The Metabotropic Glutamate 5 Receptor Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine Reduces Ethanol Self-Administration in Multiple Strains of Alcohol-Preferring Rats and Regulates Olfactory Glutamatergic Systems

• Published in: The Journal of pharmacology and experimental therapeutics 2005-11, Vol.315 (2), p.590-600
• Main Authors: Cowen, Michael S, Djouma, Elvan, Lawrence, Andrew J
• Format: Article
• Language: English
• Subjects: Alcohol Drinking - genetics; Alcohol Drinking - psychology; Alcoholism - drug therapy; Alcoholism - psychology; Animals; Autoradiography; Biomarkers; Brain Chemistry - drug effects; Conditioning, Operant - drug effects; Depression - drug therapy; Depression - psychology; Drinking - drug effects; Glutamic Acid - physiology; In Situ Hybridization; Male; Motor Activity - drug effects; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Smell - drug effects; Smell - physiology; Swimming - psychology; Thiazoles - pharmacology; Thiazoles - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.090449

The metabotropic glutamate 5 receptor (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 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on operant ethanol self-administration by two strains of rats, the Fawn-Hooded (FH) rat and the inbred alcohol-preferring (iP) rat. MTEP (2 mg/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 (2 mg/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 (2 mg/kg i.p.) caused significant reductions in expression of the mRNA encoding the NR1 subunit of the N -methyl- d -aspartate receptor and the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate 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 D 2 -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.