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

Abstract

Depression and anxiety are more common among females than males and represent a leading cause of diseaserelated 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.

Sex differences in innate and adaptive neural oscillatory patterns link resilience and susceptibility to chronic stress in rats

“…We performed testing in the elevated plus maze as previously described. 43 Animals were placed in the centre square of the maze (head facing an open arm) and allowed to explore for 10 minutes. We recorded behaviour using ANY-maze software (Stoelting Co.), and we measured the number of open- and closed-arm entries and the total time spent in the open and closed arms.…”

Expression of cannabinoid CB1R–GPR55 heteromers in neuronal subtypes of the Macaca fascicularis striatum

“…The model was also challenged by the discovery of projecting neurons containing both D 1 and D 2 receptors that may interact to form D 1 –D 2 receptor heteromers in rodents and primates 35–37 . Differential expression of these heteromers, depending on the gender, results in significant changes in protein kinase B/glycogen synthase kinase 3/β‐catenin and brain‐derived neurotrophic factor/tyrosine receptor kinase B signaling pathways, making female more predisposed than male rats to anxiety and depression‐like behavior 38 . As one might expect, the BG motor control circuitry is more complex in primates than in rodents.…”

Dopamine in Health and Disease: Much More Than a Neurotransmitter

“…A physiological role of D 1 –D 2 receptor heteromers was demonstrated in the healthy brain, and a pathophysiological one in models of addiction [ 11 , 28 , 29 , 30 ]. In addition, the same laboratory has reported that expression differences depending on the sex affect anxiety- and depression-like neuropsychiatric diseases [ 31 ].…”