Effects of mGlu1 and mGlu5 receptor antagonists on negatively reinforced learning

Abstract

Effects on aversive learning of the novel highly selective mGlu5 receptor antagonist [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and mGlu1 receptor antagonist (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) were tested, after systemic administration, in the passive avoidance (PA) and fear potentiated startle (FPS) paradigms. Both MTEP at 10 mg/kg and EMQMCM at 5 and 10 mg/kg, given 30 min before training, impaired acquisition of the passive avoidance response (PAR). Co-administration of MTEP and EMQMCM at doses ineffective when administered alone, produced anterograde amnesia when given 30 min before the acquisition phase. Neither EMQMCM (5 mg/kg) nor MTEP (10 mg/kg) impaired retention of the PAR after direct post-training injections. EMQMCM (5 mg/kg), but not MTEP (10 mg/kg) blocked the PAR when given 30 min before testing. Pre-training administration of MTEP at doses of 2.5 and 5 mg/kg inhibited fear conditioning in the FPS when tested 24 h later. In contrast, EMQMCM was ineffective. Our findings suggest diverse involvement of mGlu1 and mGlu5 receptors in negatively reinforced learning.

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). In particular, the mGlu 5 NAM fenobam (McN-3377) demonstrated anxiolyticlike effects in rodents and humans yet also induced psychotomimetic-like effects in humans (Friedmann et al, 1980;Pecknold et al, 1982;Porter et al, 2005).…”

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

“…However, to our knowledge, none of the studies in the literature investigated the possible therapeutic potentials of mGluR5 antagonists in the treatment of the cognitive symptoms of the disease. It is worth noting in this regard, that experimental findings using pharmacological approaches or mGluR5 KO mice demonstrate an involvement of mGluR5 in neural plasticity, as well as in learning and memory processes (Ballard et al, 2005;Campbell et al, 2004;Gravius et al, 2005;Gubellini et al, 2003;Homayoun et al, 2004;Lu et al, 1997;ManahanVaughan and Braunewell, 2005;Simonyi et al, 2005), suggesting that mGluR5 blockade could impair learning and memory in intact animals. Nevertheless, glutamate overactivity as a consequence of striatal DA depletion, might have a causal role in the cognitive deficits of Parkinson's patients; in addition to motor dysfunction.…”

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

“…The probability of a complete absence of adverse effects, however, does not seem to be very high because, as implied by the evidence compiled in this chapter, the implications of mGluR ligands toxicity are many and far-reaching. mGluR1 selective antagonists showed efficacy in rodent models of anxiety, however, these compounds were associated with memory impairment that interrupted further development (Steckler et al, 2005a,b;Gravius et al, 2005). On the other hand, mGluR5 selective antagonists, which also has anxiolytic efficacy did not cause impairment in memory (Steckler et al, 2005a;Gravius et al, 2005).…”

“…mGluR1 selective antagonists showed efficacy in rodent models of anxiety, however, these compounds were associated with memory impairment that interrupted further development (Steckler et al, 2005a,b;Gravius et al, 2005). On the other hand, mGluR5 selective antagonists, which also has anxiolytic efficacy did not cause impairment in memory (Steckler et al, 2005a;Gravius et al, 2005). As reported (Mezler et al 2010;Chaki et al 2010;Patil et al 2007), the latest developed allosteric group II mGluR agonists have efficacy in preclinical models of psychosis and anxiety, without involving any of the most frequent side effects associated with typical and atypical antipsychotics.…”