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

Addict Biol. 2020 Jan;25(1):e12691. doi: 10.1111/adb.12691. Epub 2018 Oct 31.


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 α3β4* nAChR antagonist, AuIB, and α3β4* 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 α5 and α6 nAChR knockout (KO) mice displayed decreased rimonabant precipitated somatic withdrawal signs compared with their wild-type counterparts. In contrast, β2 and α7 nAChR KO mice showed no alterations in THC withdrawal signs. Moreover, deletion of β2 nAChR did not alter the reduced expression of somatic signs by the preferred α6β4* antagonist, BulA [T5A;P60]. Finally, the human genetic association studies indicated that variations in the genes that code for the α5, α3, β4, and α6 nAChRs were associated with cannabis disorder phenotypes. Overall, these findings suggest that α3β4* and α6β4* nAChR subtypes represent viable targets for the development of medications to counteract THC dependence.

Keywords: THC; human genetics; mice; nicotinic acetylcholine receptors; somatic signs; withdrawal.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cannabinoid Receptor Antagonists / administration & dosage
  • Disease Models, Animal
  • Dronabinol / pharmacology*
  • Humans
  • Marijuana Abuse / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Nicotinic / drug effects*
  • Rimonabant / administration & dosage
  • Substance Withdrawal Syndrome / physiopathology*


  • Cannabinoid Receptor Antagonists
  • Receptors, Nicotinic
  • Dronabinol
  • Rimonabant