Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

Abstract

The Group I family of metabotropic glutamate receptors includes subtype 1 (mGlu1) and subtype 5 (mGlu5) receptors. This family of receptors has generated interest as potential targets for different areas of therapeutic development, including intervention for alcohol and drug abuse. Most of this interest is driven by findings showing involvement of mGlu5 receptors in the regulation of drug self-administration; however, studies examining the role of mGlu1 receptors in drug self-administration are limited. The purpose of this work was to examine the role of mGlu1-receptor antagonism in the maintenance of ethanol self-administration and the self-administration of an alternate nondrug reward, sucrose. Male alcohol-preferring inbred rats were trained to self-administer ethanol (15% vol/vol) versus water on a concurrent schedule of reinforcement, and the effect of the mGlu1-receptor antagonist JNJ16259685 (0.1-1.0mg/kg intraperitoneal [IP]) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% wt/vol) versus water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential nonspecific motor effects of the antagonist. Ethanol self-administration was dose dependently reduced by JNJ16259685. This reduction was likely due to a motor impairment as the lowest effective dose (0.1mg/kg) significantly reduced locomotor behavior. Sucrose self-administration was reduced by the highest JNJ16259685 dose (1.0mg/kg), and this reduction was also likely due to a motor impairment. Interestingly, ethanol self-administration was more sensitive to mGlu1-receptor antagonism than sucrose self-administration as lower JNJ16259685 doses reduced ethanol-reinforced responding and motor behavior. Together, these results suggest that mGlu1 receptors do not play a specific role in modulating ethanol self-administration or the self-administration of an alternate nondrug reward (i.e., sucrose).

Figure 1

Panel A. Mean (± SEM) responses on the ethanol (15% v/v) and water levers after JNJ16259685 pretreatment (N=10). Panel B. Mean (± SEM) cumulative ethanol responses across the 30-min self-administration session after JNJ16259685 pretreatment (N=10). Panel C. Mean (± SEM) line crosses during the 10-min locomotor assessment after pretreatment with vehicle/JNJ16259685 (0.1 mg/kg) followed by saline/ethanol (0.7 g/kg) administration (N=10). Panel D. Mean (± SEM) responses on the sucrose (0.4% w/v) and water levers after JNJ16259685 pretreatment (N=8). Panel E. Mean (± SEM) cumulative sucrose responses across the 30-min self-administration session after JNJ16259685 pretreatment (N=8). Panel F. Mean (± SEM) line crosses during the 10-min locomotor assessment after pretreatment with JNJ16259685 (N=8). * Indicates significant difference from vehicle; + indicates significant difference from 0.1 mg/kg JNJ16259685; # indicates significant difference from 0.3 mg/kg JNJ16259685 (Tukey, p<0.05).