Effects of cannabinoid receptor antagonists on maintenance and reinstatement of methamphetamine self-administration in rhesus monkeys.
Cannabinoid receptor antagonists have shown some promise as treatments capable of reducing abuse and relapse to a number of abused drugs. In rodents, such effects have been observed with methamphetamine self-administration. However, the effects of cannabinoid receptor antagonists on methamphetamine self-administration and relapse have not been studied in primates. In the present study, rhesus monkeys were trained to respond on a three-component operant schedule. During the first 5-min component, fixed-ratio responses were reinforced by food, during the second 90- or 180-min component fixed-ratio responses were reinforced by i.v. methamphetamine. The third component was identical to the first. There was a 5-min timeout between each component. The effects of the cannabinoid receptor antagonists AM 251 and rimonabant were tested at various doses against self-administration of 3microg/kg/injection methamphetamine, and 1mg/kg AM 251 and 0.3mg/kg rimonabant were tested against the methamphetamine dose-effect function. The 1mg/kg dose of AM 251 was also tested for its ability to alter reinstatement of extinguished self-administration responding. The cannabinoid receptor antagonist AM 251 was found to reduce methamphetamine self-administration at doses that did not affect food-reinforced responding. The cannabinoid receptor antagonist rimonabant had similar, but less robust effects. AM 251 also prevented reinstatement of extinguished methamphetamine seeking that was induced by re-exposure to a combination of methamphetamine and methamphetamine-associated cues. These results indicate that cannabinoid receptor antagonists might have therapeutic effects for the treatment of methamphetamine dependence.
Schindler
Charles W
CW
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Blvd., Suite 200, Baltimore, MD 21224, United States. cschindl@helix.nih.gov
Panlilio
Leigh V
LV
Gilman
Joanne P
JP
Justinova
Zuzana
Z
Vemuri
V Kiran
VK
Makriyannis
Alex
A
Goldberg
Steven R
SR
D000818:Animals; D063387:Cannabinoid Receptor Antagonists; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D012054:Reinforcement, Psychology; D000077285:Rimonabant; D055502:Secondary Prevention; D012646:Self Administration
D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; C103505:AM 251; D008694:Methamphetamine; D000077285:Rimonabant