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Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens.

The Journal of neuroscience : the official journal of the Society for Neuroscience | 2009

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]beta-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 microg 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 microg 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 microg 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 microg 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.

Pubmed ID: 19641121 RIS Download

Mesh terms: Animals | Caudate Nucleus | Central Nervous System Depressants | Conditioning, Operant | Discrimination Learning | Ethanol | Male | Neurons | Nucleus Accumbens | Proto-Oncogene Proteins c-fos | Putamen | Rats | Rats, Long-Evans | Receptor, Metabotropic Glutamate 5 | Receptors, Metabotropic Glutamate

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Associated grants

  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA016629
  • Agency: NIAAA NIH HHS, United States
    Id: AA016009
  • Agency: NIAAA NIH HHS, United States
    Id: K01 AA016009
  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA014983-05
  • Agency: NIAAA NIH HHS, United States
    Id: K01 AA016009-04
  • Agency: NIAAA NIH HHS, United States
    Id: AA014983
  • Agency: NIAAA NIH HHS, United States
    Id: K01 AA016009-03
  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA014983-04
  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA014983
  • Agency: NIAAA NIH HHS, United States
    Id: R37 AA014983

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