New Target for Treatment of Schizophrenia
Although today’s antipsychotic medications provide effective relief from some of the symptoms of schizophrenia, not all symptoms are improved, and most patients suffer significant drug-related side effects. In the search for better drugs, recent attention has focused on the M4muscarinic acetylcholine receptordue to its ability to suppress excessive dopamine signaling in the striatum, a key contributor to schizophrenia pathogenesis. Highly selective M4positive allosteric modulators (PAMs) are impressive in their ability to combat symptoms of psychosis in animal models, and a dual agonist of M4and M1has yielded promising results in early clinical trials. However, M4PAMs also suppress signaling via the D1dopamine receptor in key targeted striatal neurons, leading to concerns that this approach could lead to unwanted side effects. These concerns led Vanderbilt University Basic Sciences investigators Jeff Conn, Craig Lindsley, and Carrie Jones to search for a better option. Their search began with the realization that M4agonists trigger the release of the endocannabinoid 2-arachidonoylglyerol (2-AG) by target neurons. It is 2-AG, acting at CB2receptors, that suppresses dopamine release in neighboring neurons. M4, however, is coupled to the Gαq/11G protein, whereas 2-AG release usually requires signaling by Gαi/o. This led the researchers to hypothesize that M4stimulates 2-AG release by activating an intermediate receptor, and they quickly focused on the mGlu1or mGlu5metabotropic glutamate receptors, which were highly expressed in target neurons and signal via Gαi/o. To test their hypothesis, the researchers first showed that M4-mediated suppression of dopamine release in mouse brain slices was blocked by a negative allosteric modulator (NAM) of mGlu1but not mGlu5. In two animal models of schizophrenia, an M4PAM blocked symptoms, and the effects of the M4PAM were reversed by an mGlu1NAM. These results suggested that M4-mediated suppression of dopamine release required the activity of mGlu1receptors. Consistently, an mGlu1PAM directly suppressed dopamine release in mouse brain slices, and it was effective against schizophrenia-like symptoms in the two animal models tested. Importantly, the mGlu1PAM had no effect on D1dopamine receptor signaling, and unlike both M4PAMs and classical antipsychotic drugs, it did not suppress motivation in an animal model. These findings validate mGlu1as a promising target for the treatment of schizophrenia. It appears to both mediate the effects of M4agonists and to act on its own to suppress dopamine signaling in the striatum. Most importantly, mGlu1activation is not associated with known side effects of M4agonists or classical antipsychotic drugs. Thus, mGlu1agonists promise to be a major stride forward in the search for better antipsychotic medications. The work is published in Molecular Psychiatry [S. E. Yohn, et al. Mol. Psychiatry, (2018) published online Aug. 16, DOI: 10.1038/s41380-018-0206-2].