Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives

Psychopharmacology (Berl). 2016 May;233(10):1765-77. doi: 10.1007/s00213-015-4196-3. Epub 2016 Jan 4.


Rationale: Several lines of evidence suggest that endocannabinoid and nicotinic cholinergic systems are implicated in the regulation of different physiological processes, including reward, and in the neuropathological mechanisms of psychiatric diseases, such as addiction. A crosstalk between these two systems is substantiated by the overlapping distribution of cannabinoid and nicotinic acetylcholine receptors in many brain structures.

Objective: We will review recent preclinical data showing how the endocannabinoid and nicotinic cholinergic systems interact bidirectionally at the level of the brain reward pathways, and how this interaction plays a key role in modulating nicotine and cannabinoid intake and dependence.

Results: Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids.

Conclusions: Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence. Research by Steven R. Goldberg has significantly contributed to the progress in this research field.

Keywords: Addiction; Cannabinoid receptors; Cannabinoids; Dependence; Nicotine; Nicotinic acetylcholine receptors.

Publication types

  • Review

MeSH terms

  • Animals
  • Behavior, Addictive / metabolism
  • Behavior, Addictive / physiopathology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiology*
  • Endocannabinoids / metabolism
  • Endocannabinoids / physiology*
  • Humans
  • Receptors, Nicotinic / metabolism
  • Receptors, Nicotinic / physiology*
  • Reward
  • Tobacco Use Disorder / metabolism
  • Tobacco Use Disorder / physiopathology


  • Endocannabinoids
  • Receptors, Nicotinic