Psychotic symptoms of schizophrenia are associated with hyperactive dopaminergic signaling in striatal and mesocortical pathways. Currently available treatments for schizophrenia are often effective in ameliorating psychotic symptoms but induce adverse parkinsonian-like effects that limit their long-term utility. Given the shortcomings of current antipsychotics, novel therapeutic approaches are needed that exhibit clinical efficacy with reduced adverse effect liability. Activation of the muscarinic M4 receptor has previously been demonstrated to have antipsychotic-like efficacy in several preclinical models. Recently the Conn laboratory reported that these antipsychotic effects are mediated through a novel wherein activation of M4 receptors reduces dopamine release through a CB2 cannabinoid-dependent mechanism. We present new data suggesting that metabotropic glutamate 1 receptor (mGlu1) plays a critical role in mediating these M4-dependent dopaminergic effects. A key role for mGlu1 in regulating DA release could provide important new insights into mechanisms by which loss of mGlu1 signaling could contribute to symptoms observed in schizophrenia patients. Interestingly, substantial preclinical and clinical evidence has implicated mGlu1 in the pathophysiology of schizophrenia and non-synonymous single nucleotide polymorphisms (nsSNPs) of GRM1 (the gene that encodes mGlu1) are enriched in schizophrenic populations. Through use of both ex vivo and in vivo fast-scan cyclic voltammetry (FSCV), application of a mGlu1 positive allosteric modulator (PAM) reduces striatal DA release and possesses antipsychotic-like efficacy in rodent models of schizophrenia, suggesting that mGlu1 selective compounds may alleviate the positive symptoms of schizophrenia. Through an integrated approach of electrophysiological and behavioral studies, Samantha hopes to determine the mechanism whereby mGluR activation alters striatal dopamine (DA) signaling and ultimately exerts antipsychotic-like effects. Developing an understanding of these mechanisms will provide insights into signaling pathways with the potential to mediate antipsychotic efficacy and will assist a drug discovery efforts aimed at developing novel treatments for schizophrenia.
Research Fellow, Conn Lab