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Neuronal nicotinic acetylcholine receptors mediate ?9 -THC dependence: Mouse and human studies.


ABSTRACT: Cessation from prolonged use of ?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 ?3?4* nAChR antagonist, AuIB, and ?3?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 ?5 and ?6 nAChR knockout (KO) mice displayed decreased rimonabant precipitated somatic withdrawal signs compared with their wild-type counterparts. In contrast, ?2 and ?7 nAChR KO mice showed no alterations in THC withdrawal signs. Moreover, deletion of ?2 nAChR did not alter the reduced expression of somatic signs by the preferred ?6?4* antagonist, BulA [T5A;P60]. Finally, the human genetic association studies indicated that variations in the genes that code for the ?5, ?3, ?4, and ?6 nAChRs were associated with cannabis disorder phenotypes. Overall, these findings suggest that ?3?4* and ?6?4* nAChR subtypes represent viable targets for the development of medications to counteract THC dependence.

SUBMITTER: Donvito G 

PROVIDER: S-EPMC6509006 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Neuronal nicotinic acetylcholine receptors mediate ∆<sup>9</sup> -THC dependence: Mouse and human studies.

Donvito Giulia G   Muldoon Pretal P PP   Jackson Kia J KJ   Ahmad Urslan U   Zaveri Nur T NT   McIntosh J Michael JM   Chen Xiangning X   Lichtman Aron H AH   Damaj M Imad MI  

Addiction biology 20181031 1


Cessation from prolonged use of ∆<sup>9</sup> -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 T  ...[more]

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