title: Roles for the endocannabinoid system in ethanol-motivated behavior.
abstract: Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination.
authors.affiliation: Department of Anesthesiology, Penn State University College of Medicine, Hershey, PA 17033, United States.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Henderson-Redmond
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Science Center, Lubbock, TX 79430, United States.
authors.forename: Josée
authors.initials: J
authors.lastname: Guindon
authors.affiliation: Department of Anesthesiology, Penn State University College of Medicine, Hershey, PA 17033, United States; Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, United States. Electronic address: dmorgan1@hmc.psu.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Morgan
mesh_terms: D019973:Alcohol-Related Disorders / Q000378:metabolism*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology* / Q000633:toxicity; D063388:Endocannabinoids / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D009042:Motivation / Q000187:drug effects* / Q000502:physiology*
chemical_list: D002492:Central Nervous System Depressants; D063388:Endocannabinoids; D000431:Ethanol
keywords: Alcohol; CB(1); Cannabinoid; Endocannabinoid; Ethanol