Atypical antipsychotics and inverse agonism at 5-HT₂ receptors

It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or “constitutive” receptor activity. Both the serotonin 5-HT_2A and 5-HT_2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for the treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have inverse agonist properties at both 5-HT_2A and 5-HT_2C receptors. This paper describes our current knowledge of inverse agonism of atypical antipsychotics at 5-HT_2A/2C receptor subtypes in vitro and in vivo. Exploiting inverse agonist properties of antipsychotic drugs may provide new avenues for drug development.