Preliminary results recently obtained in our laboratory have indicated that cocaine stimulates ACTH and corticosterone through a CRF-dependent mechanism. Consequently, this application requests funding for the investigation of the effects of cocaine on the hypothalamic-pituitary- adrenal (HPA) axis, and the mechanisms which mediate these effects in the rat.
Under SPECIFIC AIM #1, we will investigate the effects of various doses of cocaine on ACTH and corticosterone secretion, as well as on corticotropin- releasing factor (CRF) biosynthesis. These hormonal measurements will be obtained during continuous (Study 1) or intermittent (Study 2) administration of cocaine, as well as following cessation of treatment with the drug (Study 3). Because CRF interacts with factors such as vasopressin, catecholamines, and corticoids to modulate ACTH secretion, SPECIFIC AIM #2 will explore the role of such interactions in mediating the effect of cocaine on pituitary function. We will investigate the possibility that cocaine modifies the pituitary responsiveness to CRF, vasopressin and/or catecholamines during continuous (Study 4) or intermittent (Study 5) treatment with cocaine, as well as following cessation of treatment (Study 6). In order to explore the possibility that steroid feedback participates in cocaine-induced changes in pituitary responsiveness, interactions between cocaine, CRF, vasopressin and catecholamines will also be investigated in adrenalectomized rats (Study 7).
SPECIFIC AIM #3 will test the hypothesis, supported by our preliminary results, that cocaine will modify the HPA axis's response to stress. The ability of cocaine to alter stress-induced ACTH secretion will be investigated during continuous (Study 8) or intermittent Study 9 treatment with the drug, as well as following cessation of treatment (Study) 10. We believe that the results obtained will provide presently unavailable information concerning the effect of cocaine on pituitary function, the mechanisms which modulate these effects, and possible interactions with cocaine and the pituitary's response to stress.