Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Abstract

Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3-10 mg/kg) did not produce alcohollike stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 mg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 mg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 mg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

Glutamate Signaling in Alcohol Abuse and Dependence

“…Indeed, a study of the interactions between mGlu2/3 receptors and alcohol indicated that receptor stimulation is involved in mediating the sedative/hypnotic properties of the drug because systemic pretreatment with the mGlu2/3-receptor antagonist LY341495 prevented alcohol-induced sedation in C57BL/6 J mice (Sharko & Hodge, 2008). However, systemic administration of the mGlu2/3 agonist LY379268 failed to produce ethanol-like subjective effects; but when coadministered with ethanol, the agonist inhibited alcohol's discriminative stimulus effects, and this effect was mimicked upon the local infusion of LY379268 into the amygdala (Cannady, Grondin, Fisher, Hodge, & Besheer, 2011). In contrast, an infusion of LY379268 into the NAC produced a marked reduction in responding, indicative of a strong motor impairment.…”

Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

“…Surgical and microinjection procedures were identical to those described previously (Besheer et al, 2012a;Besheer et al, 2009;Cannady et al, 2011). Rats received bilateral implantation of 26-gauge guide cannulae (Plastics One, Roanoke, VA) aimed to terminate 2 mm above the nucleus accumbens core (coordinates: AP þ 1.7, ML þ 1.5 mm, DV À 5.5 mm) as described in Paxinos and Watson (1998).…”

“…Discrimination training and testing procedures were identical to those described in detail (Besheer et al, 2012b;Besheer et al, 2009;Cannady et al, 2011). Rats were trained to discriminate a moderate dose of alcohol (1 g/kg, IG) from water using standard two-lever operant procedures.…”

“…Immunohistochemistry (IHC) staining and quantification procedures were similar to those we have previously described (Besheer et al, 2012a;Besheer et al, 2009;Cannady et al, 2011). Free-floating coronal sections were incubated in a rabbit anti-c-Fos antibody (1:20 000 dilution, Oncogene Research Products/Calbiochem) for 48 h or in a rabbit anti-mGluR5 antibody (1:1000 dilution, Millipore) for 16 h at 4 1C with agitation.…”

“…Testing began when the accuracy criteria were met: the percentage of appropriate lever responses before the first reinforcer and during the entire session was 480% for at least 8 out of 10 consecutive days. For testing, cumulative dosing (Besheer et al, 2012b;Besheer et al, 2009;Cannady et al, 2011) or single alcohol dose (1 g/kg) procedures were used as indicated in the Experiments. For the studies in Experiment 4 and 5, a baseline cumulative alcohol session was conducted before the initiation of the 7-day CORT or Water procedure (Supplementary Tables 2 and 3; Supplementary Figures 1 and 2).…”