Role of the hypothalamic-pituitary-adrenal axis in reinstatement of cocaine-seeking behavior in squirrel monkeys.
BACKGROUND
Stress has been suggested to play a role in relapse to cocaine-seeking behavior. An important physiological system activated by stress is the hypothalamic-pituitary-adrenal (HPA) axis; however, evidence for a role of HPA axis activation in cocaine relapse has been contradictory.


OBJECTIVE
This study examined the effects of pharmacological stimulation of the HPA axis on reinstatement of drug-seeking behavior and salivary cortisol levels in a non-human primate model of cocaine relapse. In addition, the effect of corticotropin releasing hormone type 1 receptor (CRH-R1) blockade on cocaine priming-induced reinstatement was investigated.


METHODS
Squirrel monkeys were trained to self-administer cocaine under a second-order schedule in which behavior was maintained by IV drug injections and a drug-paired visual stimulus. A period of extinction was then imposed during which saline was substituted for cocaine and the stimulus was omitted. Subsequently, monkeys were tested for reinstatement of cocaine seeking following priming injections of drugs. During reinstatement tests, the drug-paired stimulus was restored. Salivary cortisol levels were determined to measure the effects of drug treatments on the HPA axis activity.


RESULTS
Priming with corticotropin releasing hormone (10 and 50 microg/kg), adrenocorticotropic hormone (1 microg/kg), or cortisol (1-10 mg/kg) did not induce significant reinstatement of cocaine seeking. All of these treatments, however, resulted in a significant increase in salivary cortisol. In contrast, priming injections of cocaine (0.1-1.0 mg/kg) dose-dependently induced reinstatement of drug seeking, but did not increase salivary cortisol. The CRH-R1 antagonist CP-154,526 (10 mg/kg, IV) did not modulate cocaine priming-induced reinstatement of drug seeking, but attenuated CRH-induced increases in salivary cortisol.


CONCLUSIONS
The results suggest that activation of the HPA axis is neither necessary nor sufficient for reinstatement of cocaine-seeking behavior in this non-human primate model of cocaine relapse.
Lee
Buyean
B
New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA. buyean_lee@hms.harvard.edu.
Tiefenbacher
Stefan
S
New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA.
Platt
Donna M
DM
New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA.
Spealman
Roger D
RD
New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA.
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000502:physiology; D012453:Saimiri; D012646:Self Administration; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine; D006854:Hydrocortisone