Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “COCAINE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed2002

Reinstatement of cocaine seeking in 129X1/SvJ mice: effects of cocaine priming, cocaine cues and food deprivation.

RATIONALE AND OBJECTIVES: The mechanisms underlying relapse to cocaine seeking induced by exposure to priming cocaine injections, cues associated with cocaine self-administration and environmental stressors have been studied in rats. Here we describe a reinstatement method for studying relapse to cocaine seeking in mice, a suitable species for studying the effect of genetic manipulations such as gene knockout or gene over-expression on compulsive drug use. METHODS: Male mice of the 129X1/SvJ strain were trained for 14-16 days to self-administer cocaine (0.75 mg/kg/infusion; 4 h/day; fixed-ratio-1 schedule of reinforcement; infusions were paired with a light-tone compound cue). Next, the lever-pressing behavior was extinguished by removing the cocaine syringes in the presence (Exps. 1 and 3) or absence (Exp. 2) of the cocaine cue. Subsequently, tests for reinstatement were conducted after exposure to priming injections of cocaine (0, 1.5, 3.0 and 6.0 mg/kg, IV; Exp. 1), response-contingent presentations of the cocaine-associated cue (Exp. 2), or food deprivation stress (1 and 22 h; Exp. 3). RESULTS: The effect of cocaine priming on reinstatement was modest and was only observed at the highest dose tested. On the other hand, reinstatement of cocaine seeking was observed following exposure to the cocaine-associated cue and food deprivation stress. CONCLUSIONS: The present data suggest that factors contributing to relapse to drugs can be studied in the reinstatement model using the common 129X1/SvJ mouse inbred strain.

Animals↗
PubMed2004

Increases in dopamine D3 receptor binding in rats receiving a cocaine challenge at various time points after cocaine self-administration: implications for cocaine-seeking behavior.

Previous research suggests that cocaine dysregulates dopamine D3 receptors. The present study examined the time course of changes in dopamine D3 receptor binding after terminating a cocaine self-administration regimen. [125I]-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino]-tetralin was used to label dopamine D3 receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31-32 days after their last cocaine self-administration session. The results indicated a time-dependent increase in D3 receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D3 receptor binding in cocaine-experienced rats killed at the 2- or 8-day time points relative to controls, but there was an increase in D3 receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31- to 32-day time point. In a subsequent experiment, we replicated the increase in D3 receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D3 receptors may be functionally related to changes in propensity for cocaine-seeking behavior.

Animals↗
PubMed2006

Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.

Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.

Animals↗
PubMed1990

Effect of chronic cocaine administration and cocaine withdrawal on coronary flow rate and heart rate responses to epinephrine and cocaine in isolated perfused rat hearts.

The acute dose-dependent effects of epinephrine and cocaine on heart rate and coronary flow rate (CFR) were examined in isolated, perfused (Langendorff) rat hearts from animals: i) pretreated with daily cocaine injections (20 mg/kg/day) for 8 weeks; ii) after 2-day withdrawal from 8-week cocaine pretreatment; iii) vehicle-treated controls. Chronic cocaine (CC) hearts were significantly less sensitive to the chronotropic effects of epinephrine than control (C) or withdrawal (CW) hearts. CW hearts exhibited significantly higher heart rates in response to epinephrine than C and CC hearts. Epinephrine alone (2.5 x 10(-7) M) decreased CFR 11% (C), 9%(CC), 14%(CW) from respective baseline levels. Cocaine alone had no significant effect on CFR in C hearts but produced slight dose-dependent decrements in CFR in CC and particularly CW hearts at higher doses. Cocaine plus epinephrine markedly decreased CFR in all groups, particularly in CW hearts. The results indicate that chronic daily cocaine administration produces a functional tolerance of the heart to the chronotropic actions of epinephrine but a 2-day withdrawal from chronic cocaine results in a rebound supersensitivity to adrenergic stimulation and cocaine's sympathomimetic effects. In addition, cocaine produces only minor decrements in coronary flow in the rat heart, while cocaine acts synergisticallly with epinephrine to produce a marked decrease in CFR.

Animals↗
PubMed2006

Negative cocaine effect expectancies are associated with subjective response to cocaine challenge in recreational cocaine users.

Although many studies have shown that cognitive effect expectancies are associated with drug use and drug treatment outcomes, few studies have compared effect expectancies with drug response following drug challenge. Healthy male and female volunteers (n=19, ages 21-35) who reported using cocaine 1-4 times per month completed the Cocaine Effect Expectancy Questionnaire (CEEQ: [Schafer, J. and Brown, S.A. (1991). Marijuana and cocaine effect expectancies and drug use patterns. Journal of Consulting and Clinical Psychology, 59, 558-565.]), were challenged with cocaine (0.9 mg/kg, i.n.), then completed a series of visual analog scales (VAS) and the Addiction Research Center Inventory (ARCI) at 15 min intervals for 3 h following cocaine administration. Significant positive correlations were found between global negative expectancies and peak responses on the VAS measures "Good," "Happy," "High," "Stimulated," and "Desire to Use Cocaine," and on the LSD subscale of the ARCI post-cocaine administration, and between global positive expectancies and the MBG subscale of the ARCI, and on VAS items "Anxious" and "Good" post-cocaine administration. Global positive expectancies also were positively correlated with peak systolic blood pressure, and global negative expectancies with peak heart rate after cocaine administration. These results suggest that negative and positive effect expectancies both play a complex role in the subjective experience of cocaine effects, and thus likely in the progression of non-use to recreational use, in the transition to abuse, and in individualized treatment strategies.

Adult↗
PubMed2000

Effects of N-methyl-D-aspartate receptor antagonists on reinstatement of cocaine-seeking behavior by priming injections of cocaine or exposures to cocaine-associated cues in rats.

The reinstatement of extinguished cocaine self-administration behavior was studied in rats pretreated with N-methyl-D-aspartate receptor antagonists. Rats were trained to self-administer intravenous cocaine (0.32 mg/kg/infusion) during five consecutive daily sessions that were followed by five consecutive daily extinction sessions, during which cocaine was unavailable and cocaine-associated cues (sound and light) were absent. Neither the competitive N-methyl-D-aspartate receptor antagonist D-CPPene (0.3-3 mg/kg) nor the low-affinity N-methyl-D-aspartate receptor channel blocker memantine (1-10 mg/kg) reinstated extinguished responding. Priming injections of intravenous cocaine (Experiment 1), and exposures to cocaine-associated stimuli (buzzer and light; Experiment 2) engendered responding on the reinforced lever in excess of that on the non-reinforced lever. In Experiment 1, administration of D-CPPene or memantine prior to the priming injection of cocaine eliminated the difference between reinforced-lever and non-reinforced-lever response rates. For both D-CPPene and memantine, however, this effect was largely due to increased responding upon the non-reinforced lever rather than to decreased reinforced-lever responding. In Experiment 2, D-CPPene, but not memantine, abolished in a dose-dependent manner the selective increase in reinforced-lever over non-reinforced-lever responding that was induced by exposures to cocaine-related stimuli. This effect of D-CPPene was not due to increased non-reinforced-lever responding. These data help define the boundaries within which N-methyl-D-aspartate receptor antagonists can prevent reinstatement of cocaine-seeking behavior (e.g. type of antagonist used and reinstatement procedure).

Animals↗
PubMed1989

Validity testing of commercial urine cocaine metabolite assays: III. Evaluation of an enzyme-linked immunosorbent assay (ELISA) for detection of cocaine and cocaine metabolite.

A validity assessment study was performed on the Genetic Diagnostic Enzyme Immunoassay test kit, a new enzyme-linked immunosorbent assay (GDC ELISA) for detection of cocaine and cocaine metabolite in urine. A set of 290 urine specimens, comprised of clinical cocaine urines collected from 5 male subjects who had received single doses of intravenous cocaine, drug-free urines spiked with cocaine, cocaine metabolites, cocaine isomers, and other drugs of abuse, were assayed by GDC ELISA. The results were compared with results by gas chromatography/mass spectrometry (GC/MS) assay for benzoylecgonine. Concordance was high between the GDC ELISA assay and GC/MS and with results reported earlier for other commercial assays. Detection times and specificity of the GDC ELISA antibody were most similar to those of the Abuscreen radioimmunoassay for cocaine metabolite. Overall, the assay produced no false negative or false positive results and appeared to be a reliable screening test for detection of cocaine and benzoylecgonine in human urine.

Cocaine↗
PubMed2005

Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia.

Risk for cocaine dependence (CD) is genetically influenced. We recruited a sample of small nuclear families (528 full and 155 half sibpairs) with at least one subject affected with CD. The sample was classified via Bayesian clustering as 45.5% European American (EA) and 54.5% African American (AA). Assessment, via the Semi-Structured Assessment for Drug Dependence and Alcoholism, allowed for detailed evaluation of substance dependence-related traits. To define subgroups with increased genetic homogeneity, consistent with our a priori analytic plan, we used cluster analytic methods to identify six cocaine-related symptom clusters; membership was shown to be significantly heritable. We then completed a genomewide linkage scan (409 markers) for the CD diagnosis, cocaine-induced paranoia (CIP; an outcome that occurs in some cocaine users) and the clusters (three of which contained >80% of the CD subjects). We observed a "suggestive" linkage signal on chromosome 10 for the trait of CD in the full sample; and two "suggestive" linkage signals at different locations on chromosome 3, in the EA part of the sample. We observed a genomewide-significant lod score of 3.65 for the trait of CIP on chromosome 9, in the AA part of the sample only. Our strongest results were observed for the cluster membership traits, including a lod score of 4.66 for membership in the "Heavy Use, Cocaine Predominant" cluster on chromosome 12 (in EAs only) and a lod score of 3.35 for membership in the "Moderate Cocaine and Opioid Abuse" cluster on chromosome 18. These results provide a basis for the identification of specific genes contributing to risk for these traits.

Adult↗
PubMed1990

Validity testing of commercial urine cocaine metabolite assays: IV. Evaluation of the EMIT d.a.u. cocaine metabolite assay in a quantitative mode for detection of cocaine metabolite.

The EMIT d.a.u. cocaine metabolite assay (EMIT dau) was evaluated in a quantitative mode for analysis of clinical specimens obtained after controlled cocaine administration to human subjects. The quantitative results showed high concordance with those of gas chromatography/mass spectrometry (GC/MS) assays of the same specimens for benzoylecgonine, and no false positive or false negative results were obtained. The evaluation also included analysis of standardized solutions containing benzoylecgonine, cocaine, and other cocaine metabolites and isomers. The EMIT dau antibody demonstrated high selectivity for benzoylecgonine. The precision was somewhat less than that reported earlier for other commercial cocaine metabolite immunoassays. Quantitation of initial screening results from EMIT dau testing can serve as a useful guide for confirmation by GC/MS in forensic science urine testing.

Cocaine↗
PubMed1996

Crack cocaine and cocaine hydrochloride. Are the differences myth or reality?

OBJECTIVE: To review and discuss the differences and similarities between the use of crack cocaine and cocaine hydrochloride; and to determine how these findings might affect policies on the imprisonment and treatment of cocaine users. DATA SOURCES: English-language publications were identified through a computerized search (using MEDLINE) between 1976 and 1996 using the search terms "smoked cocaine," "crack cocaine," "freebase," and "cocaine-base." In addition, manual searches were conducted on references cited in original research articles, reviews, and an annotated bibliography, and on selected journals. STUDY SELECTION: Only those articles that compared various routes of cocaine administration or types of cocaine (cocaine base or crack cocaine vs cocaine hydrochloride) were examined. DATA EXTRACTION: Studies were reviewed to obtain information on the composition of the 2 forms of cocaine, and the prevalence, pharmacokinetics and pharmacodynamics, abuse liability, pattern of use, and consequences across the various routes of cocaine administration and forms of cocaine. CONCLUSION: Cocaine hydrochloride is readily converted to base prior to use. The physiological and psychoactive effects of cocaine are similar regardless of whether it is in the form of cocaine hydrochloride or crack cocaine (cocaine base). However, evidence exists showing a greater abuse liability, greater propensity for dependence, and more severe consequences when cocaine is smoked (cocaine-base) or injected intravenously (cocaine hydrochloride) compared with intranasal use (cocaine hydrochloride). The crucial variables appear to be the immediacy, duration, and magnitude of cocaine's effect, as well as the frequency and amount of cocaine used rather than the form of the cocaine. Furthermore, cocaine hydrochloride used intranasally may be a gateway drug or behavior to using crack cocaine. Based on these findings, the federal sentencing guidelines allowing possession of 100 times more cocaine hydrochloride than crack cocaine to trigger mandatory minimum penalties is deemed excessive. Although crack cocaine has been linked with crime to a greater extent than cocaine hydrochloride, many of these crimes are associated with the addiction to cocaine. Therefore, those addicted individuals who are incarcerated for the sale or possession of cocaine are better served by treatment than prison.

Administration, Intranasal↗
PubMed2005

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

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

Administration, Oral↗
PubMed2002

Comparison of plasma cocaine levels during a "binge" pattern of cocaine administration in male and female rhesus monkeys.

RATIONALE: Cocaine is often abused in a "binge" pattern, but little is known about changes in plasma cocaine concentrations or cocaine pharmacokinetics during administration of multiple cocaine doses. Moreover, the extent to which gender may influence plasma cocaine levels during a cocaine binge has not been studied in rhesus monkeys. OBJECTIVES: To compare the effects of repeated injections of the same dose of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) on plasma cocaine concentrations, cocaine pharmacokinetics and behavioral responses in male and female rhesus monkeys. METHODS: Four injections of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) were administered at 30-min intervals to five or six male and five or six female rhesus monkeys. Samples for plasma cocaine analysis were collected at 2, 4, 8, 16 and 24 min after the first three injections. After the fourth cocaine injection, additional samples were collected at 10-min intervals over 150 min. RESULTS: Plasma cocaine peaks and nadirs increased monotonically after successive cocaine injections ( P<0.0001). Peak plasma cocaine levels measured at 2 min after cocaine administration were higher after 0.8 mg/kg cocaine than after 0.4 mg/kg cocaine ( P<0.006). There were no significant gender differences in time to peak plasma cocaine levels (t(max)), peak cocaine concentrations (C(max)) or half-life (t(1/2); min) at either dose of cocaine. Group average behavioral ratings were similar in males and females after each dose of cocaine. CONCLUSIONS: Peak plasma cocaine concentrations increased progressively during low and high dose cocaine binge episodes, and there were no significant gender differences in cocaine pharmacokinetics. These findings demonstrate the feasibility of simulating "binge" patterns of cocaine administration in rhesus monkeys.

Animals↗
PubMedDate not supplied

In vitro hepatic biotransformation of cocaine in maternal and fetal guinea pigs. Induction of cocaine N-demethylation with cocaine pretreatment.

In vitro N-demethylation of cocaine (COC) was examined in five saline (SAL) and five COC-treated pregnant guinea pigs and their fetuses (60 days, term 69 days). Microsomes from maternal and fetal guinea pigs produced norcocaine (NOR), benzoylnorecgonine (BN), and benzoylecgonine (BE) when incubated with COC. The initial rate of NOR formation was (mean +/- SE) 0.69 +/- 0.09 and 0.002 +/- 0.002 nmol/min/mg in microsomes from SAL-treated dams and their fetuses, respectively. The minimal fetal N-demethylation suggests BN seen previously in vivo after chronic maternal COC administration resulted from maternal formation of NOR and subsequent maternal or fetal hydrolysis to BN. COC pretreatment increased the initial rate of NOR formation to 1.38 +/- 0.28 nmol/min/mg (p < 0.05) and increased the extent of NOR formation by 12 min (p < 0.05). There was no change in total cytochrome P-450 concentrations in the dams. COC pretreatment had no effect on fetal hepatic N-demethylation of COC or total cytochrome P-450 content. The rate of NOR production plateaued in microsomes from both treatment groups by 20 min of incubation and could be restored when the microsomes were washed, repelleted, and reincubated. This suggests a soluble metabolite of COC inhibits COC N-demethylation. Microsomes from both SAL- and COC-treated animals produced this factor in the presence of COC, but the enzyme(s) responsible for COC N-demethylation in the SAL-treated pregnant guinea pig were more sensitive to inhibition than COC-pretreated animals.

Aminopyrine↗
PubMed2001

Antidepressants for cocaine dependence.

BACKGROUND: Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. The past decade has witnessed a sustained search for an effective pharmacotherapeutic agent for the treatment of cocaine dependence. While administration of cocaine acutely increases intercellular dopamine, serotonin, and norepinephrine levels by blocking their presynaptic reuptake, chronic cocaine abuse leads to down-regulation of monoamine systems. Post-cocaine use depression and cocaine craving may be linked to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine levels, may alleviate cocaine abstinence symptomatology, as well as relieving dysphoria and associated craving by general antidepressant action. OBJECTIVES: To conduct a systematic review of all RCTs on the use of antidepressants for treating cocaine dependence. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Other searches:reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of antidepressants on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: 18 studies were included in the review, with 1177 people randomised. Positive urine sample for cocaine metabolites was the main efficacy outcome, with no significant results obtained regardless the type of antidepressant. Compared to other drugs, desipramine performed better but showing just a non significant trend with heterogeneity present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial showed imipramine performed better than placebo in terms of clinical response according to patient's self-report. A similar rate of patients remaining in treatment was found for both patients taking desipramine or placebo. Results from one single trial suggest fluoxetine patients on SSRIs are less likely to dropout. Similar results were obtained for trials where patients had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. REVIEWER'S CONCLUSIONS: There is no current evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment.

Antidepressive Agents↗
PubMed1998

Cocaine conditioning and cocaine sensitization: what is the relationship?

With repeated cocaine use, cocaine conditioned behavior develops to associated stimuli, and in addition, sensitization can occur to the unconditioned stimulant effects of cocaine. To investigate the relationship between the conditioned and unconditioned behavioral effects of repeated cocaine use, two groups of rats (n = 7) were given five daily paired cocaine treatments (10 mg/kg i.p.) immediately before a 20-min placement in an open-field environment. Other groups received either saline before testing or cocaine unpaired which was administered 30 min after testing in the homecage. When tested in the open-field with saline for conditioned effects, the two cocaine paired groups selectively exhibited substantial and equivalent cocaine conditioned responses. One of these groups was subjected to an extinction procedure which was effective in eliminating the cocaine conditioned responses. Subsequently, all the rats which had received cocaine in the first phase of the experiment, paired and unpaired, along with a subset of saline animals were given a cocaine (10 mg/kg i.p.) challenge test. The paired cocaine animals exhibited an earlier onset of the cocaine induced behavioral response (sensitization) as compared with the saline and the unpaired cocaine animals. Critically, the sensitization effects were unaffected by extinction, and in addition, the conditioned response did not contribute to the sensitization effect. It is suggested that the cocaine drug response occludes the cocaine conditioned response. Subsequent to this sensitization test, the animals were retested for conditioning. In this test, the paired cocaine animals which had not been subjected to the extinction procedure still exhibited a conditioned cocaine response, whereas, the paired cocaine group subjected to extinction was indistinguishable from saline controls. Although the present results show that Pavlovian conditioned responses to exteroceptive contextual cues do not directly contribute to cocaine induced behavioral sensitization effects, the sensitization effects were context-specific, and therefore, were tied to associative processes. It is suggested that context specificity is mediated by a compound stimulus complex comprised of exteroceptive stimuli and interoceptive cocaine drug cues. Furthermore, these exteroceptive and interoceptive cues associated with cocaine effectively expedite the onset of cocaine effects, and thereby, facilitate the addictive potency of cocaine.

Animals↗
PubMed2006

Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats.

RATIONALE: Recent evidence suggests that prolonged cocaine self-administration produces escalation in drug-seeking behavior in rats analogous to the increased intake patterns observed in cocaine-dependent individuals. However, the contributions of prolonged access to cocaine taking vs the pharmacologic effects of the consequent increased cocaine exposure on escalation of drug-seeking behaviors have not been investigated. OBJECTIVE: The present study assessed the effects of these two factors on maintenance of cocaine self-administration and reinstatement of cocaine seeking. METHODS: Male, Sprague-Dawley rats were trained to self-administer cocaine (0.2 mg/i.v. infusion; FR1) for 1 h per day for 10 sessions followed by short access (1 h/day), contingent long access (6 h/day), or noncontingent long access (1 h contingent + 5 h of yoked cocaine infusions/day; i.e., short access + yoked) to cocaine for 14 daily sessions. All rats underwent extinction training and were subsequently tested for the ability of cocaine-paired cues or a cocaine-priming injection (7.5 mg/kg i.p.) to reinstate extinguished cocaine seeking. RESULTS: Rats in all groups maintained stable responding for cocaine reinforcement and subsequently showed significant reinstatement of cocaine-seeking behavior. Conditioned-cued reinstatement was enhanced after the contingent long access and short access + yoked cocaine exposure relative to short access cocaine exposure. Conversely, cocaine-primed reinstatement was enhanced after contingent long-access cocaine exposure relative to the other two conditions. CONCLUSIONS: Enhanced drug seeking produced by prolonged daily cocaine self-administration is due to a combination of behavioral and pharmacological factors. Specifically, conditioned-cued reinstatement is enhanced by increased cocaine intake and cocaine-primed reinstatement is enhanced by increased cocaine taking.

Animals↗
PubMed2001

Dopamine agonists for cocaine dependence.

BACKGROUND: Cocaine is a major drug of abuse. Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. OBJECTIVES: To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. SEARCH STRATEGY: We searched: The Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: Twelve studies were included, with 587 participants randomised. Amantadine and Bromocriptine were compared to placebo in most of trials. In two studies amantadine was directly compared to bromocriptine, while amantadine was compared to desipramine, an antidepressant in three. The main efficacy outcome presented was positive urine sample for cocaine metabolites, with no significant differences between interventions. When retention in treatment was assessed as an acceptability measure, it was found a similar rate of patients remaining in treatment in both placebo and active drugs. There were no significant differences in trials where participants had primary cocaine dependence or had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. REVIEWER'S CONCLUSIONS: Current evidence does not support the clinical use of dopamine agonists in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment.

Amantadine↗
PubMed2002

Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration.

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2-23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01-0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17-23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (<2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.

Animals↗