mGlu₂and mGlu₃receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats

Abstract

All drugs with the potential for addiction liability, including alcohol, produce distinct interoceptive stimulus effects that influence drug intake. Our lab has shown involvement of Group II metabotropic receptors (mGlu2/3) in the expression of alcohol interoceptive effects using a nonspecific mGlu2/3 agonist and antagonist. Furthermore, the anterior insular cortex (aIC) is a hub for interoceptive processing, including the interoceptive effects of alcohol. Therefore, the goal of the present work was to assess the independent functional contribution of mGlu2 and mGlu3, and the role of mGlu3 in the aIC, in the interoceptive effects of alcohol. As such, male, Long-Evans rats were trained to discriminate the stimulus effects of alcohol (2 g/kg, i.g.) from water (i.g.) using an operant, 2-lever drug discrimination procedure. To assess involvement of mGlu2 and mGlu3 in the discriminative stimulus effects of alcohol, rats were administered the mGlu2 negative allosteric modulator (NAM, VU6001966; 0, 3, 6 mg/kg, i.p.) and the mGlu3-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol (2 g/kg, i.g.). mGlu2-NAM (6 mg/kg) and mGlu3-NAM (12 mg/kg) decreased alcohol-appropriate lever responses without affecting response rate, reflecting diminished interoceptive alcohol sensitivity. mGlu3-NAM microinjection (3 ug) into the aIC before alcohol decreased response rate to such an extent that alcohol-appropriate lever responding could not be determined. As such, mGlu3-NAM was tested in the aIC before water administration to determine if VU6010572 substitutes for alcohol. mGlu3-NAM VU6010572 (3 ug) in the aIC produced partial alcohol-like stimulus effects without affecting response rate. These data indicate that the newly developed mGlu2 and mGlu3 NAMs can modulate interoceptive effects of alcohol. The opposing effects of systemic vs. microinjected (aIC) mGlu3-NAM on alcohol interoceptive effects may reflect differences in receptor binding, a functionally relevant metabolite, and/or brain region differences in receptor function.