Abstract
Intravenously self-administered cocaine produces a dose-dependent release of adrenocorticotropic hormone (ACTH) and cortisol in male rhesus monkeys. This study investigated whether the acute disruption of cortisol and/or ACTH release had any effect on ongoing cocaine-maintained responding. Four hypothalamic-pituitary-adrenal (HPA) axis inhibitors were examined: etomidate and ketoconazole, both of which are cortisol synthesis inhibitors; astressin, a peptidic corticotropin-releasing factor (CRF) antagonist that binds CRF1 receptors predominantly in the pituitary gland; and dexamethasone, a highly selective glucocorticoid receptor agonist whose long-lasting effects reduce or abolish the endogenous release of ACTH and cortisol. The reinforcing effects of a range of cocaine doses, with or without pretreatment with an HPA inhibitor, were evaluated using a fixed ratio 30 time-out 10-min schedule of reinforcement in six male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine increased plasma cortisol and ACTH. Pretreatment with etomidate and ketoconazole dose-dependently inhibited the cocaine-induced rise in cortisol and, at the highest doses, produced a compensatory increase in ACTH release. Astressin and dexamethasone attenuated or abolished cocaine-induced cortisol and ACTH release. Despite the efficacy exhibited by these pretreatments and the variety of mechanisms by which they inhibited the HPA axis, there was no evidence for any change in cocaine-reinforced behavior (response rate or infusion number), an indication that acute changes in the ACTH or cortisol response to cocaine do not play a direct role in modulating cocaine-seeking behavior under these behavioral circumstances.
Footnotes
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Send reprint requests to: Dr. Jillian Broadbear, Department of Pharmacology, University of Michigan, 1301 MSRB 3, Ann Arbor, MI 48109. E-mail: jillianb{at}umich.edu
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↵1 This work was supported by U.S. Public Health Service Grant DA 09161. Results from this study were originally presented at the annual meeting of the American College of Neuropsychopharmacology in Hawaii, December 6–12, 1997.
- Abbreviations:
- HPA
- hypothalamic-pituitary-adrenal
- ACTH
- adrenocorticotropic hormone
- CRF
- corticotropin-releasing factor
- FR
- fixed ratio
- TO
- time-out
- AUC
- area under curve
- Received October 1, 1998.
- Accepted April 27, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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