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Psychopharmacology (Berl). 2005 Feb;178(1):83-91. Epub 2004 Aug 21.

Self-administration of methohexital, midazolam and ethanol: effects on the pituitary-adrenal axis in rhesus monkeys.

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Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.



There is disagreement in the literature with respect to how drugs of abuse affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, and whether these changes in endocrine function may be related to the rewarding effects of these drugs.


To determine whether reinforcing drugs with different mechanisms of action affect HPA axis function at doses at which they serve as reinforcers.


Seven monkeys (6 male) were randomly assigned to self-administer methohexital-a barbiturate (n=4), midazolam-a benzodiazepine (n=3), or ethanol (n=5). Each monkey had a surgically implanted indwelling venous catheter, and was trained to respond on a fixed ratio of 30 lever presses to receive an injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions for the measurement of ACTH and cortisol by radioimmunoassay.


Although methohexital, midazolam, and ethanol all maintained self-administration behavior across a range of doses, they differed in their effects on ACTH and cortisol. Ethanol inhibited ACTH and cortisol secretion. Methohexital and midazolam both tended to decrease ACTH and cortisol at large doses, and increase these hormones at small doses, but the HPA effects of neither drug differed significantly from when saline was available.


The neutral overall effect of methohexital and midazolam on HPA activity is consistent with other monkey and human studies, whereas the inhibitory effect of self-administered ethanol in the monkey contrasts with both the rat and human literature. The data in this study suggest that a change in HPA axis activity is not a requirement for drug-reinforced behavior in monkeys.

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