Repeated Clozapine Increases the Level of Serotonin 5-HT(1A)R Heterodimerization with 5-HT(2A) or Dopamine D(2) Receptors in the Mouse Cortex

G-protein–coupled receptor (GPCR) heterodimers are new targets for the treatment of schizophrenia. Dopamine D(2) receptors and serotonin 5-HT(1A) and 5-HT(2A) receptors play an important role in neurotransmission and have been implicated in many human psychiatric disorders, including schizophrenia. Therefore, in this study, we investigated whether antipsychotic drugs (clozapine (CLZ) and haloperidol (HAL)) affected the formation of heterodimers of D(2)–5-HT(1A) receptors as well as 5-HT(1A)–5-HT(2A) receptors. Proximity ligation assay (PLA) was used to accurately visualize, for the first time, GPCR heterodimers both at in vitro and ex vivo levels. In line with our previous behavioral studies, we used ketamine to induce cognitive deficits in mice. Our study confirmed the co-localization of D(2)/5-HT(1A) and 5-HT(1A)/5-HT(2A) receptors in the mouse cortex. Low-dose CLZ (0.3 mg/kg) administered repeatedly, but not CLZ at 1 mg/kg, increased the level of D(2)–5-HT(1A) and 5-HT(1A)–5-HT(2A) heterodimers in the mouse prefrontal and frontal cortex. On the other hand, HAL decreased the level of GPCR heterodimers. Ketamine affected the formation of 5-HT(1A)–5-HT(2A), but not D(2)–5-HT(1A), heterodimers.