Weeks Of Cocaine Abstinence Research Articles

Hippocampal BDNF regulates a shift from flexible, goal-directed to habit memory system function following cocaine abstinence.

ABSTRACTThe transition from recreational drug use to addiction involves pathological learning processes that support a persistent shift from flexible, goal‐directed to habit behavioral control. Here, we examined the molecular mechanisms supporting altered function in hippocampal (HPC) and dorsolateral striatum (DLS) memory systems following abstinence from repeated cocaine. After 3 weeks of cocaine abstinence (experimenter‐ or self‐administered), we tested new behavioral learning in male rats using a dual‐solution maze task, which provides an unbiased approach to assess HPC‐ versus DLS‐dependent learning strategies. Dorsal hippocampus (dHPC) and DLS brain tissues were collected after memory testing to identify transcriptional adaptations associated with cocaine‐induced shifts in behavioral learning. Our results demonstrate that following prolonged cocaine abstinence rats show a bias toward the use of an inflexible, habit memory system (DLS) in lieu of a more flexible, easily updated memory system involving the HPC. This memory system bias was associated with upregulation and downregulation of brain‐derived neurotrophic factor (BDNF) gene expression and transcriptionally permissive histone acetylation (acetylated histone H3, AcH3) in the DLS and dHPC, respectively. Using viral‐mediated gene transfer, we overexpressed BDNF in the dHPC during cocaine abstinence and new maze learning. This manipulation restored HPC‐dependent behavioral control. These findings provide a system‐level understanding of altered plasticity and behavioral learning following cocaine abstinence and inform mechanisms mediating the organization of learning and memory more broadly.

Topiramate in the treatment of cocaine use disorder.

The literature on topiramate use in cocaine-dependent patients was reviewed. Six randomized, double-blind, controlled clinical trials evaluating the use of topiramate in patients who were cocaine dependent were analyzed. The results from the studies indicated that topiramate, when used in combination with cognitive behavioral therapy, may be effective in reducing short-term cocaine use and should be considered as a possible treatment option. Other trials suggested that topiramate was not effective in patients with a dual diagnosis of opioid and cocaine dependence. Two trials suggested that short-term abstinence assisted by pharmacotherapy is a predictor of longer-term (6 months and 1 year, respectively) abstinence. Cocaine use is dependent on multiple factors; therefore, a reduction in use or craving is not definitively associated with abstinence. However, decreased use reduces potential patient harm and the amount of money spent on illicit cocaine. The findings of this literature review should be used to encourage the completion of more trials that are appropriately designed. Topiramate was shown to be effective for increasing cocaine abstinence, the proportion of cocaine nonuse days, and the proportion of patients to attain 3 consecutive weeks of cocaine abstinence and decreasing the abuse liability of cocaine. Conflicting results in clinical trials do not provide a definitive answer regarding topiramate's efficacy in managing cocaine dependence. Available research neither validates nor invalidates the hypothesis that topiramate is efficacious in attaining abstinence in cocaine-dependent patients.

A randomized, controlled trial of combined cognitive-behavioral therapy plus prize-based contingency management for cocaine dependence

BackgroundCocaine has become one of the drugs of most concern in Switzerland, being associated with a wide range of medical, psychiatric and social problems. Available treatment options for cocaine dependence are rare. The study sought to compare combined prize-based contingency management (prizeCM) plus cognitive-behavioral therapy (CBT) to CBT alone in cocaine-dependent patients. MethodsSixty cocaine-dependent patients participated in a randomized, controlled trial with two treatment conditions. The participants were randomly assigned to the experimental group (EG; n=29), who received CBT combined with prizeCM, or to the control group (CG; n=31), who received CBT only during 24 weeks. The primary outcome measures were retention, at least 3 consecutive weeks of cocaine abstinence, the maximum number of consecutive weeks of abstinence and proportions of cocaine-free urine samples during the entire 24-week and at 6-month follow-up. ResultsSixty-three percent of the participants completed the study protocol. Participants in both groups significantly reduced cocaine use over time. Overall, no difference in cocaine-free urine screens was found across the two treatment groups, except at weeks 8, 9, 10, 17 and 21 in favor of the EG. ConclusionsThe addition of prizeCM to CBT seems to enhance treatment effects, especially in the early treatment period, supporting results from previous studies. Both the combined intervention and CBT alone, led to significant reductions in cocaine use during treatment and these effects were sustained at 6-month follow-up. These findings underline the importance in implementing CM and CBT interventions as treatment options for cocaine dependence in the European context.

Randomized clinical trial of disulfiram for cocaine dependence or abuse during buprenorphine treatment

BackgroundDisulfiram may be efficacious for treating cocaine dependence or abuse, possibly through inhibiting dopamine β-hydroxylase (DβH). Consequently, this randomized, placebo-controlled clinical trial of disulfiram during buprenorphine maintenance treatment evaluated the study hypothesis that disulfiram is superior to placebo and explored whether disulfiram response is greatest for participants with a single nucleotide polymorphism coding for genetically low DβH (T-allele carriers). MethodsWe randomized 177 buprenorphine-treated opioid dependent participants with cocaine dependence or abuse to 12 weeks of double-blind treatment with disulfiram 250mg daily (n=91) or placebo (n=86). Of 155 participants genotyped, 84 were CC-homozygous, and 71 CT or TT genotypes. Primary outcomes included days per week cocaine use, number of cocaine-negative urine tests, and maximum consecutive weeks of cocaine abstinence. We analyzed an intention-to-treat comparison between disulfiram and placebo. We also explored potential pharmacogenetic interactions and examined treatment responses of four participant groups based on medication (disulfiram or placebo) by genotype (CC-homozygous or T-allele carrier) classification. ResultsDisulfiram participants reported significantly less frequent cocaine use; the differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant. Frequency of cocaine use was lowest in disulfiram-treated T-allele carriers; differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant among the four medication-genotype groups. ConclusionsThe findings provide limited support for the efficacy of disulfiram for reducing cocaine use and suggest that its mechanism of action may involve inhibition of DβH. Further studies of its efficacy, mechanism of action, and pharmacogenetics of response are warranted.

Conditioned Contribution of Peripheral Cocaine Actions to Cocaine Reward and Cocaine-Seeking

Cocaine has actions in the peripheral nervous system that reliably precede--and thus predict--its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood-brain barrier, to isolate the peripheral actions of cocaine and determine their central and behavioral effects in animals first trained to lever-press for cocaine hydrochloride (the centrally acting and abused form of the drug). We first confirmed with fast-scan cyclic voltammetry that cocaine methiodide causes rapid dopamine release from dopamine terminals in cocaine hydrochloride-trained rats. We then compared the ability of cocaine hydrochloride and cocaine methiodide to establish conditioned place preferences in rats with self-administration experience. While cocaine hydrochloride established stronger place preferences, cocaine methiodide was also effective and its effectiveness increased (incubated) over weeks of cocaine abstinence. Cocaine self-administration was extinguished when cocaine methiodide or saline was substituted for cocaine hydrochloride in the intravenous self-administration paradigm, but cocaine hydrochloride and cocaine methiodide each reinstated non-rewarded lever-pressing after extinction. Rats extinguished by cocaine methiodide substitution showed weaker cocaine-induced reinstatement than rats extinguished by saline substitution. These findings suggest that the conditioned peripheral effects of cocaine can contribute significantly to cocaine-induced (but not stress-induced) cocaine craving, and also suggest the cocaine cue as an important target for cue-exposure therapies for cocaine addiction.

Delay discounting is associated with treatment response among cocaine-dependent outpatients.

Delay discounting (DD) describes the rate at which reinforcers lose value as the temporal delay to their receipt increases. Steeper discounting has been positively associated with vulnerability to substance use disorders, including cocaine use disorders. In the present study, we examined whether DD of hypothetical monetary reinforcers is associated with the duration of cocaine abstinence achieved among cocaine-dependent outpatients. Participants were 36 adults who were participating in a randomized controlled trial examining the efficacy of voucher-based contingency management (CM) using low-magnitude (N = 18) or high-magnitude (N = 18) voucher monetary values. DD was associated with the number of continuous weeks of cocaine abstinence achieved, even after adjusting for treatment condition during the initial 12-week, t(33) = 2.48, p = .045 and entire recommended 24-week of treatment, t(33) = 2.40, p = .022. Participants who exhibited steeper discounting functions achieved shorter periods of abstinence in the Low-magnitude voucher condition (12-week: t(16) = 2.48, p = .025; 24-week: t(16) = 2.68, p = .017), but not in the High-magnitude voucher condition (12-week: t(16) = 0.51, p = .618; 24-week: t(16) = 1.08, p = .298), although the interaction between DD and treatment condition was not significant (12-week: t(32) = -1.12, p = .271; 24-week: t(32) = -0.37, p = .712). These results provide further evidence on associations between DD and treatment response and extend those observations to a new clinical population (i.e., cocaine-dependent outpatients), while also suggesting that a more intensive intervention like the High-magnitude CM condition may diminish this negative relationship between DD and treatment response.

Contingency management for cocaine use in methadone maintenance patients: When does abstinence happen?

Contingency management (CM) is an efficacious intervention for cocaine abusing methadone patients, but typically only about half of patients respond. By investigating time to onset of cocaine abstinence and factors associated with abstinence, we may be able to more efficiently direct CM approaches to patients most likely to benefit. Onset of cocaine abstinence was evaluated in cocaine abusing methadone maintenance patients (N = 193) enrolled in one of three randomized clinical trials of CM. Participants received standard treatment with frequent urine toxicology monitoring or standard treatment plus CM during the trials. Slightly more than half the sample obtained at least 1 week of cocaine abstinence, and approximately a third of the sample obtained at least 4 weeks of cocaine abstinence. Discrete-time survival and hazard analyses found Weeks 1 and 2 of the intervention period had the greatest probability for the initiation of abstinence, and few participants initiated any period of abstinence after Week 4. Patients randomized to CM, those with more years of cocaine use, and those with less recent cocaine use were more likely to achieve abstinence. Overall, these results indicate onset of cocaine abstinence is likely to occur early in treatment and in individuals with less severe cocaine use. Practical implications of these results for designing and implementing CM interventions in methadone maintenance clinics are discussed.

Linking Process and Outcome in the Community Reinforcement Approach for Treating Cocaine Dependence: A Preliminary Report

This preliminary study evaluated the relationship between therapy process variables (mechanistic processes and interpersonal processes), and treatment outcome (i.e., retention and cocaine abstinence) among 16 cocaine‐dependent pregnant or postpartum women treated with the Community Reinforcement Approach (CRA). Two new rating scales were developed for this purpose. The Mechanisms of Action Rating Scale (MARS) assesses five CRA mechanistic domains (Big Picture goals, functional analyses of behavior, nondrug‐related activities, skills training, and homework). The Interpersonal Variables Rating Scale (IVRS) measures three nonspecific or interpersonal dimensions of psychotherapy (i.e., empathy, response to resistance, and therapeutic alliance). These rating scales were used to rate one, early treatment, videotaped CRA session for each subject. Results indicated that: 1) sessions with patients who achieved three or more consecutive weeks of cocaine abstinence were rated significantly higher on therapist empathy and positive responses to resistance, and total IVRS scores (all of which indicate positive interpersonal processes); and 2) Big Picture goals, positive therapeutic alliance, and total IVRS scores were significantly and positively correlated with number of consecutive weeks of cocaine‐negative urine toxicology tests. Only MARS homework scores were significantly and positively associated with number of study weeks completed. Finally, the pattern of interrelationships among the MARS subdomains suggests the coherence of the multifaceted CRA treatment. The findings of this preliminary study suggest the importance of monitoring both mechanistic and interpersonal processes during CRA treatment of cocaine dependence.

Neuroendocrine effects of d-fenfluramine and bromocriptine following repeated smoked cocaine in humans

To study the consequences of repeated smoked cocaine use on central serotonergic and dopaminergic function, the effects of d-fenfluramine ( d-FEN) and bromocriptine on plasma hormones were determined at three time-points following repeated cocaine self-administration under carefully controlled conditions. In a 20-day inpatient study, male cocaine abusers ( d-FEN: n=10; bromocriptine: n=8) self-administered smoked cocaine (12–50 mg) for 3 days followed by 2 weeks of abstinence. The acute effects of d-FEN (0 or 30 mg po) or bromocriptine (0 or 1.25 mg po) on plasma neuroendocrine levels were determined 1–2, 7–8, and 13–14 days after the last cocaine dose. Blood was drawn before and then every 30–60 min for 4 h after capsule administration. The effects of d-FEN and bromocriptine were also determined in healthy, outpatient controls; d-FEN was removed from medical use in the US midway through the study due to complications associated with chronic administration, so all of the control participants were tested in Italy. Cocaine users had a blunted prolactin and cortisol response to d-FEN that lasted for at least 2 weeks of cocaine abstinence, but had a normal response to bromocriptine, which suppressed prolactin by 50% of baseline. The long-lasting and selective disruptions in serotonin pathways following chronic cocaine use may provide a neurochemical basis for changes in mood commonly reported during cocaine withdrawal.

Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans

In the present study, homovanillic acid in plasma (pHVA) and benzodiazepine receptors ( 3H-PK11195 binding) in neutrophil membranes were determined in blood ontained from cocaine-dependent (DSM-III-R) adult male inpatients at baseline (within 72 hr of last cocaine use) and after 3 weeks of cocaine abstinence, and normal controls. The mean (± SEM) pHVA at baseline (10.3 ng/ml ± 1.1) was similar to normals and did not change after 3 weeks of cocaine abstinence. Similarly, the binding indices of benzodiazepine receptors in cocaine-dependent subjects as a group were not significantly different than in normal controls. In 10 cocaine-dependent subjects, however, where both blood samples were available, the number of 3H-PK11195 binding sites was significantly ( p < 0.05) decreased after 3 weeks of cocaine abstinence (mean ± sem: B max = 6371 ± 657 fmol/mg protein) compared with baseline (B max = 7553 ± 925 fmol/mg protein), although there were no differences in the binding affinity (mean ± sem: K D = 8.6 ± 1.2 nmol/L after 3 weeks of abstinence compared with 8.1 ± 1.0 nmol/L at baseline). These preliminary results suggests that peripheral benzodiazepine receptors may play an important role in the pathophysiology of cocaine withdrawal in cocaine-dependent human subjects.