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

Abstract

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 Nmethyl-D-aspartate receptor and the GluR2 subunit of the ␣-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.

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

“…These data indicate a substantial degree of resilience in expression this receptor in the frontal cortex in response to repeated administration of the antagonists MPEP or MTEP (10 mg/kg each twice daily for 5 days). These data are consistent with that of a previous report, which showed that repeated treatment of MTEP (2 mg/kg/day for 12 days) to rats produced no changes in mGlu5 mRNA expression in the cingulate cortex, dorsal striatum or nucleus accumbens, as measured by in situ hybridization (Cowen et al, 2005). However, these authors did note a 25% reduction in mGlu5 mRNA expression in the olfactory tubercle induced by repeated MTEP administration, suggesting that the mechanisms regulating the expression of mGlu5 in response to repeated antagonist treatment may be brain region-specific.…”

“…However, some investigators have reported that multiple dosing procedures with these compounds produces increases efficacy in the anxiolytic, antidepressant or anti-addictive effects as compared with acute administration (Backstrom et al, 2004;Cowen et al, 2005;Klodzinska et al, 2004;Li et al, 2006;Nordquist et al, 2007;Pilc et al, 2002). This raises the possibility that changes in gene expression may underlie some of the behavioral effects of MPEP and/or MTEP following repeated exposure.…”

Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

“…For example, the non-competitive mGluR5 antagonist MPEP has been shown suppress the reinforcing effects of ethanol in rats and mice (Backstrom et al, 2004;Hodge et al, 2006;Schroeder et al, 2005), attenuate the motivation to self-administer ethanol (Besheer et al, 2007b), block relapse-like behavior in multiple models (Backstrom et al, 2004;Schroeder et al, 2005), and inhibit the discriminative stimulus properties of investigator-and selfadministered ethanol (Besheer et al, 2003;Besheer et al, 2006). Similarly, the mGluR5 antagonist MTEP also reduces the reinforcing effects of ethanol in rats and mice (Cowen et al, 2005;Cowen et al, 2007). Importantly, these dose-dependent effects of mGluR5 antagonists on ethanol self-administration are not associated with disruptions in motor performance (Besheer et al, 2007b;Cowen et al, 2007;Hodge et al, 2006).…”

Metabotropic Glutamate 5 Receptor (mGluR5) Antagonists Decrease Nicotine Seeking, But Do Not Affect the Reinforcement Enhancing Effects of Nicotine

“…The moderate to high density localization of mGlu5 receptors in the frontal cortex, striatum, nucleus accumbens, and hippocampus , as well as their modulatory role in membrane excitability in these regions (eg Domenici et al, 2003) has made them a target of interest for pharmacotherapeutic intervention in substance dependence (Chiamulera et al, 2001) and obesity (Bradbury et al, 2005). Noncompetitive antagonists of mGluR5 decrease selfadministration of cocaine (Kenny et al, 2005), ethanol (Cowen et al, 2005), and nicotine (Paterson and Markou, 2005;Paterson et al, 2003). Many of these studies suggest that mGlu5 receptors mediate drug reinforcement and reward-related learning (see also Bäckström and Hyytiä, 2007).…”