Role of interaction of mGlu2 and 5-HT 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-coupled serotonin 5-HT (5-HT) and the G-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 and mGlu2 are required. The 5-HT/mGlu2 heteromeric complex is necessary for the activation of G proteins and for the subsequent increase in the levels of the intracellular messenger Ca. 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 and mGlu2/3 agonists, respectively. Synaptic and epigenetic mechanisms have also been found to be significantly associated with the mGlu2/5-HT heteromeric complex. This review summarizes the role of crosstalk between mGlu2 and 5-HT in the mechanism of antipsychotic effects and introduces recent key advancements on this topic.

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