Role of interaction of mGlu2 and 5-HT2A receptors in antipsychotic effects

Abstract

The serotonergic and glutamatergic neurotransmitter systems have been implicated in the pathophysiology of schizophrenia, and increasing evidence shows that they interact functionally. Of note, the G_q/11-coupled serotonin 5-HT_2A (5-HT_2A) and the G_i/o-coupled metabotropic glutamate type 2 (mGlu2) receptors have been demonstrated to assemble into a functional heteromeric complex that modulates the function of each individual receptor.

For conformation of the heteromeric complex, corresponding transmembrane-4 segment of 5-HT_2A and mGlu2 are required. The 5-HT_2A/mGlu2 heteromeric complex is necessary for the activation of G_q/11 proteins and for the subsequent increase in the levels of the intracellular messenger Ca²⁺. Furthermore, signaling via the heteromeric complex is dysregulated in the post-mortem brains of patients with schizophrenia, and could be linked to altered cortical function. From a behavioral perspective, this complex contributes to the hallucinatory and antipsychotic behaviors associated with 5-HT_2A and mGlu2/3 agonists, respectively. Synaptic and epigenetic mechanisms have also been found to be significantly associated with the mGlu2/5-HT_2A heteromeric complex. This review summarizes the role of crosstalk between mGlu2 and 5-HT_2A in the mechanism of antipsychotic effects and introduces recent key advancements on this topic.