P.1.006 - Chronic administration of clozapine increases the level of serotonin 5-HT1A receptor heterodimerisation with 5-HT2A or D2 receptors in the mouse cortex

Abstract

Background and Aims It is well established that dopamine D2 receptors and serotonin 5-HT1A and 5-HT2A receptors play an important role in neurotransmission and that alterations in their functioning are implicated in many psychiatric disorders, including schizophrenia. Only since the 1990s has there emerged an appreciation of the effects of atypical antipsychotic medications, which can be beneficial for the negative (cognitive) symptoms via combined action at dopamine as well as serotonin and other classes of neuroreceptors [1]. In recent years, various lines of evidence have revealed the formation of physiologically active GPCR heteromers in the plasma membrane [2,3]. GPCR heteromers offer a novel set of drug targets because the functional association of heteroreceptors, which are partners in the complex, can result in pharmacological and functional properties distinct from those of the monomers (and homomers). Clozapine (CLZ), an antipsychotic drug currently used in the clinic but still being the object of basic studies designed to search for its unique molecular features, has been also shown to act via various heterodimers [4]. Therefore, in the present study, we investigated whether atypical antipsychotic drug, CLZ, and typical drug, haloperidol (HAL), administered to mice acutely or repeatedly affected the formation of heterodimers of dopamine D2–5-HT1A receptors as well as 5-HT1A–5-HT2A receptors in the mouse brain cortex. Materials and Methods Mice C57Bl/6J were treated CLZ in two doses; however, HAL was administered in one dose. In line with our previous behavioral studies, we used ketamine to induce cognitive deficits in mice [5]. To visualize co-localization D2–5-HT1A receptors and 5-HT1A–5-HT2A receptors in the mouse brain immunohistochemistry was used. Proximity ligation assay (PLA) was used to accurately visualize, for the first time, GPCR heterodimers in the native tissue. Data were analyzed using two-way analysis of variance (ANOVA) with Bonferroni post-test to compare all groups of the experiments. Results Our study confirmed the co-localization of D2–5-HT1A and 5-HT1A–5-HT2A receptors in the mouse brain cortex. Low-dose clozapine (0.3 mg/kg) administered repeatedly increased the level of D2–5-HT1A heterodimers in the mouse prefrontal and frontal cortex ([F(2,22)] = 4.630; p Conclusion Our results provide interesting evidence that antipsychotic drugs have effect on the level of D2–5-HT1A as well as 5-HT1A–5-HT2A receptors heterodimerization, which may represent a novel, interesting therapeutic target for many psychiatric disorders.