Sex difference in dopamine D1-D2 receptor complex expression and signaling affects depression- and anxiety-like behaviors

Ahmed Hasbi,Susan R George,Haneen Rahal,Melissa L Perreault,Joshua D Manduca,Sharon Miksys,Bertha K Madras,Rachel F Tyndale,Tuan Nguyen

doi:10.1186/s13293-020-00285-9

Abstract

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/β-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.

Highlights

The World Health Organization [1] estimated that globally, the total number of people with depression exceeded 300 million in 2015, representing ~ 4.4% of the global population
Co-immunoprecipitation and Western blot (WB) D1-D2 heteromer was immunoprecipitated by a specific D2 receptor (D2R) antibody followed by WB using a specific D1 receptor (D1R) antibody as described [14, 19]
D2R expression (Fig. 1c, d right panel) was not different between male and female rats in either region (t test, NAc: t = 0.35, p = 0.736; CPu: t = 0.67, p = 0.52). This showed that female rats expressed a higher amount of D1-D2 heteromer in NAc and CPu and lower D1R in NAc than males, with no sex difference in D2R expression

Summary

Introduction

The World Health Organization [1] estimated that globally, the total number of people with depression exceeded 300 million in 2015, representing ~ 4.4% of the global population. Depressive disorders are the single largest contributor to disease-related disabilities and the major contributor to suicides [1]. Depression is more common among females (5.1%) than males (3.6%) [1] and the leading cause of disease-related disability in women (reviewed, [2, 3]). Sex differences in animal model systems and humans were shown in the few studies that took this into consideration, this aspect has been largely ignored in most preclinical studies [9,10,11] as it is easier and cheaper to use only males [10, 11].

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Results

Conclusion