Effects of acute and chronic ketoconazole administration on hypothalamo--pituitary--adrenal axis activity and brain corticotropin-releasing hormone.
We have been investigating the effects of ketoconazole on cocaine reward in rats for several years now. However, we recently confirmed that ketoconazole-induced changes in cocaine self-administration and reinstatement do not always correspond with decreases in plasma corticosterone, which suggests that other mechanisms must be underlying the behavioral effects that we observe. This experiment was therefore designed to determine the effects of acute, repeated and chronic ketoconazole administration on corticotropin-releasing hormone (CRH) content in hypothalamic and extra-hypothalamic brain sites in rats following the same dosing regimen that we use in our behavioral studies. Although ketoconazole significantly increased the concentration of ACTH in trunk blood, there were no significant effects on plasma cortisol, corticosterone or testosterone. There was also a significant increase in CRH content in the median eminence after the acute administration of ketoconazole that just failed to reach statistical significance following repeated or chronic administration. However, acute, repeated and chronic treatment with ketoconazole each significantly increased CRH content in the medial prefrontal cortex (MPC), but did not consistently affect the peptide in any other brain region studied. Since the MPC and CRH have been implicated in the neurobiology of cocaine, CRH-induced alterations in dopaminergic neurotransmission may play an important role in this peptide's effects on cocaine responsiveness. Taken together with the results from previous studies, these data suggest that ketoconazole may affect cocaine reward, at least in part, through interactions with dopamine and CRH within the MPC.
Department of Pharmacology and Therapeutics, LSU Health Sciences Center, P.O. Box 33932, 1501 Kings Hwy, Shreveport, LA 71130-3932, USA.
Gennady N
GN
Smagin
Nick E
NE
Goeders
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001070:Appetitive Behavior / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration
D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine; D007654:Ketoconazole; D004298:Dopamine