CP-154,526, a CRF type-1 receptor antagonist, attenuates the cue-and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior in rats.
BACKGROUND
Previous studies from our laboratory and others have indicated a role for the hypothalamo-pituitary-adrenal (HPA) axis in the extinction/reinstatement animal model of cocaine relapse


OBJECTIVE
This present study was designed to investigate the potential role for the HPA axis in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior by determining the effects of ketoconazole and the corticotropin-releasing hormone (CRF) type 1 receptor antagonist, CP-154,526, on these behaviors.


METHODS
Male Wistar rats were trained to self-administer methamphetamine (0.03 mg/kg/infusion). The delivery of methamphetamine was paired with the presentation of a tone and the illumination of a house light. Once stable responding was reached, the rats were placed into extinction. The effects of pretreatment with ketoconazole (25, 50, or 100 mg/kg, i.p.) or CP-154,526 (20 or 40 mg/kg, i.p.; 3 micro g, i.c.v) on cue-induced reinstatement were then evaluated.


RESULTS
Cue-induced reinstatement was not significantly attenuated by pretreatment with peripherally administered CP-154,526 or by pretreatment with ketoconazole. However, centrally administered CP-154,526 (3 micro g, i.c.v.) significantly attenuated cue-induced reinstatement. In a separate group of rats, CP-154,526 (20 mg/kg, i.p.) attenuated methamphetamine-induced reinstatement (0.12 mg/kg priming infusion); whereas a higher dose (40 mg/kg) was necessary to attenuate reinstatement induced by a priming infusion of 0.24 mg/kg/infusion. Ketoconazole (50 mg/kg) did not affect reinstatement induced by a 0.12 mg/kg priming infusion and, therefore, was not tested at the higher methamphetamine priming dose.


CONCLUSIONS
These data suggest an important role for CRF in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior.
Moffett
M C
MC
Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, LA 71130, USA. mcmoffe@emory.edu
Goeders
N E
NE
D019969:Amphetamine-Related Disorders / Q000503:physiopathology*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009042:Motivation; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011292:Premedication; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology; D012646:Self Administration; D000099052:CRF Receptor, Type 1
C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D008694:Methamphetamine; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D007654:Ketoconazole