The Behavioral Pharmacology Unit is engaged in the assessment of: A) pharmacological agents designed to modify the behavioral effects of substances subject to abuse, using monkey self-administration and drug discrimination, and B) the link between susceptibility to drug abuse and activation of the hypothalamic pituitary adrenal (HPA) axis. A) The primary current effort of the lab is to characterize the effects of GBR 12909HC1 and GBR 12935HC1 were compared. Both agents selectively decreased cocaine-maintained responding within a limited range of doses, while lower doses had no effect and higher doses decreased responding in both components. These results suggest that these GBR analogs can selectively attenuate cocaine self-administration, without affecting alternative behaviors. In several additional studies, we have been unable to maintain drug-seeking behavior with GBR in cocaine-naive monkeys, in contrast to previous reports of maintenance under substitution paradigms where monkeys have a history of self- administration. These results suggest that GBR-based agents may be useful in the development of drugs to treat cocaine abuse. B) The primary endogenous agents involves in the HPA axis are corticotropin releasing hormone (CRH), adrenocorticotrophic hormone and cortisol. Several studies have been directed at examining the behavioral specificity of the direct effects of CRH on behavior. The behavioral consequences of the central administration of CRH in rhesus monkeys were determined using food-maintained behavior. When CRH was given repeatedly for several days, its behavioral suppressant effects increased. Home cage food intake, body weight, and subsequent responding for food decreased for up to six weeks before returning to normal. These results suggest that sustained elevations in central levels of CRH can result in a sensitization to its anorexigenic effects, an effect that has not been reported in other species. Because hyperaroused clinical states such as depression, anorexia nervosa, and some forms of drug abuse are characterized biochemically by hypercortisolism and elevated CRH in CSF, these anorexigenic effects may corroborate a potential role in CRH in affective disorders were comorbidity with drug abuse is high.
