Chronic use of cocaine in humans results in long-lasting alterations in brain structure and function. In laboratory animals, repeated intermittent cocaine administration produces an augmented behavioral response to a subsequent challenge dose of the drug. This phenomenon, referred to as behavioral sensitization, may be important in cocaine craving, a central factor in many cases of drug relapse. The endogenous opioid peptide/receptor system has been implicated in cocaine sensitization. However, the role of the OFQ/N/ORL-1 receptor system has not been characterized in this phenomenon. Our preliminary data show that concomitant OFQ/N administration with cocaine blocks the development of cocaine sensitization and this action of OFQ/N is antagonized by J-113397, an ORL-1 receptor antagonist. Thus, the OFQ/N/ORL-1 receptor system plays an important role in blocking this phenomenon and may be a potential target to develop drugs with anti-craving activity. In order to characterize the neurobiological substrate for such an action of OFQ/N, we will elucidate the site of action of OFQ/N. Additionally, since OFQ/N or related drugs will be used to treat cocaine addicts, using sensitization as an animal model of drug craving, we will determine if OFQ/N could reverse an already existing sensitized response, a more clinically relevant issue. Our preliminary data also show that the level of hypothalamic OFQ/N increases after repeated cocaine treatment, indicating that the endogenous OFQ/N/ORL-1 receptor system may be altered during development of sensitization. Thus, using RIA and binding assays, we will measure levels of OFQ/N and its receptor after cocaine treatment in brain regions involved in cocaine craving. Using knockout mice, we will also study the development of sensitization in the absence of the ORL-1 receptor or OFQ/N. The studies proposed in this grant will elucidate the role of OFQ/N/ORL-1 receptor system in cocaine sensitization and possibly provide important and useful information toward developing possible treatments for cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016682-03
Application #
7089864
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Lin, Geraline
Project Start
2004-07-15
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$168,446
Indirect Cost
Name
Western University of Health Sciences
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
093373694
City
Pomona
State
CA
Country
United States
Zip Code
91766
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