Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat. Relevance for anxiolytic actions

Juan Carlos Hernández-Mondragón; Dexter A Hernández-Hernández; Minerva Crespo-Ramírez; Oscar Prospero-García; Luisa Rocha-Arrieta; Kjell Fuxe; Dasiel O Borroto-Escuela; Miguel Perez de la Mora

doi:10.3389/fphar.2023.1251922

Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat. Relevance for anxiolytic actions

Front Pharmacol. 2023 Oct 12:14:1251922. doi: 10.3389/fphar.2023.1251922. eCollection 2023.

Authors

Juan Carlos Hernández-Mondragón¹, Dexter A Hernández-Hernández¹, Minerva Crespo-Ramírez¹, Oscar Prospero-García², Luisa Rocha-Arrieta³, Kjell Fuxe⁴, Dasiel O Borroto-Escuela^{4

5}, Miguel Perez de la Mora¹

Affiliations

¹ Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.
² Laboratorio de Cannabinoides, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
³ Department of Pharmacobiology, Centro de Investigación y Estudios Avanzados (CINVESTAV, Sede Sur), Mexico City, Mexico.
⁴ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Receptomics and Brain Disorders Lab, Department of Human Physiology, Faculty of Medicine, University of Malaga, Málaga, Spain.

Abstract

Introduction: The amygdala is a limbic region of high value for understanding anxiety and its treatment. Dopamine D2 receptors (D2Rs) and oxytocin receptors (OXTRs) have both been shown to participate in modulating anxiety involving effects in the amygdala. The goal is to understand if D2R-OXTR heterocomplexes exist in the central amygdala and if, through enhancing allosteric receptor-receptor interactions, may enhance anxiolytic actions. Methods: The methods used involve the shock-probe burying test, the in situ proximity ligation assay (PLA), image acquisition and analysis, and the BRET2 assay. Bilateral cannulas were introduced into the amygdala, and the effects of the coadministration of oxytocin and the D2R-like agonist quinpirole into the amygdala were studied. Results: The combination treatment enhanced the anxiolytic effects compared to the single treatment. The D2R/D3R antagonist raclopride blocked the effects of the combination treatment of oxytocin and the D2R agonist, although oxytocin is regarded as a distinct modulator of fear-mediating anxiolytic effects. In situ PLA results indicate the existence of D2R-OXTR heteroreceptor complexes and/or the co-location of OXTR and D2R within the same cell membrane nanodomains in the central amygdala. With BRET2, evidence is given for the existence of D2R-OXTR heteromers in HEK293 cells upon co-transfection. Discussion: The enhanced behavioral effects observed upon co-treatment with OXTR and D2R agonists may reflect the existence of improved positive receptor-receptor interactions in the putative D2R-OXTR heterocomplexes in certain neuronal populations of the basolateral and central amygdala. The D2R-OXTR heterocomplex, especially upon agonist co-activation in the central amygdala, may open a new pharmacological venue for the treatment of anxiety.

Keywords: G protein-coupled receptors; amygdala; anxiety; dopamine D2 receptor; heteroreceptor complexes; oligomerization; oxytocin receptor.

Grants and funding

JC-HM conducted this study to fulfill the requirements of Programa de Doctorado en Ciencias Biomédicas of Universidad Nacional Autónoma de México and received a doctoral scholarship from Consejo Nacional de Humanidades Ciencias y Tecnologías (647051). This work has been partially supported by grants IN206820 (MPM) and IN217221 (OP-G) from Dirección General del Personal Acadéemico (DGAPA) Universidad Nacional Autónoma de México (UNAM); supported by Stiftelsen Olle Engkvist Byggmästare 2018 and 2021 to KF and DB-E; by Hjärnfonden (F02018-0286), Hjärnfonden (F02019-0296), and Karolinska Institutet Forskningsstiftelser; and also from EMERGIA 2020-39318 (Plan Andaluz de Investigación, Desarrollo e Innovación 2020) and CONSOLIDACION INVESTIGADORA (CNS2022-136008, Programa Estatal para Desarrollar, Atraer y Retener Talento, del Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023) to DB-E.