Repeated THC administration produces motivational and somatic/nadaptive changes leading to dependence in rodents. To/ninvestigate the molecular basis for cannabinoid dependence/nand its possible relationship with the endogenous opioid system,/nwe explored Δ9-tetrahydrocannabinol (THC) activity in mice lacking μ-, δ- or κ-opioid receptor genes. Acute THCinduced hypothermia, antinociception, and ypolocomotion 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 μ receptors abolishes THC place preference. Deletion of κ receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of μ- and κ-opioid receptors in modulating reward pathways forms the basis for the dual euphoric–dysphoric activity of THC.

This work was supported by the European Commission (Biomed-2 Grant 98-2227,to R.M.), Dr. Esteve S. A. Laboratories (R.M.), Generalitat de C atalunya (Research Distinction, to R.M.), the Spanish Ministry of Health (Fondo de Investigación Sanitaria Grant 99/0624, to R.M.), the Mission Interministerielle de Lutte contre la Drogue et la Toxicomanie (B.K .), and the Centre National de la Recherche Scientifique (B.K.). We thank J.F. Poirier and N. Scallon for animal care.