Differential effects of intermittent or continuous exposure to cocaine on the hypothalamic-pituitary-adrenal axis and c-fos expression.
Accumulating evidence indicates that acute administration of cocaine alters neuroendocrine functions. In order to ascertain the long-term effects of cocaine on the male rat's hypothalamic-pituitary-adrenal (HPA) axis, a series of experiments were performed utilizing two different paradigms of cocaine administration for 6 days. In the first paradigm, rats received daily intravenous injections of cocaine (5 mg/kg), while in the second, they were continuously exposed to the drug (5 or 100 mg/kg/day) via osmotic pumps. We measured plasma adrenocorticotropin hormone (ACTH) and corticosterone levels, as well as the brain pattern of the proto-oncogene c-fos expression in response to either mode of drug administration. Repeated, intermittent injections of cocaine caused consistent increases in ACTH and corticosterone secretion over a 30-min sampling period on days 2, 4 and 6. This paradigm of drug administration also induced considerable, short-lasting and reversible c-fos expression in the caudate putamen but not in hypothalamic regions associated with endocrine function. In contrast, we consistently failed to observe any measurable increases in ACTH or corticosterone secretion at any time during continuous exposure to the drug. Administration of cocaine by osmotic pumps also had no effect on c-fos expression in the caudate putamen, indicating that c-fos expression as well as activation of the HPA axis are dependent upon the mode and frequency in which cocaine is administered. We conclude that continuous exposure to cocaine does not appear to activate the HPA axis, while intermittent injections of the drug induce repeated increases in plasma ACTH and corticosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Torres
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Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, CA 92037.
Rivier
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C
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D000324:Adrenocorticotropic Hormone; D003042:Cocaine; D003345:Corticosterone