva D; Narasimhan, Diwahar; Sunahara, Roger K; Woods, James H

2009-09-01

Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (-)-2beta-carbomethoxy-3beta-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.

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 ...

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

PubMed

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

2017-02-01

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

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

PubMed Central

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

2010-01-01

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

A Bacterial Cocaine Esterase Protects Against Cocaine-Induced Epileptogenic Activity and Lethality

PubMed Central

Jutkiewicz, Emily M.; Baladi, Michelle G.; Cooper, Ziva D.; Narasimhan, Diwahar; Sunahara, Roger K.; Woods, James H.

2012-01-01

Study objective Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Methods Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. Results The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (−)-2β-carbomethoxy-3β-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. Conclusion The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted. PMID:19013687

Among long-term crack smokers, who avoids and who succumbs to cocaine addiction?

PubMed

Falck, Russel S; Wang, Jichuan; Carlson, Robert G

2008-11-01

Crack cocaine is a highly addictive drug. To learn more about crack addiction, long-term crack smokers who had never met the DSM-IV criteria for lifetime cocaine dependence were compared with those who had. The study sample consisted of crack users (n=172) from the Dayton, Ohio, area who were interviewed periodically over 8 years. Data were collected on a range of variables including age of crack initiation, frequency of recent use, and lifetime cocaine dependence. Cocaine dependence was common with 62.8% of the sample having experienced it. There were no statistically significant differences between dependent and non-dependent users for age of crack initiation or frequency of crack use. In terms of sociodemographics, only race/ethnicity was significant, with proportionally fewer African-Americans than whites meeting the criteria for cocaine dependence. Controlling for sociodemographics, partial correlation analysis showed positive, statistically significant relationships between lifetime cocaine dependence and anti-social personality disorder, attention deficit/hyperactivity disorder, and lifetime dependence on alcohol, cannabis, amphetamine, sedative-hypnotics, and opioids. These results highlight the importance addressing race/ethnicity and comorbid disorders when developing, implementing, and evaluating interventions targeting people who use crack cocaine. Additional research is needed to better understand the role of race/ethnicity in the development of cocaine dependence resulting from crack use.

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.

Contribution of early environmental stress to alcoholism vulnerability.

PubMed

Campbell, Joannalee C; Szumlinski, Karen K; Kippin, Tod E

2009-11-01

The most problematic aspects of alcohol abuse disorder are excessive alcohol consumption and the inability to refrain from alcohol consumption during attempted abstinence. The root causes that predispose certain individuals to these problems are poorly understood but are believed to be produced by a combination of genetic and environmental factors. Early environmental trauma alters neurodevelopmental trajectories that can predispose an individual to a number of neuropsychiatric disorders, including substance abuse. Prenatal stress (PNS) is a well-established protocol that produces perturbations in nervous system development, resulting in behavioral alterations that include hyperresponsiveness to stress, novelty, and psychomotor stimulant drugs (e.g., cocaine, amphetamine). Moreover, PNS animals exhibit enduring alterations in basal and cocaine-induced changes in dopamine and glutamate transmission within limbic structures, which exhibit pathology in drug addiction and alcoholism, suggesting that these alterations may contribute to an increased propensity to self-administer large amounts of drugs of abuse or to relapse after periods of drug withdrawal. Given that cocaine and alcohol have actions on common limbic neural substrates (albeit by different mechanisms), we hypothesized that PNS would elevate the motivation for, and consumption of, alcohol. Accordingly, we have found that male C57BL/6J mice subject to PNS exhibit higher operant responding and consume more alcohol during alcohol reinforcement as adults. Alterations in glutamate and dopamine neurotransmission within the forebrain structures appear to contribute to the PNS-induced predisposition to high alcohol intake and are induced by excessive alcohol intake. Accordingly, we are exploring the interactions between neurochemical changes produced by PNS and changes induced by consumption of alcohol in adulthood to model the biological bases of high vulnerability to alcohol abuse.

Contribution of early environmental stress to alcoholism vulnerability

PubMed Central

Campbell, Joannalee C.; Szumlinski, Karen K.; Kippin, Tod E.

2011-01-01

The most problematic aspects of alcohol abuse disorder are excessive alcohol consumption and the inability to refrain from alcohol consumption during attempted abstinence. The root causes that predispose certain individuals to these problems are poorly understood but are believed to be produced by a combination of genetic and environmental factors. Early environmental trauma alters neurodevelopmental trajectories that can predispose an individual to a number of neuropsychiatric disorders, including substance abuse. Prenatal stress (PNS) is a well-established protocol that produces perturbations in nervous system development, resulting in behavioral alterations that include hyperresponsiveness to stress, novelty, and psychomotor stimulant drugs (e.g., cocaine, amphetamine). Moreover, PNS animals exhibit enduring alterations in basal and cocaine-induced changes in dopamine and glutamate transmission within limbic structures, which exhibit pathology in drug addiction and alcoholism, suggesting that these alterations may contribute to an increased propensity to self-administer large amounts of drugs of abuse or to relapse after periods of drug withdrawal. Given that cocaine and alcohol have actions on common limbic neural substrates (albeit by different mechanisms), we hypothesized that PNS would elevate the motivation for, and consumption of, alcohol. Accordingly, we have found that male C57BL/6J mice subject to PNS exhibit higher operant responding and consume more alcohol during alcohol reinforcement as adults. Alterations in glutamate and dopamine neurotransmission within the forebrain structures appear to contribute to the PNS-induced predisposition to high alcohol intake and are induced by excessive alcohol intake. Accordingly, we are exploring the interactions between neurochemical changes produced by PNS and changes induced by consumption of alcohol in adulthood to model the biological bases of high vulnerability to alcohol abuse. PMID:19913199

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

PubMed Central

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

2012-01-01

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

The future potential for cocaine vaccines.

PubMed

Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen; Kinsey, Berma M; Singh, Rana Ak; Ramakrishnan, Muthu; Wang, Helen Y; Kosten, Thomas R

2014-09-01

Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine's pharmacodynamic effects. This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness. Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes.

Positional linker effects in haptens for cocaine immunopharmacotherapy.

PubMed

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

2007-08-01

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

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

[Follow-up of alcohol and/or cocaine dependents after their discharge from a therapeutic community: a pilot study].

PubMed

Lopez-Fernandez, Olatz; Ferrer-Pérez, Xavier; Lafarga-Lebey, Sandra; Honrubia-Serrano, María Luisa; Tudela-Marí, Maite

2011-01-01

In Spain, the Therapeutic Community (TC) constitutes a common model of treatment in the field of addictions, although there hardly exists any investigation about its efficiency and the persistence of its attainments. To evaluate the short, half and long term effects of treatment of addiction to alcohol or cocaine in the TC run by "Fundacion Salud y Comunidad" (Foundation Health and Community). descriptive pilot study, with a sequential design of cohort. 91 users completed a survey specifically designed to know their evolution at different follow-up periods (1, 3, 5 or 10 years after their exit from the TC): socio-demographic, psychoactive substance use, other variables related to the stay at the TC. Changes between before the TC and the present time regarding variables such as academic, labour, drug consumption, health, family and social adaptation and their criminal behaviour are described. the cohorts showed a relatively common previous socio-demographic pattern having received a similar treatment. The users reported to have diminished the frequent consumption of the main drug, having 48.9% never relapsed even through an occasional consumption of the drug/s. Also they perceived to have improved their health and family relations, as well as their aggressive behaviour and legal problems linked with their consumption of drug/s. after their rehabilitation in a TC, the users report a global decrease of the consumption of drugs and perceive an improvement of their health, family relations, violence and other problems linked to their former drug use.

Evaluation of buspirone for relapse-prevention in adults with cocaine dependence: An efficacy trial conducted in the real world

PubMed Central

Winhusen, Theresa; Brady, Kathleen T.; Stitzer, Maxine; Woody, George; Lindblad, Robert; Kropp, Frankie; Brigham, Gregory; Liu, David; Sparenborg, Steven; Sharma, Gaurav; VanVeldhuisen, Paul; Adinoff, Bryon; Somoza, Eugene

2012-01-01

Cocaine dependence is a significant public health problem for which there are currently no FDA-approved medications. Hence, identifying candidate compounds and employing an efficient evaluation process is crucial. This paper describes key design decisions made for a National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) study that uses a novel two-stage process to evaluate buspirone (60 mg/day) for cocaine-relapse prevention. The study includes pilot (N=60) and full-scale (estimated N=264) trials. Both trials will be randomized, double-blind, and placebo-controlled and both will enroll treatment-seeking cocaine-dependent participants engaged in inpatient/residential treatment and scheduled for outpatient treatment post-discharge. All participants will receive contingency management in which incentives are given for medication adherence as evaluated by the Medication Events Monitoring System (MEMS). The primary outcome measure is maximum days of continuous cocaine abstinence, as assessed by twice-weekly urine drug screens (UDS) and self-report, during the 15-week outpatient treatment phase. Drug-abuse outcomes include cocaine use as assessed by UDS and self-report of cocaine use, other substance use as assessed by UDS and self-report of substance use (i.e., alcohol and/or illicit drugs), cocaine bingeing, HIV risk behavior, quality of life, functioning, and substance-abuse treatment attendance. Unique aspects of the study include conducting an efficacy trial in community treatment programs, a two-stage process to efficiently evaluate buspirone, and an evaluation of mediators by which buspirone might exert a beneficial effect on relapse prevention. PMID:22613054

Evaluation of buspirone for relapse-prevention in adults with cocaine dependence: an efficacy trial conducted in the real world.

PubMed

Winhusen, Theresa; Brady, Kathleen T; Stitzer, Maxine; Woody, George; Lindblad, Robert; Kropp, Frankie; Brigham, Gregory; Liu, David; Sparenborg, Steven; Sharma, Gaurav; Vanveldhuisen, Paul; Adinoff, Bryon; Somoza, Eugene

2012-09-01

Cocaine dependence is a significant public health problem for which there are currently no FDA-approved medications. Hence, identifying candidate compounds and employing an efficient evaluation process is crucial. This paper describes key design decisions made for a National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) study that uses a novel two-stage process to evaluate buspirone (60 mg/day) for cocaine-relapse prevention. The study includes pilot (N=60) and full-scale (estimated N=264) trials. Both trials will be randomized, double-blind, and placebo-controlled and both will enroll treatment-seeking cocaine-dependent participants engaged in inpatient/residential treatment and scheduled for outpatient treatment post-discharge. All participants will receive contingency management in which incentives are given for medication adherence as evaluated by the Medication Events Monitoring System (MEMS). The primary outcome measure is maximum days of continuous cocaine abstinence, as assessed by twice-weekly urine drug screens (UDS) and self-report, during the 15-week outpatient treatment phase. Drug-abuse outcomes include cocaine use as assessed by UDS and self-report of cocaine use, other substance use as assessed by UDS and self-report of substance use (i.e., alcohol and/or illicit drugs), cocaine bingeing, HIV risk behavior, quality of life, functioning, and substance abuse treatment attendance. Unique aspects of the study include conducting an efficacy trial in community treatment programs, a two-stage process to efficiently evaluate buspirone, and an evaluation of mediators by which buspirone might exert a beneficial effect on relapse prevention. Copyright © 2012 Elsevier Inc. All rights reserved.

Substance use -- cocaine

MedlinePlus

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

Women Inmate Substance Abusers’ Reactivity to Visual Alcohol, Cigarette, Marijuana, and Crack-Cocaine Cues: Approach and Avoidance as Separate Dimensions of Reactivity

PubMed Central

Schlauch, Robert C.; Breiner, Mary J.; Stasiewicz, Paul R.; Christensen, Rita L.; Lang, Alan R.

2012-01-01

Despite the growing recognition for multidimensional assessments of cue-elicited craving, few studies have attempted to measure multiple response domains associated with craving. The present study evaluated the Ambivalence Model of Craving (Breiner et al., 1999; Stritzke et al., 2007) using a unique cue reactivity methodology designed to capture both the desire to use (approach inclination) and desire to not consume (avoidance inclination) in a clinical sample of incarcerated female substance abusers. Participants were 155 incarcerated women who were participating in or waiting to begin participation in a nine-month drug treatment program. Results indicated that all four substance cue-types (alcohol, cigarette, marijuana, and crack cocaine) had good reliability and showed high specificity. Also, the validity of measuring approach and avoidance as separate dimensions was supported, as demonstrated by meaningful clinical distinctions between groups evincing different reactivity patterns and incremental prediction of avoidance inclinations on measures of stages of change readiness. Taken together, results continue to highlight the importance of measuring both approach and avoidance inclinations in the study of cue-elicited craving. PMID:23543075

Cigarette Cue Attentional Bias in Cocaine-Smoking and Non-Cocaine-Using Cigarette Smokers.

PubMed

Marks, Katherine R; Alcorn, Joseph L; Stoops, William W; Rush, Craig R

2016-09-01

Cigarette smoking in cocaine users is nearly four times higher than the national prevalence and cocaine use increases cigarette smoking. The mechanisms underlying cigarette smoking in cocaine-using individuals need to be identified to promote cigarette and cocaine abstinence. Previous studies have examined the salience of cigarette and cocaine cues separately. The present aim was to determine whether cigarette attentional bias (AB) is higher in cigarettes smokers who smoke cocaine relative to individuals who only smoke cigarettes. Twenty cigarette smokers who smoke cocaine and 20 non-cocaine-using cigarette smokers completed a visual probe task with eye-tracking technology. During this task, the magnitude of cigarette and cocaine AB was assessed through orienting bias, fixation time, and response time. Cocaine users displayed an orienting bias towards cigarette cues. Cocaine users also endorsed a more urgent desire to smoke to relieve negative affect associated with cigarette craving than non-cocaine users (g = 0.6). Neither group displayed a cigarette AB, as measured by fixation time. Cocaine users, but not non-cocaine users, displayed a cocaine AB as measured by orienting bias (g = 2.0) and fixation time (g = 1.2). There were no significant effects for response time data. Cocaine-smoking cigarettes smokers display an initial orienting bias toward cigarette cues, but not sustained cigarette AB. The incentive motivation underlying cigarette smoking also differs. Cocaine smokers report more urgent desire to smoke to relieve negative affect. Identifying differences in motivation to smoke cigarettes may provide new treatment targets for cigarette and cocaine use disorders. These results suggest that cocaine-smoking cigarette smokers display an initial orienting bias towards cigarette cues, but not sustained attention towards cigarette cues, relative to non-cocaine-using smokers. Smoked cocaine users also report a more urgent desire to smoke to relieve negative affect

Drug and Alcohol Testing Results - 1995 Annual Report

DOT National Transportation Integrated Search

1997-03-01

The Report is a compilation and analysis of mass transit drug and alcohol testing reported by transit systems in the United States during 1995. The report covers testing for alcohol and the following drug types: marijuana (THC), cocaine, phencyclidin...

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2012-07-01

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

Nicotine, alcohol and cocaine coupling to reward processes via endogenous morphine signaling: the dopamine-morphine hypothesis.

PubMed

Stefano, George B; Bianchi, Enrica; Guarna, Massimo; Fricchione, Gregory L; Zhu, Wei; Cadet, Patrick; Mantione, Kirk J; Casares, Federico M; Kream, Richard M; Esch, Tobias

2007-06-01

Pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, nicotine, cocaine and alcohol appear to exert their pleasure providing action via endogenous morphinergic mechanisms. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways, now, in part, via endogenous morphine processes.

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

PubMed

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

2018-06-21

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

The future potential for cocaine vaccines

PubMed Central

Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen; Kinsey, Berma M; Singh, Rana AK; Ramakrishnan, Muthu; Wang, Helen Y; Kosten, Thomas R

2014-01-01

Introduction Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine’s pharmacodynamic effects. Areas covered This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness. Expert opinion Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes. PMID:24835496

Adolescent Characters and Alcohol Use Scenes in Brazilian Movies, 2000-2008.

PubMed

Castaldelli-Maia, João Mauricio; de Andrade, Arthur Guerra; Lotufo-Neto, Francisco; Bhugra, Dinesh

2016-04-01

Quantitative structured assessment of 193 scenes depicting substance use from a convenience sample of 50 Brazilian movies was performed. Logistic regression and analysis of variance or multivariate analysis of variance models were employed to test for two different types of outcome regarding alcohol appearance: The mean length of alcohol scenes in seconds and the prevalence of alcohol use scenes. The presence of adolescent characters was associated with a higher prevalence of alcohol use scenes compared to nonalcohol use scenes. The presence of adolescents was also associated with a higher than average length of alcohol use scenes compared to the nonalcohol use scenes. Alcohol use was negatively associated with cannabis, cocaine, and other drugs use. However, when the use of cannabis, cocaine, or other drugs was present in the alcohol use scenes, a higher average length was found. This may mean that most vulnerable group may see drinking as a more attractive option leading to higher alcohol use. © The Author(s) 2016.

Electroencephalographic activity and mood in cocaine-dependent outpatients: effects of cocaine cue exposure.

PubMed

Bauer, L O; Kranzler, H R

1994-08-01

Electroencephalographic (EEG) and subjective reactions to cocaine cues were evaluated in 18 cocaine-dependent outpatients, after 14 or fewer days of abstinence, and 16 noncocaine-dependent controls. EEG activity and desire for cocaine were recorded while subjects viewed three 5-min films that featured either cocaine-associated, erotic, or neutral stimuli. Other measures of mood state and cocaine craving, derived from the Mood Adjective Checklist and the Cocaine Craving Questionnaire, respectively, were recorded immediately after each film. Analyses of absolute EEG power within six frequency bands (delta, theta, slow and fast alpha, slow and fast beta) revealed no EEG abnormalities in the cocaine-dependent group under any condition. In both subject groups, the cocaine-associated and erotic films produced a similar reduction in total EEG power. The cocaine-associated and erotic films also produced a similar increase in the self-rated desire for cocaine, but this change only occurred in the cocaine-dependent group.

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).

Oral Fluid Cocaine and Benzoylecgonine Concentrations Following Controlled Intravenous Cocaine Administration

PubMed Central

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

2016-01-01

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

Preclinical validation of a novel cocaine exposure therapy for relapse prevention.

PubMed

Mihindou, Claudia; Vouillac, Caroline; Koob, George F; Ahmed, Serge H

2011-09-15

Cocaine not only induces intense rewarding sensations but also craving for more cocaine, particularly during abstinence, an effect that contributes, together with other factors, to relapse. Here we sought to prevent this effect by extinguishing the conditioned interoceptive cues of cocaine that are thought to be acquired during repeated cocaine use. Cocaine-induced craving was studied in rats using the well-validated model of drug-primed reinstatement of cocaine seeking. To extinguish the conditioned interoceptive effects of cocaine, rats received daily repeated cocaine priming in the absence of drug reinforcement. Cocaine-primed reinstatement of cocaine seeking dramatically decreased with repeated cocaine priming regardless of the testing dose and even following a history of extended access to cocaine self-administration. The extinction of cocaine-primed reinstatement of cocaine seeking was enduring, generalized to stress-another major trigger of drug craving and relapse-and was context-dependent. These findings clearly show that it is feasible to prevent the ability of cocaine and stress to induce cocaine seeking using an approach designed to extinguish the drug's conditioned interoceptive cues. Although this preclinical extinction approach has limitations that need to be overcome in future research (i.e., its context-dependency), it may nevertheless represent a promising basis for the development of a novel exposure therapy against cocaine relapse. Copyright © 2011 Society of Biological Psychiatry. All rights reserved.

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-08-01

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

Expressive language development of children exposed to cocaine prenatally: literature review and report of a prospective cohort study.

PubMed

Delaney-Black, V; Covington, C; Templin, T; Kershaw, T; Nordstrom-Klee, B; Ager, J; Clark, N; Surendran, A; Martier, S; Sokol, R J

2000-01-01

It was hypothesized that prenatal exposure to cocaine and other substances would be related to delayed expressive language development. Speech and language data were available for 458 6-year olds (204 were exposed to cocaine). No significant univariate or multivariate differences by cocaine exposure group were observed. Classification and regression tree modeling was then used to identify language variable composites predictive of cocaine exposure status. Meaningful cut points for two language measures were identified and validated. Children with a type token ratio of less than 0.42 and with fewer than 97 word types were classified into a low language group. Low language children (n = 57) were more likely to be cocaine exposed (63.1%), with cocaine-exposed children 2.4 times more likely to be in the low language group compared with control children after adjustment for covariates. Prenatal cigarette, but not alcohol exposure, was also significantly related to expressive language delays.

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

PubMed

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

2017-06-01

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

The Alcohol Relapse Situation Appraisal Questionnaire: Development and Validation

PubMed Central

Martin, Rosemarie A.; MacKinnon, Selene M.; Johnson, Jennifer E.; Myers, Mark G.; Cook, Travis A. R.; Rohsenow, Damaris J.

2011-01-01

Background The role of cognitive appraisal of the threat of alcohol relapse has received little attention. A previous instrument, the Relapse Situation Appraisal Questionnaire (RSAQ), was developed to assess cocaine users’ primary appraisal of the threat of situations posing a high risk for cocaine relapse. The purpose of the present study was to modify the RSAQ in order to measure primary appraisal in situations involving a high risk for alcohol relapse. Methods The development and psychometric properties of this instrument, the Alcohol Relapse Situation Appraisal Questionnaire (A-RSAQ), were examined with two samples of abstinent adults with alcohol abuse or dependence. Factor structure and validity were examined in Study 1 (N=104). Confirmation of the factor structure and predictive validity were assessed in Study 2 (N=161). Results Results demonstrated construct, discriminant and predictive validity and reliability of the A-RSAQ. Discussion Results support the important role of primary appraisal of degree of risk in alcohol relapse situations. PMID:21237586

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

PubMed Central

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

2012-01-01

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

The relationship between risk networks' patterns of crack cocaine and alcohol consumption and HIV-related sexual behaviors among adult injection drug users: a prospective study.

PubMed

Latkin, C A; Mandell, W; Vlahov, D

1996-11-01

Social context may be an important determinant of drug and alcohol consumption and HIV-related behaviors. To assess the influence of peers on drug users' risk behaviors this study examined the association between individual level and group level behaviors. This analysis reports on the prospective association between baseline self-reported drug and alcohol use of the network members of injection drug users, and self-reported sexual behaviors and alcohol use at 5-month follow-up. Participants were a nontreatment sample of inner-city injection drug users who volunteered for a network-oriented HIV preventive intervention. They were predominantly unemployed, African American males. Of the 71 index participants who completed both the baseline and follow-up interviews, 227 of their drug network members were enrolled in the study. At baseline indexes' sexual risk behaviors were significantly associated with their drug network members' level of crack cocaine use. At follow-up higher levels of alcohol and crack use among drug network members were associated with indexes' reports of multiple sex partners and increased alcohol consumption. Higher levels of crack use among the drug network members were associated with the indexes' reporting casual sex partners at follow-up. These results highlight the importance of studying the role of peer group influence and the social context of risk behaviors.

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

PubMed

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

2014-04-01

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

Attention deficit hyperactivity disorder in cocaine-dependent adults: a psychiatric comorbidity analysis.

PubMed

Daigre, Constanza; Roncero, Carlos; Grau-López, Lara; Martínez-Luna, Nieves; Prat, Gemma; Valero, Sergi; Tejedor, Rosa; Ramos-Quiroga, Josep A; Casas, Miguel

2013-01-01

Attention deficit hyperactivity disorder (ADHD) is highly prevalent among drug abusers. We studied the psychiatric comorbidity and characteristics of cocaine use in relation to the presence of ADHD among patients with cocaine dependence. A total of 200 cocaine-dependent patients attending an Outpatient Drug Clinic participated in the study. A systematic evaluation of ADHD (CAADID-II), the severity of addiction (EuropASI) and other axes I and II psychiatric disorders was made (SCID-I and SCID-II). A descriptive, bivariate, and multivariate analysis of the data was performed. In the multivariate analysis, the identified risk factors for the development of ADHD were a history of behavioral disorder in childhood (OR: 3.04), a lifetime history of cannabis dependence in the course of life (OR: 2.68), and age at the start of treatment (OR: 1.08). The bivariate analysis showed ADHD to be associated with other factors such as male gender, age at start of cocaine use and dependence, the amount of cocaine consumed weekly, increased occupational alteration, alcohol consumption, general psychological discomfort, depressive disorder, and antisocial personality disorder. We conclude that ADHD is associated with increased psychiatric comorbidity and greater severity of addiction. Copyright © American Academy of Addiction Psychiatry.

Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys.

PubMed

Czoty, Paul W

2015-08-01

Most cocaine abusers also abuse alcohol, but little is known about interactions that promote co-abuse. These experiments in rhesus monkeys determined the effects of >8 weeks of ethanol (EtOH) consumption on cocaine self-administration (n=6), effects of dopamine (DA) receptor antagonists on cocaine reinforcement (n=3-4 per drug) and the ability of the D2-like DA receptor agonist quinpirole to elicit yawning (n=3). Monkeys self-administered cocaine (0.0-1.0mg/kg/injection, i.v.) under a 300-s fixed-interval schedule and the above-listed variables were measured before EtOH exposure. Next, monkeys consumed a sweetened, 4% EtOH solution in the home cage under binge-like conditions: 1h, 5 days/week with daily intake equaling 2.0g/kg EtOH. After approximately 8 weeks, measures were re-determined, then EtOH drinking was discontinued. Finally, acute effects of EtOH on cocaine self-administration were determined by infusing EtOH (0.0-1.0g/kg. i.v.) prior to cocaine self-administration sessions (n=4). In five of six monkeys, EtOH drinking increased self-administration of low cocaine doses but did not alter reinforcing effects of higher doses. Self-administration returned to baseline after EtOH access was terminated (n=3). Effects of DA receptor antagonists on cocaine self-administration were not consistently altered after EtOH consumption, but the ability of quinpirole to induce yawning was enhanced in two of three monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. Taken together, the data suggest that long-term EtOH exposure can increase sensitivity to cocaine, possibly by increasing D3 receptor sensitivity. Data do not support a role for acute pharmacological interactions in promoting cocaine/EtOH co-abuse. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cocaine (Coke, Crack) Facts

MedlinePlus

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

Elevated Plasma Norepinephrine After In Utero Exposure to Cocaine and Marijuana

PubMed Central

Mirochnick, Mark; Meyer, Jerrold; Frank, Deborah A.; Cabral, Howard; Tronick, Edward Z.; Zuckerman, Barry

2008-01-01

Objective To compare plasma catecholamine concentrations between cocaine-exposed and unexposed term newborns and to determine the relationship between plasma catecholamines and newborn behavior. Methods Forty-six newborn infants participating in a prospective study of the neonatal and long-term effects of prenatal cocaine exposure were studied. Based on maternal self-report, maternal urine screening, and infant meconium analysis, 24 infants were classified as cocaine-exposed and 22 as unexposed. Between 24 and 72 hours postpartum, plasma samples for norepinephrine (NE), epinephrine, dopamine, and dihydroxyphenylalanine analysis were obtained. The Neonatal Behavioral Assessment Scale was administered at 1 to 3 days of age and at 2 weeks of age by examiners masked to the drug exposure status of the newborns. Results The cocaine-exposed newborns had increased plasma NE concentrations when compared to the unexposed infants (geometric mean, 923 pg/mL vs 667 pg/mL). There were no significant differences in plasma epinephrine, dopamine, or dihydroxyphenylalanine concentrations. Analysis for the effect of potential confounding variables revealed that maternal marijuana use was also associated with increased plasma NE, although birth weight, gender, and maternal use of alcohol or cigarettes were not. Geometric mean plasma NE was 1164 pg/mL in those infants with in utero exposure to both cocaine and marijuana compared to 812 pg/mL in those exposed to only cocaine and 667 pg/mL in those exposed to neither. Among the cocaine-exposed infants, plasma NE concentration correlated with an increased score for the depressed cluster (r = .53) and a decreased score for the orientation cluster (r = −.43) of the Neonatal Behavioral Assessment Scale administered at 1 to 3 days of age. Adjusting for marijuana exposure had no effect on these relationships between plasma NE and the depressed and orientation clusters. Conclusion Plasma NE is increased in newborns exposed to cocaine and

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

PubMed

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

2016-02-01

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

Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.

PubMed

Murthy, Vishakantha; Geng, Liyi; Gao, Yang; Zhang, Bin; Miller, Jordan D; Reyes, Santiago; Brimijoin, Stephen

2015-08-01

Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.

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

PubMed

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

2018-05-31

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

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

PubMed

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

2017-02-01

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

The cocaine-abused heart.

PubMed

Keller, Kathryn Buchanan; Lemberg, Louis

2003-11-01

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

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

PubMed Central

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

2012-01-01

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

Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.

PubMed

Vorel, Stanislav R; Ashby, Charles R; Paul, Mousumi; Liu, Xinhe; Hayes, Robert; Hagan, Jim J; Middlemiss, Derek N; Stemp, Geoffrey; Gardner, Eliot L

2002-11-01

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

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

PubMed Central

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

2010-01-01

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

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

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

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

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

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

PubMed

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

2018-04-17

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

Passive inhalation of cocaine.

PubMed

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

1995-10-01

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

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

PubMed

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

2005-11-01

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

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

PubMed

Hall, W; Carter, L

2004-08-01

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

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

PubMed

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

2015-08-01

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

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

PubMed Central

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

2015-01-01

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

Computational Design of a Thermostable Mutant of Cocaine Esterase via Molecular Dynamics Simulations

PubMed Central

Huang, Xiaoqin; Gao, Daquan; Zhan, Chang-Guo

2015-01-01

Cocaine esterase (CocE) has been known as the most efficient native enzyme for metabolizing the naturally occurring cocaine. A major obstacle to the clinical application of CocE is the thermoinstability of native CocE with a half-life of only ~11 min at physiological temperature (37°C). It is highly desirable to develop a thermostable mutant of CocE for therapeutic treatment of cocaine overdose and addiction. To establish a structure-thermostability relationship, we carried out molecular dynamics (MD) simulations at 400 K on wild-type CocE and previously known thermostable mutants, demonstrating that the thermostability of the active form of the enzyme correlates with the fluctuation (characterized as the RMSD and RMSF of atomic positions) of the catalytic residues (Y44, S117, Y118, H287, and D259) in the simulated enzyme. In light of the structure-thermostability correlation, further computational modeling including MD simulations at 400 K predicted that the active site structure of the L169K mutant should be more thermostable. The prediction has been confirmed by wet experimental tests showing that the active form of the L169K mutant had a half-life of 570 min at 37°C, which is significantly longer than those of the wild-type and previously known thermostable mutants. The encouraging outcome suggests that the high-temperature MD simulations and the structure-thermostability may be considered as a valuable tool for computational design of thermostable mutants of an enzyme. PMID:21373712

Computational design of a thermostable mutant of cocaine esterase via molecular dynamics simulations.

PubMed

Huang, Xiaoqin; Gao, Daquan; Zhan, Chang-Guo

2011-06-07

Cocaine esterase (CocE) has been known as the most efficient native enzyme for metabolizing naturally occurring cocaine. A major obstacle to the clinical application of CocE is the thermoinstability of native CocE with a half-life of only ∼11 min at physiological temperature (37 °C). It is highly desirable to develop a thermostable mutant of CocE for therapeutic treatment of cocaine overdose and addiction. To establish a structure-thermostability relationship, we carried out molecular dynamics (MD) simulations at 400 K on wild-type CocE and previously known thermostable mutants, demonstrating that the thermostability of the active form of the enzyme correlates with the fluctuation (characterized as the root-mean square deviation and root-mean square fluctuation of atomic positions) of the catalytic residues (Y44, S117, Y118, H287, and D259) in the simulated enzyme. In light of the structure-thermostability correlation, further computational modelling including MD simulations at 400 K predicted that the active site structure of the L169K mutant should be more thermostable. The prediction has been confirmed by wet experimental tests showing that the active form of the L169K mutant had a half-life of 570 min at 37 °C, which is significantly longer than those of the wild-type and previously known thermostable mutants. The encouraging outcome suggests that the high-temperature MD simulations and the structure-thermostability relationship may be considered as a valuable tool for the computational design of thermostable mutants of an enzyme.

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

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

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

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and {sup 18}FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo andmore » once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Telang, Frank; Fowler, Joanna S.; Pradhan, Kith; Jayne, Millard; Logan, Jean; Goldstein, Rita Z.; Alia-Klein, Nelly; Wong, Christopher

2010-01-01

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic

Naloxone effects on extinction of ethanol- and cocaine-induced conditioned place preference in mice.

PubMed

Font, Laura; Houck, Christa A; Cunningham, Christopher L

2017-09-01

Previous studies found that naloxone (NLX) facilitated choice extinction of ethanol conditioned place preference (CPP) using long (60 min) test sessions, but there is little information on the variables determining this effect. These studies examined repeated exposure to NLX during extinction of ethanol- or cocaine-induced CPP using both short and long tests. DBA/2J mice were injected with NLX (0 or 10 mg/kg) before three 10- or 60-min choice extinction tests (experiment 1). All mice received a final 60-min test without NLX. Post-test NLX was given in experiment 2. Experiment 3 tested whether NLX would affect a forced extinction procedure. Experiment 4 tested its effect on extinction of cocaine-induced CPP. Pre-test (but not post-test) injections of NLX-facilitated choice extinction of ethanol CPP at both test durations. Pre-test NLX also facilitated forced extinction. However, pre-test NLX had no effect on choice extinction of cocaine CPP. Extinction test duration is not critical for engaging the opioid system during ethanol CPP extinction (experiment 1). Moreover, NLX's effect does not depend on CPP expression during extinction, just exposure to previously conditioned cues (experiment 3). The null effect of post-test NLX eliminates a memory consolidation interpretation (experiment 2) and the failure to alter cocaine CPP extinction argues against alteration of general learning or memory processes (experiment 4). Overall, these data suggest that the endogenous opioid system mediates a conditioned motivational effect that normally maintains alcohol-induced seeking behavior, which may underlie the efficacy of opiate antagonists in the treatment of alcoholism.

Growth, Development, and Behavior in Early Childhood Following Prenatal Cocaine Exposure

PubMed Central

Frank, Deborah A.; Augustyn, Marilyn; Knight, Wanda Grant; Pell, Tripler; Zuckerman, Barry

2008-01-01

, scope, or kind from the sequelae of multiple other risk factors. Many findings once thought to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child’s environment. Further replication is required of preliminary neurologic findings. PMID:11268270

Cocaine intoxication

MedlinePlus

... head, if head injury or bleeding is suspected ECG (electrocardiogram, to measure electrical activity in the heart) ... to amputation Alternative Names Intoxication - cocaine Images Electrocardiogram (ECG) References Aronson JK. Cocaine. In: Aronson JK, ed. ...

Gender stereotypes in psychosocial care for female crack and powder cocaine users.

PubMed

Silva, Érika Barbosa de Oliveira; Pereira, Adriana Lenho de Figueiredo; Penna, Lúcia Helena Garcia

2018-05-10

The study analyzed health professionals' conceptions toward female users of crack and powder cocaine currently receiving psychosocial care, based on a gender perspective. Seventeen health professionals were interviewed, and systematic observations were made of the spaces for collective care in a Center for Psychosocial Care specializing in alcohol and drug addiction in Greater Metropolitan Rio de Janeiro, Brazil. Analysis of the interviews and field diaries using the hermeneutic-dialectic method revealed three categories: frailty as a constitutive attribute of women's condition, the women's emotional addiction to crack and powder cocaine use, and gender stereotypes during psychosocial care. The health professionals voiced a traditional view of the heterosexual, docile, and maternal woman and reproduced stereotypical concepts when addressing female crack and cocaine users as sensitive, frail individuals, emotionally dependent on men and more involved in the home and family. These professionals need a more refined understanding of gender issues in the mental health-disease process in order to allow overcoming preconceived notions and reductionist health care practices.

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

PubMed Central

Mello, Nancy K.; Newman, Jennifer L.

2011-01-01

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

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

PubMed

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

2014-04-01

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

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

PubMed Central

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

2014-01-01

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

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

PubMed Central

Schindler, Charles W; Goldberg, Steven R

2012-01-01

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

Association Among Periodontitis and the Use of Crack Cocaine and Other Illicit Drugs.

PubMed

Antoniazzi, Raquel P; Zanatta, Fabricio B; Rösing, Cassiano K; Feldens, Carlos Alberto

2016-12-01

Crack cocaine can alter functions related to the immune system and exert a negative influence on progression and severity of periodontitis. The aim of this study is to compare periodontal status between crack cocaine users and crack cocaine non-users and investigate the association between crack cocaine and periodontitis after adjustments for confounding variables. This cross-sectional study evaluated 106 individuals exposed to crack cocaine and 106 never exposed, matched for age, sex, and tobacco use. An examiner determined visible plaque index (VPI), marginal bleeding index, supragingival dental calculus, probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP). Logistic regression was used to model associations between crack cocaine and periodontitis (at least three sites with CAL >4 mm and at least two sites with PD >3 mm, not in the same site or tooth). Prevalence of periodontitis among crack non-users and crack users was 20.8% and 43.4%, respectively. Crack users had greater VPI, BOP, PD ≥3 mm, and CAL ≥4 mm than crack non-users. Periodontitis was associated with age >24 years, schooling ≤8 years, smoking, moderate/heavy alcohol use, and plaque rate ≥41%. Crack users had an approximately three-fold greater chance (odds ratio: 3.44; 95% confidence interval: 1.51 to 7.86) of periodontitis than non-users. Occurrence of periodontitis, visible plaque, and gingival bleeding was significantly higher among crack users, and crack use was associated with occurrence of periodontitis.

[Ten years of emergency attendances for cocaine-users in Spain].

PubMed

Galicia, Miguel; Nogué, Santiago; Burillo-Putze, Guillermo

2014-10-07

Cocaine is the second most consumed illegal drug in the western world, following cannabis. Since 1998, it is also the drug that more attendances generate in different emergency devices, and it is responsible for more of 60% of the emergencies directly related to drug consumption. This work reviews the main Spanish scientific articles published in the last 10 years, in which different factors related to the use of this drug have been analyzed in relation to the use of emergency by cocaine users. A total of 8,795 patients were included (interval 57-1,755), with an average age of 32.64 years (SD 3.02), and an average percentage of positives to cocaine of 54.78% (SD 47.03); there were 7 works with 100% of subjects being positive to cocaine. Males predominated with an average of 78.69% (SD 12). They presented cardiovascular symptoms in 30% cases (SD 22.7), neurological symptoms in 11.6% cases (SD 4.28) and psychiatric symptoms in 49.32% cases (SD 23.87). There was a multiple consumption in 49.02% of patients (interval 4.3-76.2), fundamentally associated with alcohol (57.78%, SD 6.18) and cannabis (21.56%, SD 10.72). Two hundred and forty-six patients (2.8%) needed admission and 8 died (0.09%). Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Risks associated with crack cocaine smoking among exotic dancers in Baltimore, MD.

PubMed

Sherman, Susan G; Reuben, Jacqueline; Chapman, Chris Serio; Lilleston, Pamela

2011-04-01

There is a dearth of research focusing on sex work in exotic dance clubs. We conducted a cross-sectional study to examine the prevalence and correlates of crack cocaine smoking among a sample of exotic dancers. The "block," a historical red-light district in downtown Baltimore, MD, is comprised of 30 adult-entertainment establishments. Between 01/09 and 08/09, we conducted a survey with exotic dancers (N=98). The survey explored demographic, and drug and sexual/drug risk behaviors. Bivariate and multivariate analysis was conducted using Poisson regression with robust variance estimates to examine correlates of current crack smoking. Crack cocaine smokers compared to non-crack cocaine smokers were significantly more likely to report: older age (29 vs. 23 years, respectively, p<0.0001); being White (79% vs. 50%, respectively, p=0.008); having been arrested (93% vs. 67%, respectively, p=0.008); daily alcohol consumption (36% vs. 17%, p=0.047); current heroin injection (57% vs. 13%, p<0.001); and current sex exchange (79% vs. 30%, p<0.001). In the presence of other variables, crack cocaine smokers compared to non-crack cocaine smokers were significantly older, more likely to report current heroin injection, and more likely to report current sex exchange. We found high levels of drug use and sexual risk behaviors as well as a number of risks behaviors associated with crack cocaine smoking among this very under-studied population. Targeted interventions are greatly needed. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Vaccines against stimulants: cocaine and MA

PubMed Central

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

2014-01-01

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. PMID:23509915

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. © 2013 The British Pharmacological Society.

Lifetime history of insomnia and hypersomnia symptoms as correlates of alcohol, cocaine, and heroin use and relapse among adults seeking substance use treatment in the United States from 1991 to 1994

PubMed Central

Dolsen, Michael R.; Harvey, Allison G.

2017-01-01

Aims To examine the association between a lifetime history of insomnia and hypersomnia compared with no sleep disturbance and substance use patterns and amounts before and after a substance use treatment episode. Design Secondary analysis of data from the Drug Abuse Treatment Outcome Studies conducted from 1991 to 1994. Setting Data were collected at 96 substance use treatment programs in 11 United States cities including short-term in-patient, long-term residential, methadone maintenance, and outpatient drug-free treatment modalities. Participants Study samples included 7,168 adults at treatment entry and 2,965 at 12 months post-treatment entry whose primary substance use at entry was alcohol (14.7%), cocaine (62.7%), or heroin (22.6%). Measurements Lifetime history of insomnia and hypersomnia was assessed via self-report. Type and frequency of substance use were assessed at treatment entry. Substance use was also assessed 12 months following treatment completion. Associations were examined using linear and logistic regression with age, sex, race, education level, depression history, treatment modality, and in-treatment substance use as covariates. Findings Lifetime history of insomnia, hypersomnia, both or neither was reported by 26.3%, 9.5%, 28.0% and 36.2% of participants, respectively. Compared with no sleep disturbance, lifetime insomnia and hypersomnia were associated at treatment entry with unique substance use patterns and a higher frequency of any substance use (p < .001). All types of sleep disturbance were associated with higher rates of cocaine use at 12-month post-entry (ORs: 1.30–1.57). Conclusions There is evidence of an adverse association between substance use and sleep disturbance including higher frequency of all substance use before substance abuse treatment and higher rates of cocaine use after a treatment episode. PMID:28127809

Does Cannabis Onset Trigger Cocaine Onset? A Case-Crossover Approach

PubMed Central

O’Brien, Megan S.; Comment, Leah Andrews; Liang, Kung Yee; Anthony, James C.

2016-01-01

Psychiatric researchers tend to select the discordant co-twin design when they seek to hold constant genetic influence while estimating exposure-associated disease risk. The epidemiologic case-crossover research design developed for the past two decades represents a viable alternative, not often seen in psychiatric studies. Here, we turn to the epidemiologic case-crossover approach to examine the idea that cannabis onset is a proximal trigger for cocaine use, with the power of ‘subject-as-own-control’ research used to hold constant antecedent characteristics of the individual drug user, including genetic influence and other traits experienced up to the time of the observed hazard and control intervals. Data are from newly incident cocaine users identified in the 2002–2006 U.S. National Surveys on Drug Use and Health. Among these cocaine users, 48 had both cannabis onset and cocaine onset in the same month-long hazard interval; the expected value is 30 users, based on the control interval we had pre-specified for case-crossover estimation (estimated relative risk, RR = 1.6; exact mid-p = 0.042). Within the framework of a subject-as-own-control design, the evidence is consistent with the hypothesis that cannabis onset is a proximal trigger for cocaine use, with genetic influences (and many environmental conditions and processes) held constant. Limitations are noted and implications discussed. PMID:22228642

Prenatal Cocaine Exposure: The South Looks for Answers. A SACUS Special Report.

ERIC Educational Resources Information Center

Shores, Elizabeth F.

This special report provides answers to six fundamental questions on prenatal cocaine exposure: (1) What problems do drug-exposed newborns have? (2) How many of these children are there? (3) How do we get pregnant women to avoid drugs and alcohol? (4) What should be done to help the families of substance abusers? (5) How do drug-exposed children…

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

PubMed

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

2016-06-01

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

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

PubMed

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

2012-02-01

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

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

PubMed

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

2018-06-01

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

Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction

PubMed Central

Narasimhan, Diwahar; Woods, James H; Sunahara, Roger K

2012-01-01

Cocaine is highly addictive and there are no pharmacotherapeutic drugs available to treat acute cocaine toxicity or chronic abuse. Antagonizing an inhibitor such as cocaine using a small molecule has proven difficult. The alternative approach is to modify cocaine’s pharmacokinetic properties by sequestering or hydrolyzing it in serum and limiting access to its sites of action. We took advantage of a bacterial esterase (CocE) that has evolved to hydrolyze cocaine and have developed it as a therapeutic that rapidly and specifically clears cocaine from the subject. Native enzyme was unstable at 37°C, thus limiting CocE’s potential. Innovative computational methods based on the protein’s structure helped elucidate its mechanism of destabilization. Novel protein engineering methodologies were applied to substantially improve its stability in vitro and in vivo. These improvements rendered CocE as a powerful and efficacious therapeutic to treat cocaine intoxication and lead the way towards developing a therapy for addiction. PMID:22300094

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

PubMed

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

2005-09-01

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

Acute morphine and cocaine related death after trimethoprim-adultered cocaine abuse.

PubMed

Fucci, Nadia; Pascali, Vincenzo L

2014-01-01

Over the last few decades, cocaine and morphine (heroin) have been among the primary causes of deaths related to drug abuse. Cocaine is frequently altered by dilution, substitution, contamination, and adulteration. Trimethoprim has never been identified in the powders of cocaine, making this the first post-mortem case report in which the presence of this compound is described. The case reported here is that of a 46-year-old woman with a history of cocaine and morphine abuse who was found dead inside her bathroom. The police found the corpse next to a syringe, with a telephone card containing trace of cocaine on the sink. Toxicological analysis was performed, and drug levels were measured by means of gas chromatography/mass spectrometry. In addition to the presence of cocaine and smaller alkaloids, trimethoprim was also detected on the syringe and telephone card and in the woman's nasal mucosa. Trimethoprim analysis is very quick and easy and can be added to the routine analysis of drugs of abuse seized on the illicit market to obtain more information. © 2014 by the Association of Clinical Scientists, Inc.

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

PubMed

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

2014-02-01

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

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

PubMed

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

2016-04-01

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

Hepatitis C Infection in Non-Treatment-Seeking Heroin Users: The Burden of Cocaine Injection

PubMed Central

Roux, P.; Fugon, L.; Jones, J.D.; Comer, S.D.

2014-01-01

Background and Objectives In heroin dependent individuals, the HIV epidemic has been controlled in countries where access to opioid maintenance treatment (OMT) and needle exchange programs (NEP) have been implemented. However, despite similar routes of contamination for both viruses, the prevalence of hepatitis C (HCV) infection remains high in drug users. The objective of this analysis was to identify the prevalence of HCV and the correlates of being HCV-positive in a sample of out-of-treatment heroin-dependent individuals. Methods Data were collected from five inpatient studies (n = 120 participants) conducted at the New York State Psychiatric Institute. A logistic regression was used to identify correlates of being HCV-positive at baseline. Results Among the 120 heroin-dependent volunteers, 42 were HCV-positive. Participants who had heavier alcohol use, a longer duration of heroin use, or who reported using heroin by injection were more likely to be HCV-positive. Interestingly, participants who had injected cocaine during the previous month had a ninefold greater risk of being HCV-positive compared to non-cocaine users and those who used cocaine by a non-injecting route. Conclusions and Scientific Significance These findings confirm the risk of being HCV-infected through intravenous drug use, especially with cocaine use. These results underscore the importance of rethinking interventions to prevent HCV infection with combined strategies using pharmacological approaches for cocaine dependence and tailored prevention for cocaine users. PMID:24131170

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

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

PubMed

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

2017-11-01

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

The effects of a repeated dose of a recombinant humanized anti-cocaine monoclonal antibody on cocaine self-administration in rats.

PubMed

Wetzel, Hanna N; Tsibulsky, Vladimir L; Norman, Andrew B

2016-11-01

Immunotherapy has shown potential as a treatment for cocaine abuse. The humanized recombinant anti-cocaine monoclonal antibody (mAb) with the preclinical designation h2E2 has been shown to decrease cocaine concentrations in the brain in rats, but its effects on cocaine self-administration behavior have never been tested. The amount of cocaine needed to reinstate self-administration behavior (priming threshold) was calculated and the inter-injection intervals at unit doses of 0.3μmol/kg and 3μmol/kg during maintained self-administration were measured over a five-week baseline period. Rats trained to self-administer cocaine were infused with two doses of h2E2 (120mg/kg i.v.) 35days apart. Priming threshold and inter-injection intervals were measured for 35days after both injections. After both injections of h2E2, priming thresholds were significantly increased (3-fold) compared to expected baseline and then gradually declined over 35days. A significant decrease (15-33%) in inter-injection intervals during maintained self-administration was also observed following both h2E2 infusions at the lower dose, and after the first injection at the higher dose. No significant decreases in body weight were observed after either injection, indicating a lack of toxicity following a second injection. These data predict that the safety and effectiveness of h2E2 will be maintained after multiple treatments of this potential immunotherapy for cocaine abuse. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The effects of a repeated dose of a recombinant humanized anti-cocaine monoclonal antibody on cocaine self-administration in rats

PubMed Central

Wetzel, Hanna N.; Tsibulsky, Vladimir L.; Norman, Andrew B.

2016-01-01

Background Immunotherapy has shown potential as a treatment for cocaine abuse. The humanized recombinant anti-cocaine monoclonal antibody (mAb) with the preclinical designation h2E2 has been shown to decrease cocaine concentrations in the brain in rats, but its effects on cocaine self-administration behavior have never been tested. Methods The amount of cocaine needed to reinstate self-administration behavior (priming threshold) was calculated and the inter-injection intervals at unit doses of 0.3 μmol/kg and 3 μmol/kg during maintained self-administration were measured over a five-week baseline period. Rats trained to self-administer cocaine were infused with two doses of h2E2 (120 mg/kg i.v.) 35 days apart. Priming threshold and inter-injection intervals were measured for 35 days after both injections. Results After both injections of h2E2, priming thresholds were significantly increased (3-fold) compared to expected baseline and then gradually declined over 35 days. A significant decrease (15–33%) in inter-injection intervals during maintained self-administration was also observed following both h2E2 at the lower dose, and after the first injection at the higher dose. No significant decreases in body weight were observed after either injection, indicating a lack of toxicity following a second injection. Conclusions These data predict that the safety and efficacy of h2E2 will be maintained after multiple treatments of this potential immunotherapy for cocaine abuse. PMID:27736682

Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

PubMed

Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

2010-09-01

Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

[Cocaine - Characteristics and addiction].

PubMed

Girczys-Połedniok, Katarzyna; Pudlo, Robert; Jarząb, Magdalena; Szymlak, Agnieszka

Cocaine use leads to health, social and legal problems. The aim of this paper is to discuss cocaine action, addicts characteristics, use patterns and consequences, as well as addiction treatment methods. A literature review was based on the Medline, PubMed, Polish Medical Bibliography databases and the Silesian Library resources. The Police and Central Statistical Office statistics, as well as the World Health Organization, the European Monitoring Centre for Drugs and Drug Addiction and the National Office for Combating Drug Addiction reports were used. Cocaine leads to mood improvement, appetite decrease, physical and intellectual activity enhancement, euphoria, inflated self-esteem, social networking ease and increased sexual desire. Cocaine hydrochloride is mainly used intranasaly, but also as intravenous and subcutaneous injections. Cocaine use and first addiction treatment fall in later age compared to other psychoactive substances. There is a high men to women ratio among addicts. There is a relationship between cocaine addiction, the presence of other disorders and genetic predisposition to addiction development. Polish reports indicate higher popularity of cocaine among people with a high economic and social status. Although Poland is a country with the low percentage of cocaine use, its popularity is growing. The consequences of cocaine use concern somatic and mental health problems, socioeconomic and legal conditions. The drug plays a role in crimes and traffic accidents. Because of the risks associated with cocaine use, it has been listed in a register of drugs attached to the Act on Counteracting Drug Addiction. Addiction treatment includes psychological, pharmacological and harm reduction strategies. Med Pr 2016;67(4):537-544. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

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.

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

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

PubMed

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

2015-05-01

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

Children's cognitive ability from 4 to 9 years old as a function of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence.

PubMed

Bennett, David S; Bendersky, Margaret; Lewis, Michael

2008-07-01

This study examined the effects of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence on children's cognitive ability. Gender and age were examined as moderators of potential cocaine exposure effects. The Stanford-Binet IV intelligence test was administered to 231 children (91 cocaine exposed, 140 unexposed) at ages 4, 6, and 9 years. Neonatal medical risk and other prenatal exposures (alcohol, cigarettes, and marijuana) were also examined for their unique effects on child IQ. Mixed models analysis indicated that prenatal cocaine exposure interacted with gender, as cocaine-exposed boys had lower composite IQ scores. Age at assessment did not moderate this relation, indicating that cocaine-exposed boys had lower IQs across this age period. A stimulating home environment and high maternal verbal IQ also predicted higher composite IQ scores. Cocaine-exposed boys had lower scores on the Abstract/Visual Reasoning subscale, with trends for lower scores on the Short-Term Memory and Verbal Reasoning subscales, as exposure effects were observed across domains. The findings indicate that cocaine exposure continues to place children at risk for mild cognitive deficits into preadolescence. Possible mechanisms for the Exposure x Gender interaction are discussed.

[Cocaine base paste: experience from the Montevideo Poison Control Center].

PubMed

Pascale, Antonio; Negrin, Alba; Laborde, Amalia

2010-01-01

In Uruguay, cocaine base paste (CBP, pasta base) is a widely used form of cocaine. The aim of our study is to determine the main clinical characteristics of CBP abusers. Retrospective, single-center study of consultations at the Montevideo Poison Control Center between January 1, 2004 and December 31, 2005. One hundred and thirteen consultations were included, with an average age of 22 years (+ - 0.5 years) and a female-male sex ratio of 1:4.3. The consultations were related to drug overdose (77%), suicide attempt (16.8%), and wanting to give up CBP use (6.2%). In 48.1% the time elapsed since inhalation of CBP was less than 6 hours. Doses varied between 0.5 gr. and 25 gr. Use of other drugs at the same time, such as alcohol, marijuana or benzodiazepines, was common (51 cases). The symptoms most frequently observed were neuropsychiatric and cardiovascular, followed by respiratory symptoms. In 16.8% of patients, reason for the consultation was intentional acute ingestion of drugs, considered as a suicide attempt, occurring within a few hours of drug consumption. CBP users are mostly young males. Although clinical findings are compatible with those for cocaine abuse, euphoria is a major clinical feature in CBP abusers. The presence of respiratory symptoms reflects the complications associated with the ingestion route. Suicide attempts occurring within a few hours of CBP confirm the high prevalence of suicidal ideation reported by other authors. cocaine base paste, clinical features, suicide attempts.

When alcohol is only part of the problem: An event-level analysis of negative consequences related to alcohol and other substance use.

PubMed

Mallett, Kimberly A; Turrisi, Rob; Hultgren, Brittney A; Sell, Nichole; Reavy, Racheal; Cleveland, Michael

2017-05-01

While alcohol remains the drug of choice for most college students, national data show that 40% of college students also use other substances (e.g., marijuana, cocaine, etc.). Longitudinal studies indicate that students who report use of both alcohol and other substances experience more consequences (e.g., blackout, arrests). The current study expands upon this research by using a multilevel approach to examine average and event-level alcohol combined with other substance use (ALC+) and its role on consequences experienced. In addition, the research examined which substance combined with alcohol posed the most risk. A total of 461 students reported on alcohol use, substance use, and consequences experienced (e.g., Young Adult Alcohol Consequences Questionnaire [YAACQ]) on 12 weekend nights (Thursday, Friday, Saturday) across 4 weekends in an academic year. Multilevel model analyses revealed a positive association between both average and event-level ALC+ use and the number of consequences experienced. A significant cross-level interaction was also revealed indicating students who typically combine alcohol and other substances experienced more consequences on occasions when they use more substances relative to students who typically use alcohol only. Finally, alcohol plus nicotine, or marijuana, or attention-deficit/hyperactivity disorder (ADHD) medications, or cocaine were all significantly positively related to increased consequences. These findings provide consistent evidence that ALC+ use is a highly prevalent behavior among college students that increases risk of problematic consequences. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

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

PubMed Central

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

2011-01-01

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

Vaccines for cocaine abuse.

PubMed

Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Kosten, Thomas R

2009-04-01

Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.

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

PubMed Central

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

2011-01-01

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

Quality of Web-based information on cocaine addiction.

PubMed

Khazaal, Yasser; Chatton, Anne; Cochand, Sophie; Zullino, Daniele

2008-08-01

To evaluate the quality of web-based information on cocaine use and addiction and to investigate potential content quality indicators. Three keywords: cocaine, cocaine addiction and cocaine dependence were entered into two popular World Wide Web search engines. Websites were assessed with a standardized proforma designed to rate sites on the basis of accountability, presentation, interactivity, readability and content quality. "Health on the Net" (HON) quality label, and DISCERN scale scores aiding people without content expertise to assess quality of written health publication were used to verify their efficiency as quality indicators. Of the 120 websites identified, 61 were included. Most were commercial sites. The results of the study indicate low scores on each of the measures including content quality. A global score (the sum of accountability, interactivity, content quality and aesthetic criteria) appeared as a good content quality indicator. While cocaine education websites for patients are widespread, their global quality is poor. There is a need for better evidence-based information about cocaine use and addiction on the web. The poor and variable quality of web-based information and its possible impact on physician-patient relationship argue for a serious provider for patient talk about the health information found on Internet. Internet sites could improve their content using the global score as a quality indicator.

Cocaine/Crack: The Big Lie.

ERIC Educational Resources Information Center

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

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

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

PubMed

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

2013-01-01

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

Preventing Abuse of Drugs, Alcohol, and Tobacco by Adolescents.

ERIC Educational Resources Information Center

Falco, Mathea

From the mid-1960s until 1980, adolescent drug use rose sharply. Although use has declined somewhat since, adolescent cocaine use remains at peak levels, and crack presents a major threat. Treatment for compulsive drug or alcohol use is needed by 5 to 15 percent of the teenagers who experiment with drugs and alcohol. Drug abuse experts now believe…

Toxic effects of prenatal exposure to alcohol, tobacco and other drugs.

PubMed

Scott-Goodwin, A C; Puerto, M; Moreno, I

2016-06-01

Tobacco, alcohol, cannabis and cocaine are the most consumed psychoactive drugs throughout the population. Prenatal exposure to these drugs could alter normal foetal development and could threaten future welfare. The main changes observed in prenatal exposure to tobacco are caused by nicotine and carbon monoxide, which can impede nutrient and oxygen exchange between mother and foetus, restricting foetal growth. Memory, learning processes, hearing and behaviour can also be affected. Alcohol may cause physical and cognitive alterations in prenatally exposed infants, fundamentally caused by altered NMDAR and GABAR activity. Tetrahydrocannabinol, the psychoactive compound of cannabis, is capable of activating CB1R, inducing connectivity deficits during the foetal brain development. This fact could be linked to behavioural and cognitive deficits. Many of the effects from prenatal cocaine exposure are caused by altered cell proliferation, migration, differentiation and dendritic growth processes. Cocaine causes long term behavioural and cognitive alterations and also affects the uteroplacental unit. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Diffusion Tensor Imaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children

PubMed Central

Warner, Tamara Duckworth; Behnke, Marylou; Eyler, Fonda Davis; Padgett, Kyle; Leonard, Christiana; Hou, Wei; Garvan, Cynthia Wilson; Schmalfuss, Ilona M.; Blackband, Stephen J.

2011-01-01

BACKGROUND Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children. METHODS Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test). RESULTS Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter. CONCLUSIONS Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The

Diffusion tensor imaging of frontal white matter and executive functioning in cocaine-exposed children.

PubMed

Warner, Tamara Duckworth; Behnke, Marylou; Eyler, Fonda Davis; Padgett, Kyle; Leonard, Christiana; Hou, Wei; Garvan, Cynthia Wilson; Schmalfuss, Ilona M; Blackband, Stephen J

2006-11-01

Although animal studies have demonstrated frontal white matter and behavioral changes resulting from prenatal cocaine exposure, no human studies have associated neuropsychological deficits in attention and inhibition with brain structure. We used diffusion tensor imaging to investigate frontal white matter integrity and executive functioning in cocaine-exposed children. Six direction diffusion tensor images were acquired using a Siemens 3T scanner with a spin-echo echo-planar imaging pulse sequence on right-handed cocaine-exposed (n = 28) and sociodemographically similar non-exposed children (n = 25; mean age: 10.6 years) drawn from a prospective, longitudinal study. Average diffusion and fractional anisotropy were measured in the left and right frontal callosal and frontal projection fibers. Executive functioning was assessed using two well-validated neuropsychological tests (Stroop color-word test and Trail Making Test). Cocaine-exposed children showed significantly higher average diffusion in the left frontal callosal and right frontal projection fibers. Cocaine-exposed children were also significantly slower on a visual-motor set-shifting task with a trend toward lower scores on a verbal inhibition task. Controlling for gender and intelligence, average diffusion in the left frontal callosal fibers was related to prenatal exposure to alcohol and marijuana and an interaction between cocaine and marijuana exposure. Performance on the visual-motor set-shifting task was related to prenatal cocaine exposure and an interaction between cocaine and tobacco exposure. Significant correlations were found between test performance and fractional anisotropy in areas of the frontal white matter. Prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and subtle microstructural changes suggesting less mature development of frontal white matter pathways. The relative contribution of postnatal

Fluorescence Immunoassay for Cocaine Detection.

PubMed

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

2016-04-01

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

The ability for cocaine and cocaine-associated cues to compete for attention

PubMed Central

Pitchers, Kyle K.; Wood, Taylor R.; Skrzynski, Cari J.; Robinson, Terry E.; Sarter, Martin

2017-01-01

In humans, reward cues, including drug cues in addicts, are especially effective in biasing attention towards them, so much so they can disrupt ongoing task performance. It is not known, however, whether this happens in rats. To address this question, we developed a behavioral paradigm to assess the capacity of an auditory drug (cocaine) cue to evoke cocaine-seeking behavior, thus distracting thirsty rats from performing a well-learned sustained attention task (SAT) to obtain a water reward. First, it was determined that an auditory cocaine cue (tone-CS) reinstated drug-seeking equally in sign-trackers (STs) and goal-trackers (GTs), which otherwise vary in the propensity to attribute incentive salience to a localizable drug cue. Next, we tested the ability of an auditory cocaine cue to disrupt performance on the SAT in STs and GTs. Rats were trained to self-administer cocaine intravenously using an Intermittent Access self-administration procedure known to produce a progressive increase in motivation for cocaine, escalation of intake, and strong discriminative stimulus control over drug-seeking behavior. When presented alone, the auditory discriminative stimulus elicited cocaine-seeking behavior while rats were performing the SAT, but it was not sufficiently disruptive to impair SAT performance. In contrast, if cocaine was available in the presence of the cue, or when administered non-contingently, SAT performance was severely disrupted. We suggest that performance on a relatively automatic, stimulus-driven task, such as the basic version of the SAT used here, may be difficult to disrupt with a drug cue alone. A task that requires more top-down cognitive control may be needed. PMID:27890441

Safety of Atomoxetine in Combination with Intravenous Cocaine in Cocaine- Experienced Participants

PubMed Central

Cantilena, Louis; Kahn, Roberta; Duncan, Connie C.; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

2012-01-01

Objectives Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine, and also whether cognitive function was affected by atomoxetine during short-term administration. Methods In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 mg and 40 mg) was infused intravenously in sequential daily sessions. Results Pre-infusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Pre-infusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80 mg and 100 mg atomoxetine doses. All ECG parameters were unchanged. VAS scores for “bad effect” in the atomoxetine group were significantly higher at baseline, then declined, and for “likely to use” declined with atomoxetine treatment. On the ARCI the atomoxetine group scored significantly lower on amphetamine, euphoria and energy subscales (p<0.0001). Other VAS descriptors, BSCS, POMS, and BPRS showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Conclusions Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine. PMID:22987022

Estimated effects of in utero cocaine exposure on language development through early adolescence.

PubMed

Bandstra, Emmalee S; Morrow, Connie E; Accornero, Veronica H; Mansoor, Elana; Xue, Lihua; Anthony, James C

2011-01-01

The potential longitudinal effects of prenatal cocaine exposure (PCE) on language functioning were estimated from early childhood through early adolescence in a large, well-retained urban sample of 451 full-term children (242 cocaine-exposed, 209 non-cocaine-exposed) participating in the Miami Prenatal Cocaine Study (MPCS). The sample was enrolled prospectively at birth, with documentation of prenatal drug exposure status through maternal interview, and toxicology assays of maternal and infant urine, and infant meconium. Age-appropriate versions of the Clinical Evaluation of Language Fundamentals (CELF) were used to measure total, expressive, and receptive language at ages 3, 5, and 12years. Longitudinal latent growth curve (LLGC) modeling of the data revealed an association between PCE (measured dichotomously as yes/no) and lower functioning in expressive and total language scores, after considering other sources of variation including child's age at testing, sex, prenatal exposure to alcohol, marijuana, and tobacco, and additional medical and social-demographic covariates. Analyses of level of PCE showed a gradient, i.e. dose-dependent, relationship between PCE level and expressive, receptive, and total language scores in the models controlling for age, child's sex, and other prenatal drug exposures. With additional covariate control these findings were most stable for the total language score. The evidence supports an inference about an enduring stable cocaine-specific effect on children's language abilities, with no effect on language growth over time in the longitudinal trajectory of language development. Copyright © 2010 Elsevier Inc. All rights reserved.

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

PubMed Central

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

2013-01-01

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

Covalent modification of proteins by cocaine

NASA Astrophysics Data System (ADS)

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

2002-03-01

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

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

PubMed Central

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

2012-01-01

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

Cocaine, Appetitive Memory and Neural Connectivity

PubMed Central

Ray, Suchismita

2013-01-01

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

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

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

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

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

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

PubMed Central

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

2014-01-01

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

Psychopathology and Special Education Enrollment in Children with Prenatal Cocaine Exposure

PubMed Central

Levine, Todd P.; Lester, Barry; Lagasse, Linda; Shankaran, Seetha; Bada, Henrietta S.; Bauer, Charles R.; Whitaker, Toni M.; Higgins, Rosemary; Hammond, Jane; Roberts, Mary B.

2012-01-01

Objective This study evaluated how enrollment in special education services in 11 year old children relates to prenatal cocaine exposure, psychopathology, and other risk factors. Method Participants were 498 children enrolled in The Maternal Lifestyle Study, a prospective, longitudinal, multisite study examining outcomes of children with prenatal cocaine exposure. Logistic regression was used to examine the effect of prenatal cocaine exposure and psychopathology on enrollment in an individualized education plan (a designation specific to children with special education needs), with environmental, maternal, and infant medical variables as covariates. Results Prenatal cocaine exposure, an interaction of prenatal cocaine exposure and Oppositional Defiant Disorder, child Attention Deficit Hyperactivity Disorder, parent-reported internalizing behaviors, and teacher-reported externalizing behaviors, predicted enrollment in an individualized education plan. Other statistically significant variables in the model were male gender, low birth weight, being small for gestational age, white race, caregiver change, low socio-economic status, low child intelligence quotient, caregiver depression, and prenatal marijuana exposure. Conclusions Prenatal cocaine exposure increased the likelihood of receiving an individualized education plan with adjustment for covariates. Psychopathology also predicted this special education outcome, in combination with and independent of prenatal cocaine exposure. PMID:22487696

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

PubMed

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

2012-05-01

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

Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

PubMed

Cantilena, Louis; Kahn, Roberta; Duncan, Connie C; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

2012-12-01

Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

Prenatal cocaine effects on brain structure in early infancy.

PubMed

Grewen, Karen; Burchinal, Margaret; Vachet, Clement; Gouttard, Sylvain; Gilmore, John H; Lin, Weili; Johns, Josephine; Elam, Mala; Gerig, Guido

2014-11-01

Prenatal cocaine exposure (PCE) is related to subtle deficits in cognitive and behavioral function in infancy, childhood and adolescence. Very little is known about the effects of in utero PCE on early brain development that may contribute to these impairments. The purpose of this study was to examine brain structural differences in infants with and without PCE. We conducted MRI scans of newborns (mean age = 5 weeks) to determine cocaine's impact on early brain structural development. Subjects were three groups of infants: 33 with PCE co-morbid with other drugs, 46 drug-free controls and 40 with prenatal exposure to other drugs (nicotine, alcohol, marijuana, opiates, SSRIs) but without cocaine. Infants with PCE exhibited lesser total gray matter (GM) volume and greater total cerebral spinal fluid (CSF) volume compared with controls and infants with non-cocaine drug exposure. Analysis of regional volumes revealed that whole brain GM differences were driven primarily by lesser GM in prefrontal and frontal brain regions in infants with PCE, while more posterior regions (parietal, occipital) did not differ across groups. Greater CSF volumes in PCE infants were present in prefrontal, frontal and parietal but not occipital regions. Greatest differences (GM reduction, CSF enlargement) in PCE infants were observed in dorsal prefrontal cortex. Results suggest that PCE is associated with structural deficits in neonatal cortical gray matter, specifically in prefrontal and frontal regions involved in executive function and inhibitory control. Longitudinal study is required to determine whether these early differences persist and contribute to deficits in cognitive functions and enhanced risk for drug abuse seen at school age and in later life. Copyright © 2014 Elsevier Inc. All rights reserved.

Post-Retrieval Extinction Attenuates Cocaine Memories

PubMed Central

Sartor, Gregory C; Aston-Jones, Gary

2014-01-01

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

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

PubMed

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

2015-01-01

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

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

21 CFR 862.3250 - Cocaine and cocaine metabolite test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cocaine and cocaine metabolite test system. 862.3250 Section 862.3250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology...

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

PubMed

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

2014-01-01

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

Late Reduction of Cocaine Cravings in a Randomized, Double-Blind Trial of Aripiprazole vs Perphenazine in Schizophrenia and Comorbid Cocaine Dependence.

PubMed

Beresford, Thomas; Buchanan, Jennifer; Thumm, Elizabeth Brie; Emrick, Chad; Weitzenkamp, David; Ronan, Patrick J

2017-12-01

Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients. In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable. Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points. A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.

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

PubMed

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

2015-08-01

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

Cocaine use and the breastfeeding mother.

PubMed

Jones, Wendy

2015-01-01

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

Language Outcomes at 12 Years for Children Exposed Prenatally to Cocaine

ERIC Educational Resources Information Center

Lewis, Barbara A.; Minnes, Sonia; Short, Elizabeth J.; Min, Meeyoung O.; Wu, Miaoping; Lang, Adelaide; Weishampel, Paul; Singer, Lynn T.

2013-01-01

Purpose: In this study, the authors aimed to examine the long-term effects of prenatal cocaine exposure (PCE) on the language development of 12-year-old children using a prospective design, controlling for confounding prenatal drug exposure and environmental factors. Method: Children who were exposed to cocaine in utero (PCE; "n" = 183)…

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

PubMed Central

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

2012-01-01

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

A potential vaccine for cocaine abuse prophylaxis.

PubMed

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

1992-01-01

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

Prolonged withdrawal following cocaine self-administration increases resistance to punishment in a cocaine binge.

PubMed

Gancarz-Kausch, Amy M; Adank, Danielle N; Dietz, David M

2014-11-03

Drug addiction is characterized by compulsive drug-taking behaviors and a high propensity to relapse following drug cessation. Drug craving and seeking can increase during a period of abstinence, but this phenomenon is not observed in drug-induced reinstatement models. To investigate the effect of withdrawal on cocaine relapse, rats were exposed to extended-access cocaine self-administration and subjected to either 1 or 30 d of withdrawal. When tested during 12 h unlimited access to cocaine (binge), the duration of the withdrawal did not influence cocaine intake. However, using a histamine punishment procedure that greatly suppresses drug-taking behavior, we demonstrate that longer periods of abstinence from cocaine induce a greater persistence in responding for drug in the face of negative consequences.

Drug and alcohol testing results 1996 annual report

DOT National Transportation Integrated Search

1997-12-01

The report is a compilation and analysis of mass transit drug and alcohol testing reported by transit systems in the United States during 1996. The report covers testing results for the following drug types: marijuana (THC), cocaine, phencyclidine (P...

Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence.

PubMed

Potenza, Marc N; Hong, Kwang-ik Adam; Lacadie, Cheryl M; Fulbright, Robert K; Tuit, Keri L; Sinha, Rajita

2012-04-01

Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.

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

PubMed

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

2018-04-18

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

Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review.

PubMed

Frank, D A; Augustyn, M; Knight, W G; Pell, T; Zuckerman, B

2001-03-28

to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child's environment. Further replication is required of preliminary neurologic findings.

Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage.

PubMed

Gao, Yang; Geng, Liyi; Orson, Frank; Kinsey, Berma; Kosten, Thomas R; Shen, Xiaoyun; Brimijoin, Stephen

2013-03-25

In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100-120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ~400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Cocaine-induced neuroadaptations in glutamate transmission

PubMed Central

Schmidt, Heath D.; Pierce, R. Christopher

2017-01-01

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

Effects of inhibitory GABA-active neurosteroids on cocaine seeking and cocaine taking in rats.

PubMed

Schmoutz, Christopher D; Runyon, Scott P; Goeders, Nicholas E

2014-09-01

Several compounds that potentiate GABA-induced inhibitory currents also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds that reduce stress-induced responses might be efficacious in treating addiction. Since endogenous neurosteroids such as allopregnanolone may function in a manner similar to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli, we hypothesized that exogenously applied neurosteroids would reduce cocaine reinforcement in two animal models. Male Wistar rats were trained to self-administer cocaine and food under a concurrent alternating operant schedule of reinforcement. Two separate groups of rats were trained to self-administer cocaine or food pellets and were then exposed to similar cue-induced reinstatement paradigms. Both groups of rats were pretreated with various doses of neurosteroids. Allopregnanolone and 3α-hydroxy-3β-methyl-17β-nitro-5α-androstane (R6305-7, a synthetic neurosteroid) were ineffective in selectively decreasing cocaine relative to food self-administration. On the other hand, both allopregnanolone and R6305-7 significantly decreased the cue-induced reinstatement of extinguished cocaine seeking, confirmed by one-way ANOVA. These results suggest that neurosteroids may be effective in reducing the relapse to cocaine use without affecting ongoing cocaine self-administration.

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

PubMed

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

2016-11-25

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

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

PubMed Central

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

2013-01-01

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

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).

How emotional traits and affective temperaments relate to cocaine experimentation, abuse and dependence in a large sample.

PubMed

Fuscaldo, Liane V; Bisol, Luisa W; Lara, Diogo R

2013-03-01

The contribution of specific traits in cocaine experimentation, abuse and addiction is not yet clear. Our aim was to evaluate how temperament was associated with cocaine experimentation, abuse and dependence using a recently developed scale for the assessment of emotional traits (e.g. anger, volition) and affective temperaments (e.g. cyclothymic). An anonymous web-survey provides the optimal means to evaluate sensitive issues such as drug related behavior in the general population. The data was collected by the Brazilian Internet Study on Temperament and Psychopathology (BRAINSTEP), which included the Affective and Emotional Composite Temperament Scale (AFECTS) and the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). The final sample consisted of 28,587 subjects (26.6% males, mean age=30.8±9.8yrs). Trait analysis was controlled for age, gender, ethanol and marijuana use. For emotional traits, Caution, Coping and Control were significantly lower in the cocaine-using groups when compared to controls, particularly in those with cocaine dependence. Anger and Desire increased in relation to the degree of cocaine involvement. The associations with Emotional Sensitivity and Volition were less robust. For affective temperaments, greater cocaine use was related to a lower proportion of stable types (obsessive, euthymic and hyperthymic) and the anxious type, and to a higher proportion of cyclothymic and euphoric temperaments in both sexes. Specific externalized and unstable traits were associated with cocaine related behavior. Addressing these traits may be important for recovery and prevention strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

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

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

Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved. To test this we compared brain metabolism (using PET and {sup 18}FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video. Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreasedmore » metabolism (-8.6% {+-} 10) whereas males tended to increase it (+5.5% {+-} 18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus). Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from 'control networks' (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.« less

Neuroticism associated with cocaine-induced psychosis in cocaine-dependent patients: a cross-sectional observational study.

PubMed

Roncero, Carlos; Daigre, Constanza; Barral, Carmen; Ros-Cucurull, Elena; Grau-López, Lara; Rodríguez-Cintas, Laia; Tarifa, Nuria; Casas, Miguel; Valero, Sergi

2014-01-01

Cocaine consumption can induce transient psychotic symptoms, which has been correlated with more severe addiction and aggressive behavior. However, little is known about the nature of the relationship between personality traits and psychotic symptoms in cocaine-dependent patients. This study examined the relationship between neuroticism and cocaine-induced psychosis. A total of 231 cocaine-dependent patients seeking treatment were recruited to the study. Personality was evaluated by the Zuckerman-Kuhlman Personality Questionnaire. Cocaine-induced psychosis questionnaire, SCID-I, and SCID-II were used to evaluate comorbidity and clinical characteristics. Data analysis was performed in three steps: descriptive, bivariate, and multivariate analyses. Cocaine-induced psychosis was reported in 65.4% of the patients and some personality disorder in 46.8%. Two personality dimensions (Neuroticism-Anxiety and Aggression-Hostility) presented a significant effect on the risk of experiencing psychotic symptoms (t(229) = 2.69, p = 0.008; t(229) = 2.06, p = 0.004), and patients with psychotic symptoms showed higher scores in both variables. On the multivariate analysis, only Neuroticism remained as a significant personality factor independently associated with psychotic symptoms (Wald = 7.44, p<0.05, OR = 1.08, CI 95% 1.02-1.16) after controlling for age, gender and number of consumption substances. An association between high neuroticism scores and presence of psychotic symptoms induced by cocaine has been found, independently of other consumption variables. Personality dimensions should be evaluated in cocaine-dependent patients in order to detect high scores of neuroticism and warn patients about the risk of developing cocaine-induced psychotic symptoms.

Cocaine and Pregnancy

MedlinePlus

... oxygen to the developing baby, even full- term newborns may have low birth weight. Cocaine may increase the risk for preterm delivery. ... breast milk following cocaine use by the mother. Newborns do not have ... your choices for breastfeeding. Is it a problem if the baby’s father ...

Predominance of alcohol and illicit drugs among traffic accidents fatalities in an urban area of Brazil.

PubMed

Pelição, Fabrício Souza; Peres, Mariana Dadalto; Pissinate, Jauber Fornaciari; de Paula, Daniela Mendes Louzada; de Faria, Maria das Graças Corrêa; Nakamura-Palacios, Ester Miyuki; De Martinis, Bruno Spinosa

2016-10-02

The objective of this study was to determine the prevalence of alcohol and illicit drug use among victims of fatal traffic accidents in the Metropolitan Region of Vitória, Brazil, during the period 2011-2012. Blood samples were collected and analyzed for the presence of drugs from 391 deceased victims of traffic crashes that occurred in the Metropolitan Region of Vitória, Brazil. The victims included drivers, passengers, and pedestrians. Sociodemographic variables such as age, gender, day of the week, and period of the year in which the accidents occurred were recorded. The analyses were performed by a gas chromatography-flame ionization method for alcohol and by a gas chromatography-mass spectrometry for amphetamines, cocaine, and cannabis. The results showed that 44.8% (n = 175) of all cases were positive for alcohol and/or illicit drugs. The detection of alcohol and/or drugs was more frequent in young males, aged 17 to 34, whose samples were positive in 46.8% of cases. Small differences among drivers, passengers, and pedestrians were observed (drivers = 45.9%, passengers = 46.4%, and pedestrians = 45.6%). In general, the most prevalent drug was alcohol, with 141 positive cases (36.1%), followed by cocaine, with 47 positive cases (12%). Amphetamines and cannabis had positivity rates of 4.1 and 4.3%, with 16 and 17 positive cases, respectively. The combined use of alcohol and other drugs was found in 36 cases (9.2%). Crack cocaine use was observed in 27.7% of the positive cases for cocaine. For the effective reduction of traffic accidents related to driving under influence of drugs (DUID), we suggest the intensification of enforcement actions against the use of alcohol by drivers, the definition of which illicit drugs should be surveyed, as well the cutoff values, the promotion of changing legislation to oblige drivers to provide samples for toxicological testing, and the establishment of public information programs and specific actions aimed at young drivers to

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

PubMed

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

2016-05-01

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

Promising medications for cocaine dependence treatment.

PubMed

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

2011-05-01

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

Crystal structure of a cocaine-binding antibody.

PubMed

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

2001-08-03

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

Recent Advances in Nicotinic Receptor Signaling in Alcohol Abuse and Alcoholism.

PubMed

Rahman, Shafiqur; Engleman, Eric A; Bell, Richard L

2016-01-01

Alcohol is the most commonly abused legal substance and alcoholism is a serious public health problem. It is a leading cause of preventable death in the world. The cellular and molecular mechanisms of alcohol reward and addiction are still not well understood. Emerging evidence indicates that unlike other drugs of abuse, such as nicotine, cocaine, or opioids, alcohol targets numerous channel proteins, receptor molecules, and signaling pathways in the brain. Previously, research has identified brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric ligand-gated cation channels expressed in the mammalian brain, as critical molecular targets for alcohol abuse and dependence. Genetic variations encoding nAChR subunits have been shown to increase the vulnerability to develop alcohol dependence. Here, we review recent insights into the rewarding effects of alcohol, as they pertain to different nAChR subtypes, associated signaling molecules, and pathways that contribute to the molecular mechanisms of alcoholism and/or comorbid brain disorders. Understanding these cellular changes and molecular underpinnings may be useful for the advancement of brain nicotinic-cholinergic mechanisms, and will lead to a better translational and therapeutic outcome for alcoholism and/or comorbid conditions. Copyright © 2016. Published by Elsevier Inc.

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

PubMed Central

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

2014-01-01

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

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

Probing Cocaine-Antibody Interactions in Buffer and Human Serum

PubMed Central

Ramakrishnan, Muthu; Alves De Melo, Fernando; Kinsey, Berma M.; Ladbury, John E.; Kosten, Thomas R.; Orson, Frank M.

2012-01-01

metabolites provide valuable information for characterization of their interactions and thermodynamic properties. In addition MST measurements of antibody affinity in the presence of biological fluids will provide a better opportunity to make reliable decisions and facilitate the design of cocaine vaccines and immunization conditions. The methods should be more widely adopted in characterization of antibody complexes. PMID:22859949

Manipulating a "cocaine engram" in mice.

PubMed

Hsiang, Hwa-Lin Liz; Epp, Jonathan R; van den Oever, Michel C; Yan, Chen; Rashid, Asim J; Insel, Nathan; Ye, Li; Niibori, Yosuke; Deisseroth, Karl; Frankland, Paul W; Josselyn, Sheena A

2014-10-15

Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the "cocaine memory trace" or "cocaine engram"). We found that a small population of neurons (∼10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine-conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsáki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. Copyright © 2014 the authors 0270-6474/14/3414115-13$15.00/0.

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

PubMed Central

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

2011-01-01

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

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

PubMed Central

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

2010-01-01

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

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

PubMed

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

2010-12-01

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

Behaviors, Attitudes and Knowledge of UNO Students Regarding Drugs, Alcohol and Tobacco: 1989.

ERIC Educational Resources Information Center

Hunnicutt, David; Davis, Joe

1989-01-01

This report describes alcohol, tobacco, and other drug use among 715 University of Nebraska at Omaha (UNO) students. The report focuses on drug use at the higher frequency levels, rather than reporting proportions who have ever used various drugs. The separate classes of drugs distinguished are alcohol, tobacco, cocaine, marijuana, and…

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)

Transplacental cocaine exposure. 2: Effects of cocaine dose and gestational timing.

PubMed

Wilkins, A S; Jones, K; Kosofsky, B E

1998-01-01

We have utilized a mouse model of transplacental cocaine exposure to investigate the effects of cocaine dose and gestational timing in altering brain and body growth and postnatal behavior in exposed offspring. Pregnant dams were injected with cocaine HCl at 40 mg/kg/day (COC 40) or 20 mg/kg/day (COC 20), or 10 mg/kg/day (COC 10) SC from embryonic day (E) 8 to E17, or cocaine HCl at 40 mg/kg/day SC from E8 to E13 (COC Early) or from E13 to E17 (COC Late) divided in two daily doses. COC 40 and COC Late dams, as well as dams in nutritionally paired control groups (injected with saline vehicle and pair-fed with the COC dams: SPF 40, SPF 20, SPF 10), demonstrated less weight gain than SAL controls (injected with saline vehicle and allowed access to food ad lib). The surrogate fostered offspring of COC 40 and SPF 40 dams demonstrated brain and body growth retardation [on postnatal day (P) 1 and P9] when compared to pups born to SAL dams. Offspring of COC Late, SPF 20, and SPF 10 dams demonstrated brain and body growth retardation on P1 when compared to pups born to SAL dams. Pups from all groups were tested for first-order Pavlovian conditioning on P9, or for the ability to ignore redundant information in a blocking paradigm on P50. Only COC 40 mice (i.e., offspring born to COC 40 dams) were unable to acquire an aversion to an odor previously paired with shock on P9. When compared with SAL controls, COC 40 mice (and to a less significant extent SPF 40 mice) demonstrated a persistent behavioral deficit in the blocking paradigm on P50, which may reflect alterations in selective attention. Correlation analyses indicated that the dose and gestational timing of transplacental cocaine exposure, and varying degrees of malnutrition, had effects on blocking performance, with greater prenatal cocaine exposure and increased prenatal malnutrition resulting in more significant behavioral impairments. A path regression analysis demonstrated independent and significant effects of

Sinus Bradycardia in Habitual Cocaine Users.

PubMed

Franklin, Sona M; Thihalolipavan, Sudarone; Fontaine, John M

2017-05-15

Common physiological manifestations of cocaine are related to its adrenergic effects, due to inhibition of dopamine and norepinephrine uptake at the postsynaptic terminal. Few studies have documented bradycardia secondary to cocaine use, representing the antithesis of its adrenergic effects. We assessed the prevalence of sinus bradycardia (SB) in habitual cocaine users and postulated a mechanism for this effect. One hundred sixty-two patients with a history of cocaine use were analyzed and compared with age- and gender-matched controls. SB was defined as a rate of <60 beats/min and habitual cocaine use as 2 or more documented uses >30 days apart. Propensity score-matching analysis was applied to balance covariates between cocaine users and nonusers and reduce selection bias. Patients with a history of bradycardia, hypothyroidism, or concomitant beta-blocker use were excluded. Mean age of study patients was 44 ± 8 years. SB was observed in 43 of 162 (27%) cocaine users and in 9 of 149 (6%) nonusers (p = 0.0001). Propensity score-matching analysis matched 218 patients from both groups. Among matched patients SB was observed in 25 of 109 (23%) cocaine users and in 5 of 109 (5%) nonusers (p = 0.0001). Habitual cocaine use was an independent predictor of SB and associated with a sevenfold increase in the risk of SB (95% CI 2.52 to 19.74, p = 0.0002). In conclusion, habitual cocaine use is a strong predictor of SB and was unrelated to recency of use. A potential mechanism for SB may be related to cocaine-induced desensitization of the beta-adrenergic receptor secondary to continuous exposure. Symptomatic SB was not observed; thus, pacemaker therapy was not indicated. Copyright © 2017 Elsevier Inc. All rights reserved.

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine.

PubMed

Brodnik, Zachary D; Black, Emily M; Clark, Meagan J; Kornsey, Kristen N; Snyder, Nathaniel W; España, Rodrigo A

2017-10-01

Patients with post-traumatic stress disorder have a heightened vulnerability to developing substance use disorders; however, the biological underpinnings of this vulnerability remain unresolved. We used the predator odor stress model of post-traumatic stress disorder with segregation of subjects as susceptible or resilient based on elevated plus maze behavior and context avoidance. We then determined behavioral and neurochemical differences across susceptible, resilient, and control populations using a panel of behavioral and neurochemical assays. Susceptible subjects showed a significant increase in the motoric and dopaminergic effects of cocaine, and this corresponded with heightened motivation to self-administer cocaine. Resilient subjects did not show differences in the motoric effects of cocaine, in dopamine signaling in vivo, or in any measure of cocaine self-administration. Nonetheless, we found that these animals displayed elevations in both the dopamine release-promoting effects of cocaine and dopamine autoreceptor sensitivity ex vivo. Our results suggest that the experience of traumatic stress may produce alterations in dopamine systems that drive elevations in cocaine self-administration behavior in susceptible subjects, but may also produce both active and passive forms of resilience that function to prevent gross changes in cocaine's reinforcing efficacy in resilient subjects. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.…

Community-Dwelling Cocaine-Dependent Men and Women Respond Differently to Social Stressors versus Cocaine Cues

PubMed Central

Waldrop, Angela E.; Price, Kimber L.; DeSantis, Stacia M.; Simpson, Annie N.; Back, Sudie E.; McRae, Aimee L.; Spratt, Eve G.; Kreek, Mary Jeanne; Brady, Kathleen T.

2009-01-01

Summary There are likely to be gender differences in determinants of relapse to drug use following abstinence in cocaine-dependent individuals. Cocaine-dependent women are more likely to attribute relapse to negative emotional states and interpersonal conflict. Cocaine dependence has also been linked to dysregulation of stress response and the hypothalamic pituitary adrenal (HPA) axis which may differ between genders. Subjective and HPA axis responses to a social evaluative stressor, the Trier Social Stress Test (TRIER), and in vivo cocaine-related cues were examined in the present study. Results There were no gender differences in magnitude of craving responses to the TRIER or the CUE. Both genders had a greater craving response to the CUE than to the TRIER, but the magnitude of the difference was greater for men than women (p=0.04). Cocaine-dependent subjects, compared to the control group, had significantly higher response throughout the TRIER (p<0.0001) and CUE (p<0.0001) testing sessions. There were no gender differences and no gender by cocaine interaction for ACTH responses to the TRIER, although women had lower baseline ACTH (p=0.049). On the CUE task, in contrast, female cocaine-dependent subjects had a more blunted ACTH response than did the other three groups (p=0.02). Female cocaine-dependent subjects also had a lower odds of a positive cortisol response to the TRIER as compared to the other three groups (OR=0.84, 95% CI=[0.02, 1.01]). During the CUE task, cocaine-dependent subjects had overall higher mean cortisol levels (p=0.0001), and higher odds of demonstrating a positive cortisol response to the CUE (OR=2.61, 95% CI=[1.11, 6.11]). No gender differences were found in ACTH responses to the CUE. The results are reviewed in the context of the existing literature on gender differences in cocaine dependence and potential implications for treatment are discussed. PMID:20004523

Severity of dependence and motivation for treatment: comparison of marijuana- and cocaine-dependent treatment seekers.

PubMed

Levin, Frances R; Brooks, Daniel J; Bisaga, Adam; Raby, Wilfred; Rubin, Eric; Aharonovich, Efrat; Nunes, Edward V

2006-01-01

Although marijuana dependence is prevalent, most individuals with marijuana dependence do not seek treatment. There are few data characterizing treatment seeking marijuana-dependent patients compared to patients presenting for treatment of other drugs regarding the severity of illness and motivation for treatment. Forty-two marijuana-dependent individuals were compared to 58 cocaine-dependent individuals seeking treatment. Compared to cocaine-dependent patients, those with marijuana dependence were younger and less likely to be dependent on alcohol or other drugs. Both groups had similar rates of comorbid anxiety and affective disorders. Marijuana-dependent individuals had lower total number of dependence symptoms but had a higher percentage of individuals endorsing withdrawal symptoms. Although marijuana-dependent individuals had less outpatient treatment exposure, the difference between the two groups was not significant and motivation for change, based on the University of Rhode Island Change Assessment, was similar for both groups of treatment seekers. However, the Circumstances, Motivation, Readiness for Treatment Scale suggested that cocaine-dependent individuals were more motivated for treatment. Taken together, these data suggest that treatment seeking marijuana-dependent individuals have substantial withdrawal dependence symptomatology although it is less clear if they are as motivated to seek out treatment as cocaine-dependent treatment seekers.

Quality of life, social functioning, family structure, and treatment history associated with crack cocaine use in youth from the general population.

PubMed

Narvaez, Joana C M; Pechansky, Flávio; Jansen, Karen; Pinheiro, Ricardo T; Silva, Ricardo A; Kapczinski, Flávio; Magalhães, Pedro V

2015-01-01

To assess the relationship between crack cocaine use and dimensions of quality of life and social functioning in young adults. This was a cross-sectional, population-based study involving 1,560 participants in Pelotas, Brazil. Crack cocaine use and abuse were investigated using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) inventory. Outcomes of interest were quality of life, religiosity, and social functioning in terms of education, occupational status, family structure, and medical treatment history. Lifetime crack cocaine use was associated with poor quality of life, worse functioning, impaired academic performance, and lower religious involvement. A greater maternal presence and higher paternal absence were more also more pronounced in crack cocaine users, who were also more likely to seek psychological and psychiatric treatment than the general population. Quality of life was severely impacted by crack cocaine use, especially in terms of general and physical health. Social functioning also differed between the general population and crack users, who had lower educational attainment and religious involvement. Maternal presence, paternal absence, and mental health-seeking behaviors were also more frequent among crack cocaine users, although these individuals reported lower rates of treatment satisfaction. Crack cocaine users also had significant social impairment, so that interventions involving family management and a greater focus on general health, quality of life, and functioning may make crucial contributions to the recovery of this group.

Maternal Cocaine Use and Mother-Toddler Aggression

PubMed Central

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

2011-01-01

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

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

PubMed

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

2013-05-01

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

Cocaine use trajectories of club drug-using young adults recruited using time-space sampling

PubMed Central

Ramo, Danielle E.; Grov, Christian; Delucchi, Kevin; Kelly, Brian C.; Parsons, Jeffrey T.

2011-01-01

Cocaine is the most widely used club drug. Yet, little is known about how patterns of cocaine use vary over time among young adults of diverse gender and sexual identities. This study used latent class growth analysis to identify trajectories of cocaine use over a year and explored individual and substance use factors associated with these trajectories. A sample of 400 young adults (mean age = 23.9 years) with recent club drug use were recruited from New York City bars and nightclubs using time-space sampling. Participants completed quantitative measures at baseline, 4-, 8- and 12-months follow-up. A 4-class model fit the data best. Patterns were: Consistent use (48%), Inconsistent use (14%), Decreasing Likelihood of use (28%), and Consistent non-use (11%). Those most likely to be in the Consistent use class had the highest frequency of baseline club drug dependence (χ2 (3, 397) = 15.1, p < .01), cocaine dependence (χ2 (3, 397) = 18.9, p < .01), recent alcohol use (χ2 (3, 397) = 12.48, p < .01), and drug sensation-seeking (χ2 (3, 397) = 9.03, p < .01). Those most likely to be in the Consistent Non-use class had the highest frequency of baseline marijuana use (χ2 (3, 397) = 2.71, p < .05). Contrary to hypotheses, there were no differences in most-likely trajectory class by gender/sexual-orientation, age, ethnicity, education, employment status, or income. Findings highlight the diversity of cocaine use patterns over time among young adults, and the personal and substance use characteristics that are associated with each. PMID:21907497

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

PubMed

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

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

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

PubMed

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

2017-09-01

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

US federal cocaine essential (‘precursor’) chemical regulation impacts on US cocaine availability: an intervention time–series analysis with temporal replication

PubMed Central

Callaghan, Russell C.; Liu, Lon‐Mu

2015-01-01

Abstract Background and Aims Research shows that essential/precursor chemical controls have had substantial impacts on US methamphetamine and heroin availability. This study examines whether US federal essential chemical regulations have impacted US cocaine seizure amount, price and purity—indicators of cocaine availability. Design Autoregressive integrated moving average (ARIMA)‐intervention time–series analysis was used to assess the impacts of four US regulations targeting cocaine manufacturing chemicals: potassium permanganate/selected solvents, implemented October 1989 sulfuric acid/hydrochloric acid, implemented October 1992; methyl isobutyl ketone, implemented May 1995; and sodium permanganate, implemented December 2006. Of these chemicals, potassium permanganate and sodium permanganate are the most critical to cocaine production. Setting Conterminous United States (January 1987—April 2011). Measurements Monthly time–series: purity‐adjusted cocaine seizure amount (in gross weight seizures < 6000 grams), purity‐adjusted price (all available seizures), and purity (all available seizures). Data source: System to Retrieve Information from Drug Evidence. Findings The 1989 potassium permanganate/solvents regulation was associated with a seizure amount decrease (change in series level) of 28% (P < 0.05), a 36% increase in price (P < 0.05) and a 4% decrease in purity (P < 0.05). Availability recovered in 1–2 years. The 2006 potassium permanganate regulation was associated with a 22% seizure amount decrease (P < 0.05), 100% price increase (P < 0.05) and 35% purity decrease (P < 0.05). Following the 2006 regulation, essentially no recovery occurred to April 2011. The other two chemical regulations were associated with statistically significant but lesser declines in indicated availability. Conclusions In the United States, essential chemical controls from 1989 to 2006 were associated with pronounced downturns in cocaine availability. PMID:25559418

Efficacy of a therapeutic cocaine vaccine in rodent models.

PubMed

Fox, B S; Kantak, K M; Edwards, M A; Black, K M; Bollinger, B K; Botka, A J; French, T L; Thompson, T L; Schad, V C; Greenstein, J L; Gefter, M L; Exley, M A; Swain, P A; Briner, T J

1996-10-01

Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.

Effects of repeated cocaine exposure and withdrawal on voluntary ethanol drinking, and the expression of glial glutamate transporters in mesocorticolimbic system of P rats.

PubMed

Hammad, Alaa M; Althobaiti, Yusuf S; Das, Sujan C; Sari, Youssef

2017-07-01

Glutamatergic neurotransmission within the brain's reward circuits plays a major role in the reinforcing properties of both ethanol and cocaine. Glutamate homeostasis is regulated by several glutamate transporters, including glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). Cocaine exposure has been shown to induce a dysregulation in glutamate homeostasis and a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc). In this study, alcohol preferring (P) rats were exposed to free-choice of ethanol (15% and 30%) and/or water for five weeks. On Week 6, rats were administered (i.p.) cocaine (10 and 20mg/kg) or saline for 12 consecutive days. This study tested two groups of rats: the first group was euthanized after seven days of repeated cocaine i.p. injection, and the second group was deprived from cocaine for five days and euthanized at Day 5 after cocaine withdrawal. Only repeated cocaine (20mg/kg, i.p.) exposure decreased ethanol intake from Day 3 through Day 8. Co-exposure of cocaine and ethanol decreased the relative mRNA expression and the expression of GLT-1 in the NAc but not in the medial prefrontal cortex (mPFC). Importantly, co-exposure of cocaine and ethanol decreased relative expression of xCT in the NAc but not in the mPFC. Our findings demonstrated that chronic cocaine exposure affects ethanol intake; and ethanol and cocaine co-abuse alters the expression of glial glutamate transporters. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2016-10-01

Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

[Comorbidity in panic disorders and alcoholism (II). Alcoholism in a sample of 148 patients with panic disorders].

PubMed

Segui, J; Salvador, L; Canet, J; Aragón, C; Herrera, C

1995-01-01

Among 148 patients presenting Panic Disorder (DSM-III-R), 18.9% have an alcohol disorder, 8.8% present abuse and 10.1% dependence. Mean age of onset of alcoholism was much earlier than panic disorder. Patients with alcoholism: a) are males more frequently (0.001); b) present more alcoholism in first grade relatives (0.05); c) use more often other drugs like: tobacco (0.01), coffee (p < 0.01), cocaine (p < 0.01) and cannabis (p < 0.001), d) patients with alcoholism refer a greater severity of their panic attacks when drinking large amounts of alcohol (25%) than the group without these problems (2.5%) (x2:14.8) (p < 0.001) e) according to the GAS the overall level of performance is lower in alcoholics (p < 0.005); f) present more anxiety measured by the HARS (p < 0.01), and therefore have more comorbid anxiety disorders according to DSM-III-R (p < 0.01). The clinical significance of these findings is discussed.

An Antidote for Acute Cocaine Toxicity

PubMed Central

Treweek, Jennifer B.; Janda, Kim D.

2012-01-01

Not only has immunopharmacotherapy grown into a field that addresses the abuse of numerous illicit substances, but also the treatment methodologies within immunopharmacotherapy have expanded from traditional active vaccination to passive immunization with anti-drug monoclonal antibodies, optimized mAb formats, and catalytic drug-degrading antibodies. Many laboratories have focused on transitioning distinct immunopharmacotherapeutics to clinical evaluation, but with respect to the indication of cocaine abuse, only the active vaccine TA-CD, which is modeled after our original cocaine hapten GNC1, has been carried through to human clinical trials.2 The successful application of murine mAb GNC92H2 to the reversal of cocaine overdose in a mouse model prompted investigations of human immunoglobulins with the clinical potential to serve as cocaine antidotes. We now report the therapeutic utility of a superior clone, human mAb GNCgzk (Kd = 0.18 nM), which offers a 10-fold improvement in cocaine binding affinity. The GNCgzk manifold was engineered for rapid cocaine clearance, and administration of the F(ab′)2 and Fab formats even after the appearance of acute behavioral signs of cocaine toxicity granted nearly complete prevention of lethality. Thus, contrary to the immunopharmacotherapeutic treatment of drug self-administration, minimal antibody doses were shown to counteract the lethality of a molar excess of circulating cocaine. Passive vaccination with drug-specific antibodies represents a viable treatment strategy for the human condition of cocaine overdose. PMID:22380623

Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review.

PubMed

Garcia, Alexandra N; Salloum, Ihsan M

2015-10-01

In the United States, approximately 60 million Americans suffer from sleep disorders and about 22 million Americans report substance dependence or use disorders annually. Sleep disturbances are common consequences of substance use disorders and are likely found in primary care as well as in specialty practices. The aim of this review was to evaluate the effects of the most frequently used substances-nicotine, alcohol, opioids, cocaine, caffeine, and cannabis-have on sleep parameters measured by polysomnography (PSG) and related clinical manifestations. We used electronic databases such as PubMED and PsycINFO to search for relevant articles. We only included studies that assessed sleep disturbances using polysomnography and reviewed the effects of these substances on six clinically relevant sleep parameters: Total sleep time, sleep onset latency, rapid-eye movement, REM latency, wake after sleep onset, and slow wave sleep. Our review indicates that these substances have significant impact on sleep and that their effects differ during intoxication, withdrawal, and chronic use. Many of the substance-induced sleep disturbances overlap with those encountered in sleep disorders, medical, and psychiatric conditions. Sleep difficulties also increase the likelihood of substance use disorder relapse, further emphasizing the need for optimizing treatment interventions in these patients. Our review highlights the importance of systematically screening for substance use in patients with sleep disturbances and highlights the need for further research to understand mechanisms underlying substances-induced sleep disturbances and on effective interventions addressing these conditions. © American Academy of Addiction Psychiatry.

Cocaine and metabolite concentrations in DBS and venous blood after controlled intravenous cocaine administration

PubMed Central

Ellefsen, Kayla N; da Costa, Jose Luiz; Concheiro, Marta; Anizan, Sebastien; Barnes, Allan J; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A

2015-01-01

Background: DBS are an increasingly common clinical matrix. Methods & results: Sensitive and specific methods for DBS and venous blood cocaine and metabolite detection by LC–HRMS and 2D GC–MS, respectively, were validated to examine correlation between concentrations following controlled intravenous cocaine administration. Linear ranges from 1 to 200 µg/l were achieved, with acceptable bias and imprecision. Authentic matched specimens’ (392 DBS, 97 venous blood) cocaine and benzoylecgonine concentrations were qualitatively similar, but DBS had much greater variability (21.4–105.9 %CV) and were lower than in blood. Conclusion: DBS offer advantages for monitoring cocaine intake; however, differences between capillary and venous blood and DBS concentration variability must be addressed. PMID:26327184

77 FR 29307 - Control of Alcohol and Drug Use: Addition of Post-Accident Toxicological Testing for Non...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-17

... post-accident testing, FRA routinely conducts tests for alcohol, marijuana, cocaine, phencyclidine (PCP..., as part of its accident investigation program, FRA has conducted post-accident alcohol and drug tests... conduct post-accident tests for any substance (e.g., carbon [[Page 29308

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 ...

Investigation on the combined effect of cocaine and ethanol administration through a liquid chromatography-mass spectrometry metabolomics approach.

PubMed

Sánchez-López, Elena; Marcos, Alberto; Ambrosio, Emilio; Mayboroda, Oleg A; Marina, María Luisa; Crego, Antonio L

2017-06-05

Alcohol is the most widely consumed legal drug, whereas cocaine is the illicit psychostimulant most commonly used in Europe. The combined use of alcohol and cocaine is frequent among drug-abuse consumers and leads to further exacerbation of health consequences compared to individual consumption. The pharmacokinetic and metabolic interactions leading to an increase in their combined toxicity still remains poorly understood. Here, the first metabolomics study of combined cocaine and ethanol chronic exposure effects is reported. A Liquid Chromatography strategy based on sample derivatization with 9-fluorenylmethyloxycarbonyl chloride and using a C18 column coupled to high resolution Mass Spectrometry (time of flight analyzer) was employed to analyze plasma from rats exposed intravenously to these drugs in a 52-min analysis. Using a combination of non-supervised and supervised multivariate analysis the metabolic differences between our experimental groups were explored and unraveled. A comparative analysis of the individual models and their variable importance in the projection values have shown that every experiment intervention includes a subset of specific metabolites. Eleven of these metabolites were annotated, where eight were unequivocally identified using standards and three were tentatively identified by matching the MS/MS spectra to libraries. The results demonstrated that the affected metabolic pathways were mainly those related to the metabolism of different amino acids. Copyright © 2017 Elsevier B.V. All rights reserved.

[Current pharmacotherapies and immunotherapy in cocaine addiction].

PubMed

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

2008-04-01

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

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

PubMed

Gostic, T; Klemenc, S

2007-07-04

An abandoned clandestine laboratory was seized in Slovenia. All confiscated exhibits were analysed in a forensic laboratory, where the following analytical methods were applied: capillary gas chromatography coupled with mass spectrometry (GC-MS) combined also by solid-phase micro extraction (SPME) and pyrolysis (Py) technique, Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy with energy dispersive X-ray detector (SEM-EDX). The most interesting analytical findings can be summarised as follows: at the crime scene some plastic pieces, which contained cocaine dissolved (as solid solution) in polymethyl methacrylate-plexiglass (PMMA), were found. The highest cocaine concentration measured in the plastic sample was about 15% by weight. Two larger lumps of material (12 and 3 kg) were composed mainly of PMMA and CaCO3 and contained only 0.4 and 0.5% of cocaine, respectively. As for the low cocaine concentration, we assume that those two lumps of material represent discarded waste product--residue after the isolation of cocaine from plastic. Higher quantities of pure solvents (41 l) and solvent mixtures (87 l) were seized. We identified three types of pure solvents (acetone, gasoline and benzine) and two different types of solvent mixtures (benzine/acetone and gasoline/acetone). The total seized volume (87 l) of solvent mixtures holds approximately 395 g of solid residue formed mainly of PMMA and cocaine. Obviously solvent mixtures were used for isolation of cocaine from the plastic. Small quantities of relatively pure cocaine base were identified on different objects. There were two cotton sheets, most probably used for filtration. One sheet had traces of cocaine base (76% purity) on the surface, while cocaine in hydrochloride form (96%) was identified on the other sheet. GC-MS analyses of micro traces isolated from analytical balances showed the presence of cocaine and some common adulterants: phenacetine, lidocaine and procaine. A cocaine

Motivated attention to cocaine and emotional cues in abstinent and current cocaine users--an ERP study.

PubMed

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

2011-05-01

Event-related potentials (ERPs) are a direct measure of neural activity and are ideally suited to study the time-course of attentional engagement with emotional and drug-related stimuli in addiction. In particular, the late positive potential (LPP) appears to be enhanced following cocaine-related compared with neutral stimuli in human participants with cocaine use disorders (CUD). However, previous studies have not directly compared cocaine-related with emotional stimuli while examining potential differences between abstinent and current cocaine users. The present study examined ERPs in 55 CUD (27 abstinent and 28 current users) and 29 matched healthy controls while they passively viewed pleasant, unpleasant, neutral and cocaine-related pictures. To examine the time-course of attention to these stimuli, we analysed both an early and later window in the LPP as well as the early posterior negativity (EPN), established in assessing motivated attention. Cocaine pictures elicited increased electrocortical measures of motivated attention in ways similar to affectively pleasant and unpleasant pictures in all CUD, an effect that was no longer discernible during the late LPP window for the current users. This group also exhibited deficient processing of the other emotional stimuli (early LPP window - pleasant pictures; late LPP window - pleasant and unpleasant pictures). Results were unique to the LPP and not EPN. Taken together, results support a relatively early attention bias to cocaine stimuli in cocaine-addicted individuals, further suggesting that recent cocaine use decreases such attention bias during later stages of processing but at the expense of deficient processing of other emotional stimuli. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd. No claim to original US government works.

Cocaine in the UK--1991.

PubMed

Strang, J; Johns, A; Caan, W

1993-01-01

More than 100 years after Freud's original endorsement of the drug, the use of cocaine is a problem for both users and for society, which struggles to organise effective responses to the epidemic of the last decade. During the 1980s the rapid spread of smokeable cocaine (including 'crack') was seen in the Americas (particularly the US). The initial simple predictions of an identical European epidemic were mistaken. The available data on the extent of cocaine use and of cocaine problems in the UK are examined. New forms of cocaine have been developed by black-market entrepreneurs ('freebase' and 'crack'), and new technologies have emerged for their use; with these new technologies have come new effects and new problems. The general psychiatrist now needs a knowledge of directly and indirectly related psychopathology which has an increasing relevance to the diagnosis and management of the younger patient.

Atomoxetine Does Not Alter Cocaine Use in Cocaine Dependent Individuals: A Double Blind Randomized Trial

PubMed Central

Middleton, Lisa S.; Wong, Conrad J.; Nuzzo, Paul A.; Campbell, Charles L.; Rush, Craig R.; Lofwall, Michelle R.

2016-01-01

Background Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n=25), compared to placebo (n=25). Subjects were initially stratified on cocaine use (<15 days or ≥15 days of the last 30), age and race using urn randomization. Attendance, medication adherence and study compliance were reinforced with contingency management, and weekly counseling was offered. An array of measures (vital signs, laboratory chemistries, cognitive and psychomotor tests, cocaine craving and urine samples for drug testing) was collected throughout the study and at follow-up. Results Survival analysis revealed no differences in study retention between the two groups, with approximately 56% of subjects completing the 12-week study (Cox analysis X2=.72; p=.40; Hazard Ratio 1.48 [CI 0.62–3.39]). GEE analysis of the proportion of urine samples positive for benzoylecgonine, a cocaine metabolite, revealed no differences between the atomoxetine and placebo groups (X2=0.2, p=.66; OR=0.89 [95% CI 0.41 – 1.74). Atomoxetine was generally well tolerated in this population. Conclusions These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence. PMID:23200303

Alcohol preference influences the subthalamic nucleus control on motivation for alcohol in rats.

PubMed

Lardeux, Sylvie; Baunez, Christelle

2008-02-01

In addition to its role in motor and attentional processes, the subthalamic nucleus (STN) has also been recently demonstrated to be involved in motivational function. Indeed, bilateral STN lesions modulate differentially the motivation for natural rewards and drugs of abuse, increasing motivation for food and decreasing motivation for cocaine in rats. Here, we show that in outbred rats, the STN can modulate the motivation for alcohol according to alcohol preference, without affecting alcohol intake. When performed on 'High-Drinker' rats, STN lesions enhanced the breaking point (BP) under a progressive ratio schedule of reinforcement and increased the time spent in the environment previously paired with alcohol access in the place preference paradigm. In contrast, when performed on 'Low-Drinker' rats, STN lesions decreased the BP and increased the time spent in the environment paired with water. These results show that STN lesions enhance the motivation for alcohol in rats showing a high alcohol preference, whereas they decrease it in rats showing a low preference for alcohol. These results suggest that the STN plays a complex role in the reward circuit, that is not limited to a

Proteasome phosphorylation regulates cocaine-induced sensitization.

PubMed

Gonzales, Frankie R; Howell, Kristin K; Dozier, Lara E; Anagnostaras, Stephan G; Patrick, Gentry N

2018-04-01

Repeated exposure to cocaine produces structural and functional modifications at synapses from neurons in several brain regions including the nucleus accumbens. These changes are thought to underlie cocaine-induced sensitization. The ubiquitin proteasome system plays a crucial role in the remodeling of synapses and has recently been implicated in addiction-related behavior. The ATPase Rpt6 subunit of the 26S proteasome is phosphorylated by Ca 2+ /calmodulin-dependent protein kinases II alpha at ser120 which is thought to regulate proteasome activity and distribution in neurons. Here, we demonstrate that Rpt6 phosphorylation is involved in cocaine-induced locomotor sensitization. Cocaine concomitantly increases proteasome activity and Rpt6 S120 phosphorylation in cultured neurons and in various brain regions of wild type mice including the nucleus accumbens and prefrontal cortex. In contrast, cocaine does not increase proteasome activity in Rpt6 phospho-mimetic (ser120Asp) mice. Strikingly, we found a complete absence of cocaine-induced locomotor sensitization in the Rpt6 ser120Asp mice. Together, these findings suggest a critical role for Rpt6 phosphorylation and proteasome function in the regulation cocaine-induced behavioral plasticity. Copyright © 2017 Elsevier Inc. All rights reserved.

[Cocaine induced psychotic disorders: a review].

PubMed

Karila, L; Petit, A; Phan, O; Reynaud, M

2010-11-01

Cocaine remains the second most used illicit drug in Europe, after cannabis, though levels of use vary between countries. This psychostimulant has become a noticeable part of the European drug scene. Cocaine dependence, a chronic, relapsing and multifactorial disorder, is a significant worldwide public health problem with somatic, legal, social, cognitive and psychological complications. The relationship between clinical psychotic symptoms and use of specific substances other than cannabis has received minimal attention in the literature. Psychotic symptoms and experience of paranoia and suspiciousness are reported during the use and the withdrawal of cocaine. Furthermore, although psychotic symptoms were found to be common among substance users, the risk for development of chronic psychotic disorder was found. In the light of recent epidemiological data stating that there is an increased cocaine use, that there is an increased number of patients entering drug treatment for primary cocaine use in Europe for several years and that cocaine users are an heterogeneous group, we made a review on the specific topic of cocaine-induced psychotic disorders. This review is based on Medline, EMBASE, PsycINFO and Google Scholar searches of English and French-language articles published between 1969 and February, 2010.

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

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

Brim, Remy L.; Nance, Mark R.; Youngstrom, Daniel W.

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 greatermore » 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.« less

The Cardiovascular Effects of Cocaine.

PubMed

Havakuk, Ofer; Rezkalla, Shereif H; Kloner, Robert A

2017-07-04

Cocaine is the leading cause for drug-abuse-related visits to emergency departments, most of which are due to cardiovascular complaints. Through its diverse pathophysiological mechanisms, cocaine exerts various adverse effects on the cardiovascular system, many times with grave results. Described here are the varied cardiovascular effects of cocaine, areas of controversy, and therapeutic options. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Dopamine transporter occupancy by RTI-55 determined using labeled cocaine, and displacement of RTI-55 with unlabeled cocaine

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

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

We have previously visualized dopamine transporters (DAT) in human and baboon striatum using PET and C-11 cocaine. Cocaine analogs such as 3{beta}-(4-iodophenyl) tropane-2{beta}-carboxylic acid methyl ester (RTI-55 or {beta}CIT) with a higher affinity for the DAT may be potentially useful in interfering with cocaine`s actions in brain. We evaluated the time course of the effects of RTI-55 on C-11 cocaine binding in baboon brain prior to and 90 minutes, 24 hours, 4-5 days and 11-13 days after RTI-55(0.3 mg/kg iv). RTI-55 significantly inhibited C-11 cocaine binding at 90 minutes and 24 hours after administration. The half life for the clearancemore » of RTI-55 from the DAT was estimated to be 2 to 3 days in the baboon brain. Parallel studies with H-3 cocaine and RTI-55 (0.5 mg/kg iv or 2 mg/kg ip) were performed in mice, where RTI-55 significantly inhibited 5 minute striatum-to-cerebellium ratios (S/C) at 60 and 180 minutes after administration, and recovery was obtained at 12 hours. However, unlabeled cocaine (20 mg/Kg, i/p) given 60 minutes after RTI-55 led to a greater recovery of H-3 cocaine uptake measured at 180 minutes (S/C = 1.23 {plus_minus} 0.07, n= 5), than in control animals given saline after RTI-55 (S/C = 9.5{plus_minus}0.08). Animals given saline instead of RTI-55 had S/C = 1.45{plus_minus}0.04. These results document long lasting inhibition of cocaine binding by RTI-55 and corroborate the assumption that the binding kinetics of RTI-55 in striatum observed in SPECT imaging studies with I-123 RTI-55 represents binding to DAT`s. However, a pharmacological dose of cocaine is able to displace a fraction of the previously bound RTI-55 from the DAT. These findings have implications for drug development strategies for cocaine abuse.« less

Effects of cocaine on honey bee dance behaviour

PubMed Central

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

2009-01-01

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

Effects of cocaine on honey bee dance behaviour.

PubMed

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

2009-01-01

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

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

Crack-cocaine use accelerates HIV disease progression in a cohort of HIV-positive drug users.

PubMed

Baum, Marianna K; Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, Bryan; Campa, Adriana

2009-01-01

HIV infection is prevalent among substance abusers. The effects of specific illicit drugs on HIV disease progression have not been established. We evaluated the relationship between substances of abuse and HIV disease progression in a cohort of HIV-1-positive active drug users. A prospective, 30-month, longitudinal study was conducted on 222 HIV-1 seropositive drug users in Miami, FL. History of illicit drug, alcohol, and medication use, CD4+ cell count, and viral load were performed every 6 months. Crack-cocaine users were 2.14 times [95% confidence interval (CI): 1.08 to 4.25, P = 0.029] more likely to present a decline of CD4 to cocaine with marijuana (hazard ratio = 2.42; 95% CI: 1.042 to 5.617, P = 0.04). Of those on HAART, a significantly lower proportion of crack-cocaine users versus nonusers had controlled viral load (P < 0.001), suggesting lower medication adherence, whereas crack-cocaine users not on HAART showed a greater risk for HIV disease progression than nonusers (hazard ratio = 3.946; 95% CI: 1.049 to 14.85, P = 0.042). Crack-cocaine use facilitates HIV disease progression by reducing adherence in those on HAART and by accelerating disease progression independently of HAART.

Multiple faces of BDNF in cocaine addiction

PubMed Central

Li, Xuan; Wolf, Marina E.

2014-01-01

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

Molecular gated nanoporous anodic alumina for the detection of cocaine

NASA Astrophysics Data System (ADS)

Ribes, Àngela; Xifré-Pérez, Elisabet; Aznar, Elena; Sancenón, Félix; Pardo, Teresa; Marsal, Lluís F.; Martínez-Máñez, Ramόn

2016-12-01

We present herein the use of nanoporous anodic alumina (NAA) as a suitable support to implement “molecular gates” for sensing applications. In our design, a NAA support is loaded with a fluorescent reporter (rhodamine B) and functionalized with a short single-stranded DNA. Then pores are blocked by the subsequent hybridisation of a specific cocaine aptamer. The response of the gated material was studied in aqueous solution. In a typical experiment, the support was immersed in hybridisation buffer solution in the absence or presence of cocaine. At certain times, the release of rhodamine B from pore voids was measured by fluorescence spectroscopy. The capped NAA support showed poor cargo delivery, but presence of cocaine in the solution selectively induced rhodamine B release. By this simple procedure a limit of detection as low as 5 × 10-7 M was calculated for cocaine. The gated NAA was successfully applied to detect cocaine in saliva samples and the possible re-use of the nanostructures was assessed. Based on these results, we believe that NAA could be a suitable support to prepare optical gated probes with a synergic combination of the favourable features of selected gated sensing systems and NAA.

Molecular gated nanoporous anodic alumina for the detection of cocaine

PubMed Central

Ribes, Àngela; Xifré -Pérez, Elisabet; Aznar, Elena; Sancenón, Félix; Pardo, Teresa; Marsal, Lluís F.; Martínez-Máñez, Ramόn

2016-01-01

We present herein the use of nanoporous anodic alumina (NAA) as a suitable support to implement “molecular gates” for sensing applications. In our design, a NAA support is loaded with a fluorescent reporter (rhodamine B) and functionalized with a short single-stranded DNA. Then pores are blocked by the subsequent hybridisation of a specific cocaine aptamer. The response of the gated material was studied in aqueous solution. In a typical experiment, the support was immersed in hybridisation buffer solution in the absence or presence of cocaine. At certain times, the release of rhodamine B from pore voids was measured by fluorescence spectroscopy. The capped NAA support showed poor cargo delivery, but presence of cocaine in the solution selectively induced rhodamine B release. By this simple procedure a limit of detection as low as 5 × 10−7 M was calculated for cocaine. The gated NAA was successfully applied to detect cocaine in saliva samples and the possible re-use of the nanostructures was assessed. Based on these results, we believe that NAA could be a suitable support to prepare optical gated probes with a synergic combination of the favourable features of selected gated sensing systems and NAA. PMID:27924950

Molecular gated nanoporous anodic alumina for the detection of cocaine.

PubMed

Ribes, Àngela; Xifré-Pérez, Elisabet; Aznar, Elena; Sancenón, Félix; Pardo, Teresa; Marsal, Lluís F; Martínez-Máñez, Ramόn

2016-12-07

We present herein the use of nanoporous anodic alumina (NAA) as a suitable support to implement "molecular gates" for sensing applications. In our design, a NAA support is loaded with a fluorescent reporter (rhodamine B) and functionalized with a short single-stranded DNA. Then pores are blocked by the subsequent hybridisation of a specific cocaine aptamer. The response of the gated material was studied in aqueous solution. In a typical experiment, the support was immersed in hybridisation buffer solution in the absence or presence of cocaine. At certain times, the release of rhodamine B from pore voids was measured by fluorescence spectroscopy. The capped NAA support showed poor cargo delivery, but presence of cocaine in the solution selectively induced rhodamine B release. By this simple procedure a limit of detection as low as 5 × 10 -7  M was calculated for cocaine. The gated NAA was successfully applied to detect cocaine in saliva samples and the possible re-use of the nanostructures was assessed. Based on these results, we believe that NAA could be a suitable support to prepare optical gated probes with a synergic combination of the favourable features of selected gated sensing systems and NAA.

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

PubMed Central

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

2012-01-01

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

Seizures in hospitalized cocaine users.

PubMed

Choy-Kwong, M; Lipton, R B

1989-03-01

We reviewed the records of 283 cocaine abusers consecutively admitted to a municipal hospital, and identified eight patients (2.8%) who presented with seizures. Four (1.4%) had focal or generalized seizures temporally associated with cocaine use. Based on these four cases and five previous reports, we conclude that although seizures are relatively rare in hospitalized cocaine users, they are provoked by all major routes of administration, and may be partial or generalized.

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

PubMed Central

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

2012-01-01

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

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

PubMed Central

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

2014-01-01

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

Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys.

PubMed

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

2016-11-01

Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Continuous 21-day treatments with ramping doses of d-amphetamine (days 1-7: 0.032mg/kg/h; days 8-21: 0.1mg/kg/h, i.v.) or risperidone (days 1-7: 0.001mg/kg/h; days 8-14: 0.0032mg/kg/h; days 15-21: 0.0056mg/kg/h, i.v.) were administered to rhesus monkeys (n=4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h 'choice' session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0-0.1mg/kg per injection) and (2) a 20-h 'extended-access' session with 0.1mg/kg per injection cocaine availability. Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys

PubMed Central

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

2016-01-01

Background Clinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. Methods Continuous 21-day treatments with ramping doses of d-amphetamine (days 1–7: 0.032 mg/kg/h; days 8–21: 0.1 mg/kg/h, i.v.) or risperidone (days 1–7: 0.001 mg/kg/h; days 8–14: 0.0032 mg/kg/h; days 15–21: 0.0056 mg/kg/h, i.v.) were administered to rhesus monkeys (n = 4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h ‘choice’ session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0–0.1 mg/kg per injection) and (2) a 20-h ‘extended-access’ session with 0.1 mg/kg per injection cocaine availability. Results Total daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. Conclusions These results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions. PMID:27615401

[Sucrose reward promotes rats' motivation for cocaine].

PubMed

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

2016-06-25

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

Features and prevalence of patients with probable adult attention deficit hyperactivity disorder who request treatment for cocaine use disorders.

PubMed

Pérez de Los Cobos, José; Siñol, Núria; Puerta, Carmen; Cantillano, Vanessa; López Zurita, Cristina; Trujols, Joan

2011-01-30

To characterize those patients with probable adult attention deficit hyperactivity disorder (ADHD) who ask for treatment of cocaine use disorders; to estimate the prevalence of probable adult ADHD among these patients. This is a cross-sectional and multi-center study performed at outpatient resources of 12 addiction treatment centers in Spain. Participants were treatment-seeking primary cocaine abusers recruited consecutively at one center and through convenience sampling at the other centers. Assessments included semi-structured clinical interview focused on Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) ADHD criteria adapted to adulthood, and the Wender-Utah Rating Scale (WURS) for screening childhood history of ADHD according to patients. Probable adult ADHD was diagnosed when patients met DSM-IV criteria of ADHD in adulthood and scored WURS>32. All participants were diagnosed with current cocaine dependence (n=190) or abuse (n=15). Patients with probable adult ADHD, compared with patients having no lifetime ADHD, were more frequently male, reported higher impulsivity, and began to use nicotine, alcohol, cannabis, or cocaine earlier. Before starting the current treatment, patients with probable adult ADHD also showed higher cocaine craving for the previous day, less frequent cocaine abstinence throughout the previous week, and higher use of cocaine and tobacco during the previous month. Impulsivity and male gender were the only independent risk factors of probable adult ADHD in a logistic regression analysis. The prevalence of probable adult ADHD was 20.5% in the sub-sample of patients consecutively recruited (n=78). A diagnosis of probable adult ADHD strongly distinguishes among treatment-seeking cocaine primary abusers regarding past and current key aspects of their addictive disorder; one-fifth of these patients present with probable adult ADHD. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

A cocaine-associated quadriplegia and motor aphasia after first use of cocaine.

PubMed

Sein Anand, Jacek; Chodorowski, Zygmunt; Wiśniewski, Marek; Gólska, Agnieszka

2007-01-01

A 31-year-old female who have snorted one "line" of cocaine hydrochloride (approximately 35 mg), for the first time in her life, was admitted to the hospital because of acute onset of right hemiplegia and left hemiparesis evolving into quadriplegia. Motor aphasia, right eye-ball divergent strabismus and right mouth recess lowering were also observed. A first time mucosal administration of cocaine hydrochloride even in low dose can cause severe neurological complications like quadriplegia and aphasia. Cocaine-associated stroke can be a diagnostic problem in the emergency room. Unconscious patients or those with acute onset of neurological disorders can form a real diagnostic challenge, especially when there is no evidence of previous drug taking.

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

ERIC Educational Resources Information Center

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

2008-01-01

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

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.

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

PubMed

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

2016-08-01

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

Prevalence of psychoactive substances, alcohol and illicit drugs, in Spanish drivers: A roadside study in 2015.

PubMed

Domingo-Salvany, Antonia; Herrero, M Jesús; Fernandez, Beatriz; Perez, Julio; Del Real, Pilar; González-Luque, Juan Carlos; de la Torre, Rafael

2017-09-01

A survey was conducted during 2015 to monitor psychoactive substance use in a sample of drivers in Spanish roads and cities. Traffic police officers recruited drivers at sites carefully chosen to achieve representativeness of the driver population. A brief questionnaire included the date, time, and personal and driving patterns data. Alcohol use was ascertained through ethanol breath test at the roadside and considered positive if concentrations >0.05mg alcohol/L were detected. Four drug classes were assessed on-site through an oral fluid screening test that, if positive, was confirmed through a second oral fluid sample at a reference laboratory. Laboratory confirmation analyses screened for 26 psychoactive substances. To evaluate the association between drug findings and age, sex, road type (urban/interurban), and period of the week (weekdays, weeknights, weekend days, weekend nights), logistic regression analyses were done (overall, and separately for alcohol, cannabis and cocaine). A total of 2744 drivers, mean age of 37.5 years, 77.8% men, were included. Overall, 11.6% of the drivers had at least one positive finding to the substances assessed. Substances more frequently testing positive were cannabis (7.5%), cocaine (4.7%) and alcohol (2.6%). More than one substance was detected in 4% of the subjects. The proportion of positive results decreased with age, and was more likely among men and on urban roads. The pattern for alcohol use was similar but did not change with age and increased among drivers recruited at night. Cannabis was more likely to be detected at younger ages and cocaine was associated with night driving. Alcohol use before driving has decreased over the last decade; however, the consumption of other illegal drugs seems to have increased. The pattern of illegal psychoactive substance observed is similar to that declared in surveys of the general population of adults. Copyright © 2017. Published by Elsevier B.V.

MDMA reinstates cocaine-seeking behaviour in mice.

PubMed

Trigo, José Manuel; Orejarena, Maria Juliana; Maldonado, Rafael; Robledo, Patricia

2009-06-01

MDMA effects are mediated by monoaminergic systems, which seem to play a central role in cocaine craving and relapse. CD1 mice trained to self-administer cocaine (1 mg/kg/infusion) underwent an extinction procedure in which the cues contingent with drug self-administration remained present. Mice achieving extinction were injected with MDMA (10 mg/kg), d-amphetamine (1 and 2 mg/kg) or saline and tested for reinstatement. Acute MDMA, but not d-amphetamine or saline reinstated cocaine-seeking behaviour in mice in which cocaine self-administration and contingent cues were previously extinguished. Acute MDMA can reinstate cocaine-seeking behaviour in mice.

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

Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function.

PubMed

Zhou, Luyi; Sun, Wei-Lun; Young, Amy B; Lee, Kunhee; McGinty, Jacqueline F; See, Ronald E

2014-10-31

Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner. These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Malignant hypertension-associated thrombotic microangiopathy following cocaine use.

PubMed

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

2016-01-01

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

A systematic review of evidence on the association between cocaine use and seizures.

PubMed

Sordo, L; Indave, B I; Degenhardt, L; Barrio, G; Kaye, S; Ruíz-Pérez, I; Bravo, M J

2013-12-15

Institutional monographs/medical textbooks mention seizures as a neurological complication of cocaine, but no systematic reviews (SRs) have been published on this issue. We aimed to conduct a SR of the literature on the relationship between cocaine use and seizures and to summarize the biological plausibility of that relationship. The pathophysiological mechanisms that may underlie an association between cocaine and seizures were summarized; a SR was then performed using three databases (EMBASE, Medline, PsycINFO) and the Cochrane-library to search for published papers (1980-2012) aimed at quantifying the associations between cocaine use and seizures. The inclusion criteria for selection were: articles based on clinical trials, cohort, case-control (CC) or cross-sectional (CS) studies, participants ≥ 14 years old and not pregnant, and use of cocaine in the last 72 h. Information was extracted, evaluated and cross-checked independently by two researchers. Of the 1243 potentially relevant articles initially identified; one CC and 22 CS studies were finally selected. The CC study did not find cocaine use to be a risk-factor for seizures. In addition to the limitations of the CS design, these studies had important methodological weaknesses and biases. Despite its biological plausibility, no rigorous scientific evidence supports a causal relationship between cocaine use and seizures. The misinterpretation of the role of cocaine may have important implications in medical services. Well-conducted studies are urgently needed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

PubMed Central

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

2011-01-01

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

Multi-Center Trial of Baclofen for Abstinence Initiation in Severe Cocaine Dependent Individuals

PubMed Central

Kahn, Roberta; Biswas, Kousick; Childress, Anna-Rose; Shoptaw, Steve; Fudala, Paul J.; Gorgon, Liza; Montoya, Ivan; Collins, Joseph; McSherry, Frances; Li, Shou-Hua; Chiang, Nora; Alathari, Husam; Watson, Donnie; Liberto, Joseph; Beresford, Thomas; Stock, Christopher; Wallace, Christopher; Gruber, Valerie; Elkashef, Ahmed

2009-01-01

Background Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABAB receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) versus placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies. PMID:19414226

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

PubMed Central

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

2016-01-01

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

[Sigmund Freud and cocaine].

PubMed

Lebzeltern, G

1983-11-11

The basic tenet proposed by J. V. Scheidt states that the narcotic drug, cocaine played a role in the development of psychoanalysis which has been underestimated up to the present day. It is a fact that Freud himself took cocaine (in small doses) for about two years, and that he began his dream interpretation approximately ten years later. Scheidt believes that a long, unconscious conflict related to the cocaine-induced states of euphoria (ten years later) suddenly led to the beginnings of dream interpretation. The question to be answered now is: Why did this happen precisely in 1895? The foundations of psychoanalysis had already been laid, the application of the new method to the treatment of nervous disorders (heart complaints, train phobias, etc.) was certainly obvious. During this self-analysis it became necessary, first of all, to come to terms with the self-reproaches-which lay on the surface and were more accessible to consciousness-related to Freud's cocaine period (Fleischl-Marxow becomes addicted to cocaine, the most terrible night ever experienced, death of this friend, Freud's warning came too late). It was only when Freud has come to terms with this phase of his life that the road to the deepest part, the discovery of the Oedipus complex in the fall of 1897, was cleared.

Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

PubMed

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

2018-06-01

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

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.

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. Copyright © 2010 Elsevier Ltd. All rights reserved.

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

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

2007-01-25

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

Cocaine

MedlinePlus

... Short-term health effects of cocaine include: extreme happiness and energy mental alertness hypersensitivity to sight, sound, ... include: constricted blood vessels nausea faster heartbeat extreme happiness and energy irritability paranoia Long-term effects include: ...

Cocaine improves inhibitory control in a human model of response conflict.

PubMed

Fillmore, Mark T; Rush, Craig R; Hays, Lon

2005-11-01

The present study was designed to test the acute effects of cocaine on behavioral control in the presence and absence of motivational conflict. Adults (N = 14) with a history of stimulant use received oral cocaine hydrogen chloride (0, 100, 200, and 300 mg) and performed a cue-dependent go/no-go task to measure inhibitory and activational mechanisms of behavioral control either with or without motivated conflict between the inhibition and the activation of responses. Cocaine improved response inhibition in both conflict conditions, as evident by a decrease in inhibitory failures following active doses. The current study provides a useful model to investigate the effects of other drugs reported to have performance-enhancing effects. Copyright 2005 APA, all rights reserved.

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. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

The epidemiology of cocaine use in Spain.

PubMed

Barrio Anta, G; Vicente Orta, J; Bravo Portela, M J; de la Fuente de Hoz, L

1993-12-01

Trends and patterns of cocaine use in Spain are described with the aid of different information sources such as population surveys, the State Information System on Drug Abuse, and anthropological studies. In recent years the magnitude of cocaine supply indicators has increased greatly. High levels of last-month prevalence of cocaine use have been detected among the general population--consistently higher than those for heroin-- and cocaine consumption among heroin users has increased. Although the frequency of some health problems related to cocaine use--treatment admissions, hospital emergency admissions--has increased, it is still 30 times less than for heroin. Various hypotheses to explain these discrepancies are discussed.

Drug smuggling using clothing impregnated with cocaine.

PubMed

McDermott, Seán D; Power, John D

2005-11-01

A case study is presented where a woman travelling from South America to the Republic of Ireland was detained at Dublin Airport and articles of clothing she had in her luggage were found to be impregnated with cocaine. The study shows that the amount of powder recovered from the garments was approximately 14% of the total weight of the garments. The cocaine was in the form of cocaine hydrochloride and the purity was approximately 80%. An examination of the garments under filtered light highlighted the areas exposed to cocaine and indicated that the method of impregnation was by pouring liquid containing cocaine onto the clothing.

Late Dose-Response Effects of Prenatal Cocaine Exposure on Newborn Neurobehavioral Performance

PubMed Central

Tronick, Edward Z.; Frank, Deborah A.; Cabral, Howard; Mirochnick, Mark; Zuckerman, Barry

2008-01-01

Objective To determine in a representative sample of full-term urban newborns of English-speaking mothers whether an immediate or late dose-response effect could be demonstrated between prenatal cocaine exposure and newborn neurobehavioral performance, controlling for confounding factors. Methods The Neonatal Behavioral Assessment Scale (NBAS) was administered by masked examiners to a total sample of 251 clinically healthy, full-term infants at 2 days and/or 17 days. Three in utero cocaine exposure groups were defined: heavily exposed (n = 44, >75th percentile self-reported days of use during pregnancy and/or >75th percentile of meconium benzoylecognine concentration); lightly exposed (n = 79, less than both 75th percentiles); and unexposed (n = 101, no positive biological or self-report marker). At the 3-week examination there were 38 heavily exposed, 73 lightly exposed, and 94 unexposed infants. Controlling for infant birth weight, gestational age, infant age at the time of examination, mothers’ age, perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use, a regression analysis evaluated the effects of levels of cocaine exposure on NBAS performance. Results No neurobehavioral effects of exposure on the newborn NBAS cluster scores or on the qualifier scores were found when confounders were controlled for at 2 to 3 days of age. At 3 weeks, after controlling for covariates, a significant dose effect was observed, with heavily exposed infants showing poorer state regulation and greater excitability. Conclusions These findings demonstrate specific dose-related effects of cocaine on 3-week neurobehavioral performance, particularly for the regulation of arousal, which was not observed in the first few days of life. PMID:8668416

Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals.

PubMed

Passamonti, Luca; Luijten, M; Ziauddeen, H; Coyle-Gilchrist, I T S; Rittman, T; Brain, S A E; Regenthal, R; Franken, I H A; Sahakian, B J; Bullmore, E T; Robbins, T W; Ersche, K D

2017-08-01

Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F 26  = 6.73, P = 0.01). During the go/no-go task, there was a treatment × trial × group interaction, although this finding only showed a trend towards statistical significance (F 26  = 3.38, P = 0.07). Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine's modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials.

The Efficacy of Contingency Management on Cocaine Craving, using Prize-based Reinforcement of Abstinence in Cocaine Users.

PubMed

Pirnia, Bijan; Tabatabaei, Seyed Kazem Rasoulzadeh; Tavallaii, Abbas; Soleimani, Ali Akbar; Pirnia, Kambiz

2016-11-01

Contingency management (CM) is one of the most common therapies in the domain of drug addiction. This study has been carried out with the purpose of evaluating the efficacy of contingency management intervention. In an experimental design, between December 15, 2014 and November 20, 2015, fifty men (between 18 and 31 with an average age of 24.6) with a history of cocaine use, were selected voluntarily and were randomly assigned into two groups of CM and control group. The CM group were awarded coupons for negative urine tests, over a period of twelve weeks. The urine tests were taken from the participants twice per week, with cutoff concentrations for positive set at 300 ng/ml and self-reporting index of cocaine craving (response rate = 96%) were evaluated in two phase, through pretest and posttest measures. The data were analyzed by parametric covariance test. Additionally, the qualitative data, resulted from demographic measures, were coded and were analyzed with the help of an analysis instrument of qualitative data i.e. ATLAS.ti-5.2. The primary outcome was the number of negative urine tests and the secondary outcome included the cocaine usage craving index over twelve weeks. The mean of (95% of confidence) number of negative cocaine urine tests was 15.4 (13.1-17.8) in the CM group and 19.7 (17.7-21.6) in the control group (P = 0.049). Also, results showed that CM has a significant effect on reducing craving (p<0.01). The findings of this study, while having practical aspects in this domain, can be valuable in planning remedial procedures.

The effects of post-extinction exercise on cocaine-primed and stress-induced reinstatement of cocaine seeking in rats.

PubMed

Ogbonmwan, Yvonne E; Schroeder, Jason P; Holmes, Philip V; Weinshenker, David

2015-04-01

Voluntary aerobic exercise has shown promise as a treatment for substance abuse, reducing relapse in cocaine-dependent people. Wheel running also attenuates drug-primed and cue-induced reinstatement of cocaine seeking in rats, an animal model of relapse. However, in most of these studies, wheel access was provided throughout cocaine self-administration and/or extinction and had effects on several parameters of drug seeking. Moreover, the effects of exercise on footshock stress-induced reinstatement have not been investigated. The purposes of this study were to isolate and specifically examine the protective effect of exercise on relapse-like behavior elicited by a drug prime or stress. Rats were trained to self-administer cocaine at a stable level, followed by extinction training. Once extinction criteria were met, rats were split into exercise (24 h, continuous access to running wheel) and sedentary groups for 3 weeks, after which, drug-seeking behavior was assessed following a cocaine prime or footshock. We also measured galanin messenger RNA (mRNA) in the locus coeruleus and A2 noradrenergic nucleus. Exercising rats ran ∼4-6 km/day, comparable to levels previously reported for rats without a history of cocaine self-administration. Post-extinction exercise significantly attenuated cocaine-primed, but not footshock stress-induced, reinstatement of cocaine seeking, and increased galanin mRNA expression in the LC but not A2. These results indicate that chronic wheel running can attenuate some forms of reinstatement, even when initiated after the cessation of cocaine self-administration, supporting the idea that voluntary exercise programs may help maintain abstinence in clinical populations.

Aripiprazole maintenance increases smoked cocaine self-administration in humans

PubMed Central

Rubin, Eric; Foltin, Richard W.

2011-01-01

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

Relationship between alcohol consumption, whether linked to other substance use or not, and antiretroviral treatment adherence in HIV+ patients.

PubMed

González-Álvarez, Sara; Madoz-Gúrpide, Agustín; Parro-Torres, Carlos; Hernández-Huerta, Daniel; Ochoa Mangado, Enriqueta

2017-07-14

Hazardous alcohol consumption is a common diagnosis among people living with HIV infection. The relationship between alcohol consumption and poor adherence to antiretroviral therapy has been highlighted in different studies, yet few of them performed a parallel analysis of other substance use. In Spain, alcohol consumption is frequently associated with other substance use, mainly cannabis and cocaine. The aim of this study is to assess the influence of hazardous alcohol consumption both combined with other substances (cocaine, heroin, methadone and/or cannabis) or alone on antiretroviral therapy adherence in our social environment. We performed an observational case-control study including 119 HIV+ individuals. We recruited 40 non-adherent patients, defined by less than 90% compliance according to hospital pharmacy refill data, and corroborated by the Simplified Medication Adherence Questionnaire (SMAQ) and referring professional's opinion. Control cases (n=79) were defined as those patients with similar characteristics but considered adherent according to the same parameters. Data collection took place between May 2013 and September 2015. Statistical analysis was performed using a binary logistic regression model. Our results indicate that alcohol consumption decreases adherence to antiretroviral therapy. The use of methadone represents a statistically significant increased risk of poor adherence. No significant differences were found between adherent and non-adherent groups regarding cocaine, heroin or cannabis use in this study. In summary, the detection of substance use and especially alcohol consumption in HIV+ patients can improve the effectiveness of antiretroviral therapy by identifying and treating at-risk individuals for a poor therapeutic adherence.

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.

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

PubMed

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

2014-09-01

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

Orexin-1 receptor signaling increases motivation for cocaine-associated cues

PubMed Central

Bentzley, Brandon S.; Aston-Jones, Gary

2015-01-01

The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1R), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light+tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then asked if cocaine demand is linked to cued-reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high demand animals, i.e., animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not for cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses. PMID:25754681

Paternal alcoholism and offspring ADHD problems: a children of twins design.

PubMed

Knopik, Valerie S; Jacob, Theodore; Haber, Jon Randolph; Swenson, Lance P; Howell, Donelle N

2009-02-01

A recent Children-of-Female-Twin design suggests that the association between maternal alcohol use disorder and offspring ADHD is due to a combination of genetic and environmental factors, such as prenatal nicotine exposure. We present here a complementary analysis using a Children-of-Male-Twin design examining the association between paternal alcoholism and offspring attention deficit hyperactivity problems (ADHP). Children-of-twins design: offspring were classified into 4 groups of varying genetic and environmental risk based on father and co-twin's alcohol dependence status. Univariate results are suggestive of a genetic association between paternal alcohol dependence and broadly defined offspring ADHP. Specifically, offspring of male twins with a history of DSM-III-R alcohol dependence, as well as offspring of non-alcohol dependent monozygotic twins whose co-twin was alcohol dependent, were significantly more likely to exhibit ADHP than control offspring. However, multivariate models show maternal variables independently predicting increased risk for offspring ADHP and significantly decreased support for a genetic mechanism of parent-to-child transmission. In support of earlier work, maternal variables (i.e., maternal ADHD and prenatal exposure) were strongly associated with child ADHP; however, the role of paternal alcohol dependence influences was not definitive. While genetic transmission may be important, the association between paternal alcohol dependence and child ADHP is more likely to be indirect and a result of several pathways.

CRF1 receptor-deficiency increases cocaine reward.

PubMed

Contarino, Angelo; Kitchener, Pierre; Vallée, Monique; Papaleo, Francesco; Piazza, Pier-Vincenzo

2017-05-01

Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF 1 receptor-deficient (CRF 1 -/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF 1 -/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF 1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF 1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF 1 -/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF 1 -/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF 1 -/- mice by exogenous corticosterone does not affect CRF 1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF 1 receptor in cocaine reward, independently of the closely related HPA axis activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

PubMed

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

2017-01-01

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

Cocaine addiction: the hidden dimension.

PubMed

Oswald, L M

1989-06-01

There is growing awareness within the nursing profession that nurses need to expand their knowledge about addiction and develop expertise in providing care for substance abusing clients. This report presents a discussion about cocaine abuse that is focused on evolving knowledge about the physiology of addiction. Researchers have recently described cocaine-induced neurochemical changes in the brain that may form the underpinnings for the behavioral manifestations and symptomatology that have been associated with cocaine addiction. These neurochemical alterations are described at the cellular level, and treatment implications for nurses are presented.

Dopaminergic sensitivity and cocaine abuse: response to apomorphine.

PubMed

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

1990-08-01

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

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2013-01-01

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

Development of a therapeutic vaccine for the treatment of cocaine addiction.

PubMed

Fox, B S

1997-12-15

No pharmacotherapies have yet been approved for the treatment of cocaine addiction. One new approach is to block the effects of cocaine with anti-cocaine antibodies induced by a therapeutic cocaine vaccine. A cocaine vaccine has been developed which induces a cocaine-specific antibody response in rodents. The antibody binds to cocaine in the circulation and can be shown to inhibit the ability of cocaine to enter the brain. Furthermore, anti-cocaine antibody can inhibit cocaine self-administration in rats. These data suggest that a cocaine vaccine may be a powerful therapeutic tool. The intent is to immunized motivated patients with the vaccine as part of a comprehensive treatment program. If the patient uses cocaine after being vaccinated, the antibody will inhibit the reinforcing activity of cocaine and decrease the likelihood of relapse.

PET Studies in Nonhuman Primate Models of Cocaine Abuse: Translational Research Related to Vulnerability and Neuroadaptations

PubMed Central

Gould, Robert W.; Duke, Angela N.; Nader, Michael A.

2013-01-01

The current review highlights the utility of positron emission tomography (PET) imaging to study the neurobiological substrates underlying vulnerability to cocaine addiction and subsequent adaptations following chronic cocaine self-administration in nonhuman primate models of cocaine abuse. Environmental (e.g., social rank) and sex-specific influences on dopaminergic function and sensitivity to the reinforcing effects of cocaine are discussed. Cocaine-related cognitive deficits have been hypothesized to contribute to high rates of relapse and are described in nonhuman primate models. Lastly, the long-term consequences of cocaine on neurobiology are discussed. PET imaging and longitudinal, within-subject behavioral studies in nonhuman primates have provided a strong framework for designing pharmacological and behavioral treatment strategies to aid drug-dependent treatment seekers. Non-invasive PET imaging will allow for individualized treatment strategies. Recent advances in radiochemistry of novel PET ligands and other imaging modalities can further advance our understanding of stimulant use on the brain. PMID:23458573

Polypeptide Functional Surface for the Aptamer Immobilization: Electrochemical Cocaine Biosensing.

PubMed

Bozokalfa, Guliz; Akbulut, Huseyin; Demir, Bilal; Guler, Emine; Gumus, Z Pınar; Odaci Demirkol, Dilek; Aldemir, Ebru; Yamada, Shuhei; Endo, Takeshi; Coskunol, Hakan; Timur, Suna; Yagci, Yusuf

2016-04-05

Electroanalytical technologies as a beneficial subject of modern analytical chemistry can play an important role for abused drug analysis which is crucial for both legal and social respects. This article reports a novel aptamer-based biosensing procedure for cocaine analysis by combining the advantages of aptamers as selective recognition elements with the well-known advantages of biosensor systems such as the possibility of miniaturization and automation, easy fabrication and modification, low cost, and sensitivity. In order to construct the aptasensor platform, first, polythiophene bearing polyalanine homopeptide side chains (PT-Pala) was electrochemically coated onto the surface of an electrode and then cocaine aptamer was attached to the polymer via covalent conjugation chemistry. The stepwise modification of the surface was confirmed by electrochemical characterization. The designed biosensing system was applied for the detection of cocaine and its metabolite, benzoylecgonine (BE), which exhibited a linear correlation in the range from 2.5 up to 10 nM and 0.5 up to 50 μM for cocaine and BE, respectively. In order to expand its practical application, the proposed method was successfully tested for the analysis of synthetic biological fluids.

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

PubMed

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

2017-05-01

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

Induction and blockade of adolescent cocaine-induced habits

PubMed Central

DePoy, Lauren M.; Zimmermann, Kelsey S.; Marvar, Paul J.; Gourley, Shannon L.

2017-01-01

Background Cocaine use during adolescence increases vulnerability to drug dependence and decreases the likelihood that individuals will seek treatment as adults. Understanding how early-life cocaine exposure influences decision-making processes in adulthood is thus critically important. Methods Adolescent or adult mice were exposed to subchronic cocaine, then behavioral sensitivity to changes in the predictive relationship between actions and their consequences was tested. Dendritic spines on the principal pyramidal neurons of the orbitofrontal prefrontal cortex (oPFC) were also imaged and enumerated. To determine whether cytoskeletal regulatory systems in the oPFC influenced decision-making strategies, we then inhibited the activity of Abl-family and Rho kinases, as well as NR2B-containing NMDA receptors. We also attempted to block the reinstatement of cocaine seeking in cocaine self-administering mice. Results Adult mice with a history of subchronic cocaine exposure in adolescence engaged habit-based response strategies at the expense of goal-directed decision-making strategies and had fewer dendritic spines in the oPFC. Inhibition of the cytoskeletal regulatory Abl-family kinases in the oPFC recapitulated these neurobehavioral deficiencies, while Rho-kinase inhibition corrected response strategies. Additionally, the NR2B-selective NMDA receptor antagonists ifenprodil and CP-101,606 blocked cocaine-induced habits, and this was dependent on Abl-family signaling in the oPFC. Ifenprodil also mitigated cue-induced reinstatement of cocaine seeking in mice self-administering cocaine. Conclusions We suggest that adolescent cocaine exposure confers a bias towards habit-based behavior in adulthood via long-term cellular structural modifications in the oPFC. Treatments aimed at mitigating the durable consequences of early-life cocaine may benefit from targeting cytoskeletal regulatory systems. PMID:27871669

Clinical ratings and plasma HVA during cocaine abstinence.

PubMed

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

1989-08-01

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

Concurrent crack and powder cocaine users from Sao Paulo: Do they represent a different group?

PubMed Central

Guindalini, Camila; Vallada, Homero; Breen, Gerome; Laranjeira, Ronaldo

2006-01-01

Background Cocaine abuse is a serious and socially damaging illegal drug problem. Different routes of administration are associated with a specific progression of use, different degrees of abuse liability, propensity for dependence and treatment response. There have been relatively few studies comparing different cocaine users groups and no studies into the characterization of the group of individuals reporting concurrent use of powder cocaine and crack cocaine. Methods Six hundred and ninety-nine cocaine users were assessed during the period August 1997 to October 1998 in one outpatient and six inpatient clinics located in the São Paulo, Brazil. Patients were interviewed using a structured questionnaire schedule in Portuguese, designed specifically for the Brazilian population. The statistical analyses were performed using either ANOVA or a chi-squared test and focusing on their preferred form of use/route of administration and other variables. Results For 83% of the variables tested in this study, the Dual Users subgroup (using both powder and crack cocaine) demonstrated statistical differences from the single drug user subgroups. Those differences include the initiation of cocaine, the abuse of other illicit drugs, and rates of criminal history. Conclusion These data suggest cocaine-dependent individuals who report use of both powder and crack cocaine are an at least partially, distinct subgroup. However, further studies will be necessary to confirm this and to determine if they also show a different treatment response. PMID:16426451

Fenobam Sulfate Inhibits Cocaine-Taking and Cocaine-Seeking Behavior in Rats: Implications for Addiction Treatment in Humans

PubMed Central

Keck, Thomas M.; Yang, Hong-Ju; Bi, Guo-Hua; Huang, Yong; Zhang, Hai-Ying; Srivastava, Ratika; Gardner, Eliot L.; Newman, Amy Hauck; Xi, Zheng-Xiong

2014-01-01

Rationale The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be critically involved in drug reward and addiction. Because the mGluR5 negative allosteric modulators (NAMs) MPEP and MTEP significantly inhibit addictive-like behaviors of cocaine and other drugs of abuse in experimental animals, it has been suggested that mGluR5 NAMs may have translational potential for treatment of addiction in humans. However, neither MPEP nor MTEP have been evaluated in humans due to their off-target actions and rapid metabolism. Objectives Herein, we evaluate a potential candidate for translational addiction research: a new sulfate salt formulation of fenobam, a selective mGluR5 NAM that has been investigated in humans. Results In rats, fenobam sulfate had superior pharmacokinetics compared to the free base, with improved Cmax (maximal plasma concentration) and longer half life. Oral (p.o.) administration of fenobam sulfate (30 or 60 mg/kg) inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Fenobam sulfate also inhibited oral sucrose self-administration and sucrose-induced reinstatement of sucrose-seeking behavior, but had no effect on locomotion. Conclusions This study provides additional support for the role of mGluR5 signaling in cocaine addiction and suggests that fenobam sulfate may have translational potential in medication development for the treatment of cocaine addiction in humans. PMID:23615919

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

PubMed

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

2016-03-01

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

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

PubMed Central

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

2015-01-01

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

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

PubMed Central

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

2010-01-01

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

Incubation of Cue-Induced Craving in Adults Addicted to Cocaine Measured by Electroencephalography.