Metabotropic glutamate receptors as therapeutic targets for schizophrenia

Abstract

Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu2 and mGlu3) and the group I mGlu5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu2 and mGlu3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor’s response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu2 and mGlu5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…Within the striatum and nucleus accumbens, D 2 receptors are abundant and patients with schizophrenia have increased D 2 receptor densities as well as heightened amphetamine sensitivity (Seeman 1987;Seeman 2006;Vinson and Conn 2012). Increased dopamine resulting from hyperactivity of the mesolimbic system is thought to underlie the positive symptoms (e.g.…”

“…However, the negative and cognitive symptoms of schizophrenia are unresponsive to D 2 receptor antagonists (Vinson and Conn 2012). The dopamine hypothesis was later extended to include dysfunction of the mesocortical pathway as the mechanism underlying the negative and cognitive symptoms (Laruelle 2014).…”

“…When NMDA receptor function is reduced, depolarization of interneurons is impeded, resulting in impaired GABAergic inhibition. This disinhibition increases the glutamatergic excitatory firing in the PFC (Moghaddam et al 1997;Vinson and Conn 2012). NMDA receptor dysfunction may also have secondary effects on the dopamine system.…”

“…This is because the effect of NMDA receptor antagonists on GABAergic interneurons impairs the inhibition of these neurons on thalamic glutamatergic neurons. Glutamatergic neurons then project to PFC pyramidal neurons and increase the excitatory firing in the PFC (Moghaddam et al 1997;Vinson and Conn 2012 (Lewis et al 2005). These PV+ interneurons may be particularly vulnerable to glutamate dysfunction for several reasons (Lewis and Moghaddam 2006).…”

Altered object exploration but not temporal order memory retrieval in an object recognition test following treatment of rats with the group II metabotropic glutamate receptor agonist LY379268

“…Changes in dopamine and serotonin efflux in the mPFC of freely moving rats have also been reported following systemic administration of group II mGluR agonists [16,[18][19][20]. Thus, group II mGluRs may play a role in regulating cortical neurochemical activity during cognitive tasks such as recognition memory and could serve as novel therapeutic targets for improving the temporal memory deficits in schizophrenia and Alzheimer's disease [15,21]. This hypothesis is supported by data showing that group I and II metabotropic glutamate receptor antagonists administered together impair the acquisition of object memory in a test without a temporal component [22].…”