Investigations into the neurobiological determinants of psychostimulant abuse have largely focused on cocaine's actions on brain monoamine systems, including mesolimbic dopaminergic projections. Recent neuroscience research, however, points to the pathophysiological importance of additional modulators of neuronal function, including glucocorticoids (GC) and corticotrophin releasing factor (CRF). GC, a class of steroid hormones secreted by the hypothalamic-pituitary-adrenal (HPA) axis, facilitate psychostimulant- and stress-induced sensitization in rats. Animal studies of drug-reward indicate that GC increase the propensity to self-administer psychostimulants, while antiglucocorticoid strategies, including adrenalectomy and cortisol synthesis inhibition, block the acquisition, maintenance, and relapse of cocaine self-administration in drug-naive and drug-experienced ('addicted"""""""") rats, respectively. Despite the current availability of excellent clinical tools, comparable prospective manipulations of GC function in human cocaine abusers are lacking. The primary goal of the current research proposal is to examine whether pharmacological interventions which alter GC levels will influence cocaine's behavioral and neurochemical effects in human and non-human primates.
Three specific aims are proposed, including:
Aim #1) A within-subjects study of 30 cocaine addicts (15 HIV-, 15 HIV+) and their behavioral responses to a fixed-order, ascending dose regimen of intranasal cocaine after acute (lesser 12 hr) pretreatment with the synthetic GC prednisone, the cortisol synthesis inhibitor and GC receptor antagonist, ketoconazole, and placebo;
Aim #2) A between-subjects randomized study of 45 cocaine dependent subjects (all HIV-) and their behavioral responses to the same cocaine regimen before and after chronic (7 days) pretreatment with either prednisone (n-15), ketoconazole (n=15), or placebo (n=15);
and Aim #3) Parallel preclinical studies of the identical drug interventions in awake rhesus monkeys, including cocaine-induced psychomotor activity and concurrent in vivo microdialysis measures of basal and cocaine-induced brain dopamine and serotonin levels. We hypothesize that increasing GC (prednisone) levels will enhance cocaine-induced euphoria and neurochemical impact, and that inhibiting GC synthesis (ketoconazole) will diminish cocaine's effects. If confirmed in humans, our findings would provide strong evidence in support of a primary pathophysiological role for GC in cocaine abuse and lead to novel pharmacotherapies for cocaine dependence.
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