Agonism of the endocannabinoid system modulates binge-like alcohol intake in male C57BL/6J mice: involvement of the posterior ventral tegmental area

Abstract

Recent studies have indicated a role for the endocannabinoid system in the behavioral and physiological effects of alcohol (ethanol), particularly ethanol seeking behaviors. However, its role in modulating binge-like intake and/or the mechanism by which it may exert these effects remain poorly understood. The current study used a newly developed strain-specific animal model of binge drinking, dubbed 'Drinking In the Dark' (DID), to determine if facilitation of the endocannabinoid system with the synthetic cannabinoid agonist WIN 55-212,2 (WIN) modulates binge-like ethanol intake in male C57BL/6J (B6) mice. Based on the results of these systemic (i.p.) manipulations, and evidence in support of the involvement of subregions of the Ventral Tegmental Area (VTA) in governing self-administration of ethanol (Rodd-Henricks et al., 2000) as well as binge-like intake using the DID model (Moore & Boehm, 2009), we extended these findings to evaluate the role of the endocannabinoid system within the anterior and posterior sub regions of the VTA using sitespecific microinjections. Consistent with previous research, the lowest systemic dose of WIN (0.5 mg/kg) significantly increased ethanol intake in the first 30 minutes of access whereas the two highest doses (1 and 2 mg/kg) decreased ethanol intake within this time interval. Intra-pVTA (but not aVTA) microinjections elicited time-dependent and dose-dependent increases (0.25 and 0.5 µg/side) and decreases (2.5 µg/side) in ethanol intake. Importantly, follow-up studies revealed that in some cases alterations in fluid consumption may have been influenced by competing locomotor activity (or inactivity).The present data are consistent with previous research in that agonism of the endocannabinoid system increases ethanol intake in rodents and implicate the pVTA in the modulation of drinking to intoxication. Moreover, the dose-dependent alterations in locomotor activity emphasize the importance of directly assessing multiple (possibly competing) behaviors when evaluating drug effects on voluntary consumption.One hallmark feature of alcoholism that has recently received much attention is repeatedly drinking to intoxication or 'binge' drinking. Binge drinking was recently defined by the © 2009 IBRO. Published by Elsevier Ltd. All rights reserved.Corresponding author: D. N. L, dlinsenb@iupui.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 December 1. Published in final edited form as:Neuroscience. NIH-PA Author ManuscriptNIH-PA Author Manuscr...

The antero-posterior heterogeneity of the ventral tegmental area

“…An intra-pVTA administration of the glutamate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) also reduces ethanol-seeking, but without affecting ethanol intake (Czachowski et al, 2012). Last, the local cannabinoid system also influences ethanol action, since the administration of a CB 1 agonist (WIN 55-212) into the pVTA, but not into the aVTA, alters the time-course of binge-like ethanol intake in mice (Linsenbardt and Boehm, 2009). These various interactions may also participate in a cross-vulnerability between alcohol and other drugs of abuse.…”

Central Neuropeptide Y Modulates Binge-Like Ethanol Drinking in C57BL/6J Mice via Y1 and Y2 Receptors

“…The 'drinking in the dark' (DID) procedure is a wellestablished animal model of human binge drinking and has been used to identify neurochemical modulators of bingelike ethanol consumption (Gupta et al, 2008;Hendrickson et al, 2009;Kamdar et al, 2007;Kaur and Ryabinin, 2010;Linsenbardt and Boehm, 2009;Melon and Boehm, 2011;Moore and Boehm, 2009;Sajja and Rahman, 2011). We have recently found that corticotropin-releasing factor (CRF) type-1 receptor (CRF1R) antagonists reduce binge-like ethanol intake in C57BL/6J mice but fail to alter nonbinge-like (low level) ethanol intake (Lowery et al, 2010;Sparta et al, 2008).…”

Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes

“…Evidence obtained in the preceding decade strongly implicates the eCB system in the modulation of the behavioral effects of abused drugs (Linsenbardt and Boehm, 2009; Oleson et al, 2012; Melis and Pistis, 2012). Furthermore, the key observations that midbrain neurons possess the machinery for the synthesis and degradation of the eCB, 2-AG (Matyas et al, 2008), and the localization of CB1Rs on axon terminals impinging upon these neurons (Szabo et al, 2002; Melis et al, 2004b; Riegel and Lupica, 2004; Matyas et al, 2008), provide the likely substrates upon which these molecules act to modify reward behavior through actions in the VTA.…”