Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors.
Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, delta- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of microreceptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.
Ghozland
Sandy
S
Laboratori de Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Matthes
Hans W D
HW
Simonin
Frederic
F
Filliol
Dominique
D
Kieffer
Brigitte L
BL
Maldonado
Rafael
R
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003433:Crosses, Genetic; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004361:Drug Tolerance / Q000235:genetics; D007035:Hypothermia / Q000139:chemically induced; D002189:Marijuana Abuse / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D000077285:Rimonabant; D013037:Spatial Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D002186:Cannabinoids; D010880:Piperidines; D011619:Psychotropic Drugs; D011720:Pyrazoles; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013759:Dronabinol; D000077285:Rimonabant