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

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.