Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary-adrenal axis in rhesus monkeys.
BACKGROUND
Drugs of abuse can affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Acute administration of drugs that serve as reinforcers have been observed to stimulate the rat HPA axis, leading to the suggestion that these stimulatory effects may contribute to the development of drug-maintained behaviors.


OBJECTIVE
To determine whether reinforcing drugs that are dissimilar with respect to their mechanisms of action have similar effects on HPA axis activity at doses that are self-administered. Rhesus monkeys were randomly assigned to self-administer the mu-opioid agonist fentanyl, the psychomotor stimulant cocaine, or the NMDA antagonist ketamine.


METHODS
Each monkey was trained to press a lever in order to receive an intravenous injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions and assayed for ACTH and cortisol by radioimmunoassay.


RESULTS
Fentanyl, cocaine, and ketamine were each self-administered across a range of doses. However, the three drugs differed in their effects on ACTH and cortisol. Cocaine stimulated ACTH and cortisol secretion, a finding that is consistent with previous rat and primate studies. Self-administration of both fentanyl and ketamine inhibited HPA axis activity. HPA inhibition by fentanyl is consistent with other monkey and human studies, and contrasts with the stimulatory effects of mu-opioids in rodents. The inhibitory effect of ketamine on ACTH and cortisol secretion contrasts with findings in the few primate studies that have evaluated NMDA antagonists. Neither fentanyl nor cocaine, at doses that maintained maximum rates of responding, produced significant changes in ACTH and cortisol levels.


CONCLUSIONS
There appears to be little commonality between different classes of abused drugs and their effects on the HPA axis, which calls into question the necessity for HPA axis stimulation in the reinforcement of drug-maintained behavior.
Broadbear
Jillian H
JH
Department of Pharmacology, University of Michigan Medical School, 1301 MSRB 3, Ann Arbor, MI 48109-0632, USA. jillian.broadbear@med.monash.edu.au
Winger
Gail
G
Woods
James H
JH
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D006854:Hydrocortisone / Q000097:blood; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D000324:Adrenocorticotropic Hormone; D003042:Cocaine; D005283:Fentanyl; D006854:Hydrocortisone