A broadly effective pharmacotherapy for cocaine dependence remains an unrealized national priority. Of the multiple medications tested to date, only disulfiram has shown consistent, albeit modest, efficacy in clinical trials. While its efficacy is well demonstrated, it s therapeutic mechanism of action is largely unknown. Initial rationales for disulfiram s use in cocaine dependence derived from observations of high rates of co-morbid alcohol intake. However, recent studies indicate comparably improved outcomes in non-alcohol abusing cohorts. The latter observation has shifted attention away from peripheral targets of the drug (i.e., alcohol dehydrogenase) to neurobiologically more relevant candidates. One possible mediator is dopamine beta-hydroxylase (DbetaH), the enzyme that converts dopamine to norepinephrine. However, the direct relevance of DbetaH to cocaine reward remains to be established. The current R01 application will test the hypothesis that DbetaH is an important mediator of cocaine-induced euphoria in human cocaine abusers. Specifically, we will examine the effects of 1) allelic variation in the gene encoding DbetaH (DBH), 2) pharmacologic antagonism (disulfiram) of DbetaH function, and 3) gene-drug interactions on cocaine-induced euphoria in chronically dependent subjects. To do so, we have developed and validated a novel laboratory paradigm of """"""""binge"""""""" cocaine self-administration based on patient-controlled analgesia techniques. Preliminary results in 12 subjects provide direct support for Aim #1 and suggest that """"""""low activity"""""""" alleles at DBH are associated with a normal dose-responsively to cocaine-induced euphoria (p = 0.007), while individuals homozygous for the wild type allele have a flat, anhedonic curve). Direct demonstration of DbetaH s relevance to cocaine reward by convergent genetic, pharmacological, and pharmacogenetic data would provide powerful neurobiological support for DbetaH as a prime medication development target for cocaine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015857-03
Application #
6800396
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Gordon, Harold
Project Start
2002-09-30
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$322,903
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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