Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Prazosin (alphai-adrenergic antagonist) and DpH inhibition (disulfiram) have shown promising results in the treatment of cocaine dependence. While inhibition of DpH activity is hypothesized to increase dopamine (DA) but decrease norepinephrine neurotransmission and to intensify the dysphoric experience of cocaine use, the selective inhibition of alphai-adrenergic receptor antagonist is hypothesized to attenuate DA neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal is to determine to what extend does prospective screening for a functional polymorphism of dopamine beta hydroxylase (DBH-1021C?vT) or polymorphisms in the promoter region and the coding region ofthe alpha-la-adrenoceptor receptor gene (ADRAIA) predict the treatment efficacy of nepicastat (a new DpH inhibitor) or prazosin among newly admitted methadone treated patients. Based on our previous studies, we hypothesize that carriers ofthe low-OpH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of DpH by nepicastat. We also will assess post-hoc the impact of functional variants ofthe ADRAIA on the response to prazosin. This 12- week double-blind, placebo controlled randomized clinical trial will provide treatment for 150 cocainedependent opioid dependent patients who have 2-weeks of methadone induction and 4 week discontinuation for 18-weeks total. Participants, aged 18-65 years, will be randomized to receive prazosin 10 mg/day, nepicastat 120mg/day, or placebo while concurrently receiving treatment with methadone. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. The proposed study is expected to provide a better understanding ofthe role ofthe DpH inhibitor nepicastat and the selective alphaiA adrenergic receptor antagonist prazosin on cocaine using behavior among distinct DBH -1021C-+T genotypes or the functional variants in the promoter and coding region of ADRA1A.

Public Health Relevance

Cocaine- and MA-dependence are major public health problems in the United States. No FDA-approved treatments for cocaine- or methamphetamine-dependence exist. A greater knowledge ofthe basic biology of cocaine- and methamphetamine dependence combined with genetic matching for medication response will lead to improved treatments for the disorder.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Baylor College of Medicine
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Zhang, Xuefeng; Nielsen, David A; Domingo, Coreen B et al. (2018) Pharmacogenetics of Dopamine ?-Hydroxylase in cocaine dependence therapy with doxazosin. Addict Biol :
Patriquin, Michelle A; Hamon, Sara C; Harding, Mark J et al. (2017) Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes. Psychiatr Genet 27:178-186
Mahoney, James J; Kalechstein, Ari D; De Marco, Anthony P et al. (2017) The relationship between premorbid IQ and neurocognitive functioning in individuals with cocaine use disorders. Neuropsychology 31:311-318
Shorter, Daryl; Nielsen, David A; Hamon, Sara C et al. (2016) The ?-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals. Pharmacogenet Genomics 26:428-35
Azadeh, Shabnam; Hobbs, Brian P; Ma, Liangsuo et al. (2016) Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence. Neuroimage 125:813-824
Li, Xiaofan; Shorter, Daryl; Kosten, Thomas R (2016) Buprenorphine Prescribing: To Expand or Not to Expand. J Psychiatr Pract 22:183-92
Ayanga, Daniel; Shorter, Daryl; Kosten, Thomas R (2016) Update on pharmacotherapy for treatment of opioid use disorder. Expert Opin Pharmacother 17:2307-2318
Cao, Bo; Bauer, Isabelle E; Sharma, Ajaykumar N et al. (2016) Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele. J Affect Disord 198:198-205
Ma, Liangsuo; Steinberg, Joel L; Cunningham, Kathryn A et al. (2015) Inhibitory behavioral control: A stochastic dynamic causal modeling study comparing cocaine dependent subjects and controls. Neuroimage Clin 7:837-47
Shorter, Daryl; Domingo, Coreen B; Kosten, Thomas R (2015) Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy. Expert Opin Emerg Drugs 20:15-29

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