The most difficult aspect of treating cocaine dependence is the propensity for relapse to cocaine use after a period of abstinence. Cocaine dependent individuals often describe their relapse as being precipitated by cocaine craving which might be triggered by a """"""""priming"""""""" dose of cocaine itself. Indeed, studies in laboratory animals have shown that low dose cocaine can trigger """"""""relapse"""""""" in cocaine-seeking behavior. In rodents, dopamine (DA) D2 receptors agonists augment the priming effect of cocaine on cocaine-seeking behavior, while DA D1 receptors agonists inhibit this effect. In the current cycle of this Center, we measured with PET both D1 and D2 receptors in cocaine dependent participants and matched controls, and studied the relationship between PET measurements and increased vulnerability to cocaine primed cocaine-taking behavior. Low D1 receptor availability in the ventral striatum was associated with increased vulnerability to cocaine primed cocaine-taking behavior. This result was consistent with animal data suggesting that stimulation of D1 receptors following cocaine might be protective against cocaine-induced relapse. In the striatum, D1 receptors are mainly localized on GABAergic cells of the striatonigral or direct pathway. Thus, stimulation the direct pathway by DA via D1 receptors might be beneficial against cocaine-induced relapse. In the next cycle of this application, we plan to study in more detail the neurochemistry of the direct pathway in cocaine dependence, by measuring both D1 receptors and kappa opiate receptors (KOR), and their predictive value on cocaine primed cocaine-taking behavior. Human postmortem data suggest cocaine abuse is associated with increased dynorphin and KOR expression, i.e. upregulation of the kappa transmission. In the direct pathway, kappa stimulation inhibits D1 mediated signaling. Therefore the upregulation of the kappa system in cocaine abusers might impair transmission in the direct pathway. The hypotheses to be tested are that cocaine dependent participants will show increase KOR availability in the ventral striatum, and that both high KOR and low D1 receptor availability will be predictive of vulnerability to cocaine-induced cocaine-taking behavior, as studied in the laboratory. Results of these studies will lead to increased knowledge of the neurobiology of cocaine addiction and to the identification of participants most likely to benefit from selective pharmacological intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA009236-14
Application #
7440284
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
14
Fiscal Year
2007
Total Cost
$467,646
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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