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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 13, 2005; DOI: 10.1124/jpet.105.090449

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Received for publication June 2, 2005.
Revised July 11, 2005.
Accepted for publication July 12, 2005.

The mGlu5 antagonist MTEP reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems

Michael S. Cowen 1, Elvan Djouma 2, Andrew J. Lawrence 1*

1 Howard Florey Institute 2 Monash University

* Address correspondence to: E-mail: andrew.lawrence{at}hfi.unimelb.edu.au

Abstract

The mGlu5 receptor has been implicated as having a role in pain modulation, anxiety and depression, as well as drug-seeking behavior. In the present study, we examined the effect of the selective mGlu5 receptor antagonist MTEP on operant ethanol self-administration by two strains of rats, the Fawn-Hooded (FH) rat, and the alcohol-preferring iP (inbred Preferring) rat. MTEP (2mg/kg i.p.) caused a significant reduction in responding for ethanol by both strains of rats; however, in the iP rats MTEP also induced apparent sedation at this dose, although still reduced alcohol responding at lower doses. Chronic MTEP (2mg/kg/day) caused a significant reduction in ethanol consumption by FH rats in a two bottle preference test; however, chronic treatment with this dose had no effect on anxiety-like behavior or depressive-like behavior in FH rats, suggesting the dose used was subthreshold for anxiolytic or antidepressive-like effects. Finally, repeated dosing with MTEP (2mg/kg i.p.) caused significant reductions in expression of the mRNA encoding the NR1 subunit of the NMDA receptor and the GluR2 subunit of the AMPA receptor in the cingulate cortex. A significant decrease in NR1 expression also occurred in the piriform cortex. Chronic MTEP also caused a significant decrease in mGlu5 gene expression and a significant increase in dopamine transporter and dopamine D2-like receptor binding within the olfactory tubercle. Collectively, these data suggest that MTEP can reduce alcohol-seeking behavior in different rodent models of alcoholism, and this effect is associated with regulation of cortical glutamate systems, particularly those in olfactory-related regions.


Key words: MTEP, alcohol-preferring rats, alcoholism, glutamate, mGlu5 receptors, operant responding




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