mGlu2 and mGlu3 receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats

Ryan E Tyler; Kalynn Van Voorhies; Bruce E Blough; Antonio Landavazo; Joyce Besheer

doi:10.1016/j.pbb.2024.173767

mGlu₂ and mGlu₃ receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats

Pharmacol Biochem Behav. 2024 Jun:239:173767. doi: 10.1016/j.pbb.2024.173767. Epub 2024 Apr 10.

Authors

Ryan E Tyler¹, Kalynn Van Voorhies¹, Bruce E Blough², Antonio Landavazo², Joyce Besheer³

Affiliations

¹ Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, United States of America; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, United States of America.
² Center for Drug Discovery, RTI International, Research Triangle Park, NC, United States of America.
³ Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, United States of America; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, United States of America; Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC, United States of America. Electronic address: joyce_besheer@med.unc.edu.

PMID: 38608960
PMCID: PMC11090252 (available on 2025-06-01)
DOI: 10.1016/j.pbb.2024.173767

Abstract

Rationale: The subjective effects of alcohol are associated with alcohol use disorder (AUD) vulnerability and treatment outcomes. The interoceptive effects of alcohol are part of these subjective effects and can be measured in animal models using drug discrimination procedures. The newly developed mGlu₂ and mGlu₃ negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol.

Objectives: To determine the effects of mGlu₂ and mGlu₃ NAMs on the interoceptive effects of alcohol in rats.

Methods: Long-Evans rats were trained to discriminate the interoceptive stimulus effects of alcohol (2.0 g/kg, i.g.) from water using both operant (males only) and Pavlovian (male and female) drug discrimination techniques. Following acquisition training, an alcohol dose-response (0, 0.5, 1.0, 2.0 g/kg) experiment was conducted to confirm stimulus control over behavior. Next, to test the involvement of mGlu₂ and mGlu₃, rats were pretreated with the mGlu₂-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu₃-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.).

Results: In Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu₂-NAM and mGlu₃-NAM attenuated the interoceptive effects of alcohol in male and female rats using Pavlovian and operant discrimination. There may be a potential sex difference in response to the mGlu₂-NAM at the highest dose tested.

Conclusions: Male rats may be more sensitive to the interoceptive effects of the 2.0 g/kg alcohol training dose compared to female rats. Both mGlu₂_-and mGlu₃_-NAM attenuate the interoceptive effects of alcohol in male and female rats. These drugs may have potential for treatment of AUD in part by blunting the subjective effects of alcohol.

Keywords: Interoceptive sensitivity; Operant drug discrimination; Pavlovian drug discrimination; VU6001966; VU6010572.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Allosteric Regulation / drug effects
Animals
Dose-Response Relationship, Drug
Ethanol* / administration & dosage
Ethanol* / pharmacology
Female
Interoception / drug effects
Male
Rats
Rats, Long-Evans
Receptors, Metabotropic Glutamate* / metabolism

Substances

Ethanol
metabotropic glutamate receptor 2
metabotropic glutamate receptor 3
Receptors, Metabotropic Glutamate

Abstract

Publication types

MeSH terms

Substances

Grants and funding