Repeated Clozapine Increases the Level of Serotonin 5-HT1A R Heterodimerization with 5-HT2A or Dopamine D2 Receptors in the Mouse Cortex

Frontiers in Molecular Neuroscience
Marta SzlachtaAgata Faron-Górecka

Abstract

G-protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of schizophrenia. Dopamine D2 receptors and serotonin 5-HT1A and 5-HT2A 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 D2-5-HT1A receptors as well as 5-HT1A-5-HT2A 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 D2/5-HT1A and 5-HT1A/5-HT2A 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 D2-5-HT1A and 5-HT1A-5-HT2A 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-HT1A-5-HT2A, but not D2-5-HT1A, heterodimers.

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Citations

Aug 21, 2019·European Archives of Psychiatry and Clinical Neuroscience·Parita ShahAriel Graff-Guerrero
Sep 2, 2020·Pflügers Archiv : European journal of physiology·Motoshi OkumuraKei Sonoyama
Jan 21, 2020·Neuropharmacology·Philippe De DeurwaerdèreGiuseppe Di Giovanni
Nov 5, 2019·Progress in Neuro-psychopharmacology & Biological Psychiatry·Jefferson P GalvanhoYael Abreu-Villaça
Mar 23, 2021·Pharmacology & Therapeutics·Katarzyna MlyniecGabriel Nowak
Apr 10, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Desye Misganaw
Jan 28, 2019·Biochimie·Luc MaroteauxAnne Roumier

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Methods Mentioned

BETA
fluorescence resonance
proximity ligation assay
Assay
fluorescence microscopy
PLA
sedation
FRET

Software Mentioned

microscope
ImageGauge

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