The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety

Abstract

Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

“…These results strengthen the idea of combining different antidepressant treatments to maximize therapeutic efficacy (Connolly and Thase, 2011;Palaniyappan et al, 2009). Indeed, CTEP may serve as a basis for future antidepressants that specifically target the glutamate system, as its pharmacokinetic properties are significantly improved from previous mGluR5 antagonists such as MPEP and MTEP (Lindemann et al, 2011;Anderson et al, 2003;Busse et al, 2004).…”

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

“…MPEP and MTEP also produced robust anxiolytic-and antidepressantlike activity, suggesting that mGlu 5 NAMs may be effective in treating the comorbid symptoms observed in cocaine addicts (Busse et al, 2004;Ballard et al, 2005). Unfortunately, clinical and preclinical studies using full mGlu 5 NAMs, with little chemotype diversity, exhibited a narrow therapeutic index between doses that produced efficacy and those that induced dose-limiting adverse effects (Kinney et al, 2003;Homayoun et al, 2004;Gravius et al, 2005).…”

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

“…Importantly, at the behavioral level, antagonists of the mGluR5 have been found to potentiate the effects of NMDA receptor antagonists in several tests including prepulse inhibition (PPI) of the startle response, locomotor activity, memory tasks, and unilateral 6-OHDA-lesion model (Henry et al, 2002;Homayoun et al, 2004;Kinney et al, 2002;Turle-Lorenzo et al, 2005). Moreover, mGluR5 antagonists have been shown to mimic some behavioral effects of NMDA receptor antagonists such as an impairment of working memory (Manahan-Vaughan and Braunewell, 2005;Homayoun et al, 2004), attenuation of the development of tolerance to morphine-induced antinociception (Kozela et al, 2003), as well as anxiolytic (Busse et al, 2004;Spooren et al, 2000), antiparkinsonian (Ossowska et al, 2001;Turle-Lorenzo et al, 2005), and antidepressant (Tatarczynska et al, 2001) actions. On the basis of the above considerations, we hypothesized that pharmacological inhibition of the mGlu5 receptor, similar to NMDA receptor blockade, might also evoke schizophrenialike symptoms.…”