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The Journal of Neuroscience, July 29, 2009, 29(30):9582-9591; doi:10.1523/JNEUROSCI.2366-09.2009

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Behavioral/Systems/Cognitive
Interoceptive Effects of Alcohol Require mGlu5 Receptor Activity in the Nucleus Accumbens

Joyce Besheer, Julie J. M. Grondin, Michael C. Salling, Marina Spanos, Rebekah A. Stevenson, and Clyde W. Hodge

Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Correspondence should be addressed to Dr. Joyce Besheer, Bowles Center for Alcohol Studies, Thurston-Bowles Building, CB #7178, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Email: jbesheer{at}med.unc.edu

The interoceptive effects of alcohol are major determinants of addiction liability. Metabotropic glutamate (mGlu) receptors are widely expressed in striatal circuits known to modulate drug-seeking. Given that the interoceptive effects of drugs can be important determinants of abuse liability, we hypothesized that striatal mGlu receptors modulate the interoceptive effects of alcohol. Using drug discrimination learning, rats were trained to discriminate alcohol (1 g/kg, i.g.) versus water. We found that systemic antagonism of metabotropic glutamate subtype 5 (mGlu5) receptors [10 mg/kg 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3 mg/kg 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine], but not mGlu1 receptors ([0.3–3 mg/kg JNJ16259685) (3,4-dihydro-2H-pyrano[2,3]β-quinolin-7-yl)(cis-4-methoxycyclohexyl) methanone)], inhibited the discriminative stimulus effects of alcohol. Furthermore, mGlu5 receptor antagonism (10 mg/kg MPEP) significantly inhibited neuronal activity in the nucleus accumbens core as levels of the transcription factor c-Fos were significantly reduced. Accordingly, targeted inhibition of mGlu5 receptors (20 µg of MPEP) in the nucleus accumbens core blunted the discriminative stimulus effects of alcohol (1 g/kg). Anatomical specificity was confirmed by the lack of effect of inhibition of mGlu5 receptors (10–30 µg of MPEP) in the dorsomedial caudate–putamen and the similar cytological expression patterns and relative density of mGlu5 receptors between the brain regions. Functional involvement of intra-accumbens mGlu5 receptors was confirmed as activation of mGlu5 receptors [10 µg of (RS)-2-amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt] enhanced the discriminative stimulus effects of a low alcohol dose (0.5 g/kg), and mGlu5 receptor inhibition (20 µg of MPEP) prevented the agonist-induced enhancement. These results show that mGlu5 receptor activity in the nucleus accumbens is required for the expression of the interoceptive effects of alcohol.

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Received May 20, 2009; revised June 17, 2009; accepted June 17, 2009.

Correspondence should be addressed to Dr. Joyce Besheer, Bowles Center for Alcohol Studies, Thurston-Bowles Building, CB #7178, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Email: jbesheer{at}med.unc.edu

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