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.

The cannabis withdrawal syndrome: current insights

“…Continuous exposure to ethanol, in either cell culture or rodent models, led to an increase in endocannabinoid levels that resulted in downregulation of the CB1 receptor and uncoupling of this receptor from downstream G protein signaling pathways 116. A similar downregulation of CB1 receptors was found in multiple brain regions of chronic drinkers 116. Alcoholic drinks were reported to be co-used by 33%–46% of regular cannabis users.…”

A behavioral and pharmacological characterization of palatable diet alternation in mice

“…SR141716A has been investigated for its anti-obesity effects (Christensen et al, 2007), though has been withdrawn from the market for severe psychiatric side effects, including increased anxiety and depressed mood, effects that have been recapitulated in rat models of disordered eating (Blasio et al, 2013; Blasio et al, 2014a). CB1 antagonists/inverse agonists, including SR141716A, are also being investigated for their therapeutic potential in treating other forms of addiction (Henderson-Redmond et al, 2016; Le Foll and Goldberg, 2005), as they have been shown to modulate a variety of behaviors induced by addictive drugs, such as cocaine (Marinho et al, 2015; Mereu et al, 2015), ethanol (Economidou et al, 2006), and nicotine (Cohen et al, 2005; Le Foll and Goldberg, 2004). …”

Dysregulation of brain stress systems mediates compulsive alcohol drinking

“…Rimonabant has also shown efficacy in decreasing drinking in humans with alcohol dependence. However, the blunting of natural reward mechanisms observed in preclinical studies and the incidence of potential severe side-effects in humans (e.g., suicide) limit its clinical use [18]. Endocannabinoids, particularly in the CeA, may mediate some of the anxiety-like effects of alcohol dependence [19].…”