Corticotropin-releasing factor (CRF) is a neuropeptide well known to be one of the major hypothalamic releasing factor mediating the stress- induced release of adrenocorticotropin releasing hormone (ACTH) and consequent release of corticosterone. CRF has also been well documented to have a neurotropic role in the central nervous system to mediate behavioral responses to stressors. Stress has long been associated with drug dependence and is thought in some cases to have an important role in the maintenance of drug dependence. The purpose of the proposed fellowship is to test the hypothesis that brain CRF has a role in the dependence produced by the psychostimulant drugs cocaine and nicotine. Rats will be made dependent on cocaine and nicotine using direct intravenous self-administration (cocaine) and subcutaneous minipumps (nicotine) and the withdrawal from each drug will be assessed using measures of behavioral responses to stressors ( the elevated plus maze) and measures of brain reward thresholds (intracranial self-stimulation). An attempt will be made to reverse the anxiogenic-like and anhedonic-like effects of cocaine and nicotine withdrawal with intracerebroventricular administration of a potent CRF antagonist D-Phe CRF 12-41. Subsequent studies will explore the specific brain sites that may be involved in any anti-withdrawal effects of the CRF antagonist by employing direct intracerebral injections of the antagonist at specific brain sites. The results from the proposed study will go far towards establishing a role for CRF in the dependence associated with psychostimulant drugs , and may lead to new basic knowledge critical for the diagnosis and treatment of psychostimulant abuse.
