5-HT_2A receptor-mediated Gα_q/11 activation in psychiatric disorders: A postmortem study

Abstract

Objectives

Serotonin-2A (5-HT_2A) receptors play an important role in the regulation of many brain functions that are disturbed in patients with such psychiatric diseases as mood disorders and schizophrenia. The objective of this study was to evaluate 5-HT_2A receptor-mediated signalling pathway through Gα_q/11 activation in psychiatric patients by using post-mortem brain samples.

Methods

Functional activation of Gα_q/11 proteins coupled to 5-HT_2A receptors was determined by means of [³⁵S]GTPγS binding/immunoprecipitation assay in post-mortem prefrontal cortex of psychiatric patients diagnosed as bipolar disorder (BP), major depressive disorder (MDD), and schizophrenia, and individually matched controls. The effects of antipsychotic treatment as well as suicide were also analysed.

Results

There was no significant difference in maximum percent increase (%E_max) or slope factor among the four groups. The negative logarithm of concentration eliciting the half-maximal effect (pEC₅₀) was significantly reduced in BP and schizophrenia patients as compared to controls. These alterations were attributable to antipsychotic medication. The pEC₅₀ values in ‘non-suicide’ group of schizophrenia, but not in ‘suicide’ group, were significantly reduced as compared with controls.

Conclusions

Altered 5-HT_2A receptor-mediated signalling pathway through Gα_q/11 proteins in prefrontal cortex might be apparently involved in pathophysiology and pharmacotherapy of BP and schizophrenia. In schizophrenic patients, these alterations as a result of successful treatment with antipsychotic agents may help in prevention of suicidal behaviour.

Keywords:

• 5-HT_2A receptor
• G-protein
• bipolar disorder
• major depressive disorder
• schizophrenia

Acknowledgements

The authors thank the collaboration of the staff members of the Basque Institute of Legal Medicine.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

The research was financially supported by the Saitama Medical University Internal Grant [18-B-1-03] to Y.O., the Spanish MINECO-FEDER [SAF 2017‐88,126 R, SAF 2013‐48,586‐R and 2011‐29918 to J.J.M., L.F.C. and J.A.G‐S., respectively] and the Basque Government [IT-1211-19].