Neuronal nicotinic acetylcholine receptors mediate Delta(9)-THC dependence: Mouse and human studies

Cessation from prolonged use of Delta(9)-tetrahydrocannabinol (THC), the primary active compound responsible for the cannabimimetic effects of cannabis, results in a mild to moderate withdrawal syndrome in humans and laboratory animals. Whereas manipulations of the endogenous cannabinoid system (eg, cannabinoid receptors and endocannabinoid regulating enzymes) alter nicotine withdrawal, in this study we asked the reciprocal question. Do nicotinic acetylcholine receptors (nAChRs) modulate THC withdrawal? To assess the role of different nAChR subtypes in THC withdrawal, we used transgenic mouse, preclinical pharmacological, and human genetic correlation approaches. Our findings show that selective alpha 3 beta 4* nAChR antagonist, AuIB, and alpha 3 beta 4* nAChR partial agonist, AT-1001, dose-dependently attenuated somatic withdrawal signs in THC-dependent mice that were challenged with the cannabinoid-1 receptor antagonist rimonabant. Additionally, THC-dependent alpha 5 and alpha 6 nAChR knockout (KO) mice displayed decreased rimonabant precipitated somatic withdrawal signs compared with their wild-type counterparts. In contrast, beta 2 and alpha 7 nAChR KO mice showed no alterations in THC withdrawal signs. Moreover, deletion of beta 2 nAChR did not alter the reduced expression of somatic signs by the preferred alpha 6 beta 4* antagonist, BulA [T5A;P60]. Finally, the human genetic association studies indicated that variations in the genes that code for the alpha 5, alpha 3, beta 4, and alpha 6 nAChRs were associated with cannabis disorder phenotypes. Overall, these findings suggest that alpha 3 beta 4* and alpha 6 beta 4* nAChR subtypes represent viable targets for the development of medications to counteract THC dependence.