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Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors.

ABSTRACT: BACKGROUND:Emerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs. Recently, the cannabinoid receptor 2 (CB2R) was shown to be expressed in brain reward circuitry and is implicated in modulating the rewarding effects of alcohol. METHODS:CB2 ligands and CB2R knockout (KO) mice were used to assess CB2R involvement in alcohol reward-related behavior in 2 well-established behavioral models: limited-access 2-bottle choice drinking and conditioned place preference (CPP). For the pharmacological studies, mice received pretreatments of either vehicle, the CB2R agonist JWH-133 (10 and 20 mg/kg) or the CB2R antagonist AM630 (10 and 20 mg/kg) 30 minutes before behavioral testing. For the genetic studies, CB2R KO mice were compared to wild-type (WT) littermate controls. RESULTS:CB2R KO mice displayed increased magnitude of alcohol-induced CPP compared to WT mice. Neither agonism nor antagonism of CB2R affected alcohol intake or the expression of CPP, and antagonism of CB2R during CPP acquisition trials also did not affect CPP. CONCLUSIONS:The CB2R KO CPP data provide partial support for the hypothesis that CB2Rs are involved in the modulation of alcohol reward-related behaviors. However, pharmacological manipulation of CB2Rs did not alter alcohol's rewarding effects in the alcohol-seeking models used here. These results highlight the importance of pharmacological validation of effects seen with lifetime KO models. Given the ongoing efforts toward medications development, future studies should continue to explore the role of the CB2R as a potential neurobiological target for the treatment of alcohol use disorders.

SUBMITTER: Powers MS

PROVIDER: S-EPMC4886733 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors.

Powers Matthew S MS Breit Kristen R KR Chester Julia A JA

Alcoholism, clinical and experimental research 20151201 12

<h4>Background</h4>Emerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs. Recently, the cannabinoid receptor 2 (CB2R) was shown to be expressed in brain reward circuitry and is implicated in modulating the rewarding effects of alcohol.<h4>Methods</h4>CB2 ligands and CB2R knockout (KO) mice were used to assess CB2R involvement in alcohol reward-related behavior in 2 well-established behavioral models: limited-access 2-bott ...[more]

PMID: 26756798

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Project description:Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the ?5, ?3, and ?4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. ?4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that ?4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. ?4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, ?4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and ?4KO self-administered more than WT mice, whereas ?4-overexpressing mice avoided nicotine injections. Viral expression of ?4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of ?4KO mice revealed dose- and region-dependent differences: ?4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas ?4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional ?4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of ?4*nAChRs in the MHb-IPN. These data indicate that ?4 is a critical modulator of reward-related behaviors.SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of ?4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of ?4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the ?4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the ?4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that ?4*nAChRs provide a promising novel drug target for smoking cessation.

Dataset Information

Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors.

Publications

Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors.

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