Genetic and pharmacological manipulations of the CB₁ receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice

Abstract

Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB 1 receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB 1 receptor significantly reduced the ethanol preference. Although the stimulation of the CB 1 receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB 1 receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB 1 -/-mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB 1 receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB 1 receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB 1 receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB 1 receptor may have therapeutic potential in the treatment of ethanol dependence.

Role of the Endocannabinoid System in Alcohol-Related Behaviors

“…A reduction in conditioned place preference and increased striatal D2 receptors has also been reported in CB1-KO mice [87][88][89]. Moreover, the genetically determined changes in the activities of components of the EC system in alcohol preferring and alcohol avoiding animals might also explain differences in alcohol drinking behaviors [55,82,90]. These studies strongly support a role for the CB1 receptor in alcohol drinking behavior.…”

“…There are several studies which have attempted to investigate whether genetic or pharmacological manipulation of CB1 receptor function [54,55] and FAAH enzyme [56] could alter development of tolerance and dependence to alcohol. For instance, the CB1 receptor gene deleted mice (CB1-KO) mice, which are known to drink less alcohol, exhibit a greater sensitivity to alcohol [54].…”

“…Interestingly, the prefrontal cortex (PFC) appears to play a critical role in regulating the alcohol drinking behavior as revealed by a dose dependent suppression of alcohol self-administration in alcohol preferring rats when rimonabant was given locally into the PFC [82]. Conversely, the CB1 receptor stimulation is shown to enhance alcohol drinking behavior in both alcohol preferring and alcohol non-preferring rodents [55,61,84,104]. In addition, an increased motivation to drink more beer in rats following administration of the CB1 receptor agonist (CP-55, 940) and complete abolition of this effect after treatment with rimonabant has also been shown [83].…”

“…In this regard, generation of CB1 receptor null mutant mice has provided several insights into the role of CB1 receptor in physiology and behavior. It has been demonstrated that mice lacking CB1 receptor gene with two different genetic background (C57BL/6J and CD1) consume less alcohol [ 54,55,[84][85][86][87][88][89] (Fig. 1) and exhibit reduced effect on alcohol-induced DA release in the nucleus accumbens (NAc) compared to their WT controls [85].…”

Acute and chronic modulation of striatal endocannabinoid‐mediated plasticity by nicotine

“…The eCB system appears to modulate several phenomena related to addiction, including drug-induced reward, the motivation to procure the drug and behavioral sensitization (Vinod et al 2008). CB1Rs are highly expressed in the dorsolateral striatum (DLS), a critical brain region for the gradual acquisition of habitual and automatic behaviors (Gremel & Costa 2013).…”