Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake

Abstract

Background: Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration.

Methods: Alcohol-preferring (P) rats, a genetic model of high alcohol drinking, were trained to self-administer ethanol (15% v/v) versus water in operant conditioning chambers. Effects of brain site-specific infusion of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the mGluR2/3 agonist were then assessed on the maintenance of self-administration.

Results: Microinjection of the mGluR5 antagonist MPEP in the nucleus accumbens reduced ethanol self-administration at a dose that did not alter locomotor activity. By contrast, infusion of the mGluR2/3 agonist LY379268 in the nucleus accumbens reduced self-administration and produced nonspecific reductions in locomotor activity. The mGluR5 involvement showed anatomical specificity as evidenced by lack of effect of MPEP infusion in the dorsomedial caudate or medial prefrontal cortex on ethanol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (.4% w/v) versus water, and effects of intra-accumbens MPEP were tested. The MPEP did not alter sucrose self-administration or motor behavior.

Conclusions: These results suggest that mGluR5 activity specifically in the nucleus accumbens is required for the maintenance of ethanol self-administration in individuals with genetic risk for high alcohol consumption.

Figure 1

Illustrations of cannulae and injector placements. Injector placements from individual rats with accurate bilateral placements in the (A) nucleus accumbens, (C) dorsomedial caudate, and (E) medial prefrontal cortex. Circles represent animals trained on ethanol self-administration tested with 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP); squares represent animals trained on ethanol self-administration tested with LY379268; and diamonds represent animals trained on sucrose self-administration tested with MPEP. Representative photomicrographs showing cannula (closed arrows) and injector (open arrows) tracks in nucleus accumbens (B), dorsomedial caudate (D), and medial prefrontal cortex (F). ac, anterior commissure; cc, corpus callosum. Figures A, C, and E published in The Rat Brain in Stereotaxic Coordinates, 4th ed. (CD-ROM) by Paxinos and Watson, Copyright Elsevier (1998).

Figure 2

Intra-accumbens metabotropic glutamate 5 (mGlu5) antagonism reduces ethanol self-administration without affecting spontaneous motor activity. (A) Mean (± SEM) responses on the ethanol (15% v/v) lever after intra-accumbens administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and a sham infusion (to left of axis break). (B) Mean (± SEM) cumulative ethanol responses across the 30-min self-administration session after intra-accumbens MPEP administration. (C) Mean (± SEM) cumulative distance traveled (cm) during the 30-min locomotor assessment after intra-accumbens administration of MPEP (10 μg). (D) Mean (± SEM) responses on the ethanol (15% v/v) lever after intra-accumbens administration of the mGluR2/3 agonist LY379268 (LY) and a sham infusion (to left of axis break). (E) Mean (± SEM) cumulative ethanol responses across the 30-min self-administration session after intra-accumbens LY administration. (F) Mean (± SEM) cumulative distance traveled (cm) during the 30-min locomotor assessment after intra-accumbens administration of LY (.17 μg). aCSF, artificial cerebrospinal fluid. *Significant difference from vehicle (Tukey, p < .05).

Figure 3

Intracaudate or medial prefrontal cortex (mPFC) antagonism of mGluR5 does not alter ethanol self-administration or spontaneous motor activity. (A) Mean (± SEM) responses on the ethanol (15% v/v) lever after intra-dorsomedial caudate putamen administration of the mGluR5 antagonist MPEP and a sham infusion (to left of axis break). (B) Mean (± SEM) cumulative ethanol responses across the 30-min self-administration session after intracaudate MPEP administration. (C) Mean (± SEM) cumulative distance traveled (cm) during the 30-min locomotor assessment after intracaudate administration of MPEP (10 μg). (D) Mean (± SEM) responses on the ethanol (15% v/v) lever after intra-mPFC administration of the mGluR5 antagonist MPEP and a sham infusion (to left of axis break). (E) Mean (± SEM) cumulative ethanol responses across the 30-min self-administration session after intra-mPFC MPEP administration. (F) Mean (± SEM) cumulative distance traveled (cm) during the 30 min locomotor assessment after intra-mPFC administration of MPEP (30 μg). Abbreviations as Figures 1 and 2.

Figure 4

Intra-accumbens mGluR5 antagonism does not alter sucrose self-administration or spontaneous motor activity. (A) Mean (± SEM) responses on the sucrose (.4% w/v) lever after intra-accumbens administration of the mGluR5 antagonist MPEP and a sham infusion (to left of axis break). (B) Mean (± SEM) cumulative ethanol responses across the 30-min self-administration session after intra-accumbens MPEP administration. (C) Mean (± SEM) cumulative distance traveled (cm) during the 30-min locomotor assessment after intra-accumbens administration of MPEP (10 μg). Abbreviations as Figures 1 and 2.