Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes.Disulfiram (DPH inhibitor) and Tiagabine (GAT-1 blocker) have shown promising results in the treatment ofcocaine dependence. While inhibition of DpH activity is hypothesized to increase dopamineneurotransmission primarily in the neocortexand to intensify the dysphoric experience of cocaine use, theselective inhibition of GABA reuptake is hypothesized to attenuate dopamine neurotransmission primarily inthe nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal isto determine to what extend does prospective screening for a functional polymorphism of dopamine betahydroxylase (DBH-1021CDT) predict the treatment efficacy of disulfiram and tiagabine among newlyadmitted methadone treated patients. DBH-1021CDT regulates plasma D0H levels by influencing DBHgene expression. Based on our pilot studies, we hypothesize that carriers of the low-DpH associated T allelewill have significant reductions in cocaine use, because they are more susceptible to inhibition of D0Hbydisulfiram. In contrast, carriers of the high-DpH associatedC allele will have little reduction in cocaine usewith disulfiram, but may have significant reductions with tiagabine, because of tiagabine's contrasting actionin reducing dopamine release. This 14-week double-blind, placebo controlled randomized clinical trial willprovide treatment for 150 cocaine-dependent opioid dependent patients. Participants, aged 18-65 years, willbe randomized to receive disulfiram 250mg/day,tiagabine 24mg/day, or placebo while concurrently receivingtreatment with methadone. All participants receive weekly 1-hour psychotherapy(Cognitive BehavioralTreatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-reportand confirmed by thrice-weekly urinalyses. The proposed study is expectedto provide a betterunderstanding of the role of the DpH inhibitor disulfiram and the selective GABA reuptake inhibitor tiagabineon cocaine using behavior among distinct DBH-1021CDT genotypes.
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