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

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Abstract

Rationale

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.

Objectives

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

Methods

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.

Results

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.

Conclusions

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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Acknowledgements

The authors wish to thank Nicholas Jones, Deborah Huntzinger, Sarah Pilkington and Laurie McDowell for their expert technical assistance. Animals used in these studies were maintained in accordance with the “Principles of laboratory animal care” (http://www.nap.edu/readingroom/books/labrats/), and all studies reported here were carried out in consultation with the University of Michigan Committee on Animal Care and Guidelines of the Committee on the Care and Use of Laboratory Animal Resources, National Health Council (Department of Health, Education and Welfare, ISBN 0-309-05377-3, revised 1996). This work was supported by the United States Public Health Service Grants DA 0916, DA 00254, and AA13783.

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Authors and Affiliations

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

    Jillian H. Broadbear, Gail Winger & James H. Woods

  2. Monash Medical Centre, Monash Institute of Health Services Research, Level 1, Block E, Clayton, 3168, Australia

    Jillian H. Broadbear

  3. Department of Psychology, University of Michigan Medical School, Ann Arbor, Mich., USA

    James H. Woods

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  1. Jillian H. Broadbear
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  2. Gail Winger
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  3. James H. Woods
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Correspondence to Jillian H. Broadbear.

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Broadbear, J.H., Winger, G. & Woods, J.H. Self-administration of methohexital, midazolam and ethanol: effects on the pituitary–adrenal axis in rhesus monkeys. Psychopharmacology 178, 83–91 (2005). https://doi.org/10.1007/s00213-004-1986-4

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  • DOI: https://doi.org/10.1007/s00213-004-1986-4

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