Abstract
G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B.
Highlights
Mood alterations due to pharmacological treatments that modulate serotonergic and noradrenergic systems laid the foundations for the monoamine hypothesis that has led research on mood disorders since the late 1950s [1,2,3]
Since GPR3 has been shown to modulate cAMP levels in brain regions which can contribute to stress-related behaviors [129], a line of GPR3 knock out (KO) mice was developed to study its potential role in mood disorders [67]
Because of their profound effects, GCs have been used for pharmacotherapies; GC treatments lead to a multitude of changes: (1) an increased risk of developing stress-related behavioral problems; (2) exposure to high levels of GCs results in gene expression changes that persist through adulthood [185]
Summary
Mood alterations due to pharmacological treatments that modulate serotonergic and noradrenergic systems laid the foundations for the monoamine hypothesis that has led research on mood disorders since the late 1950s [1,2,3]. Morphological studies in animal models, together with neuroimaging in MDD patients, demonstrated that stress-induced depression is associated with the atrophy of important limbic and cortical brain regions, characterized by the reduction in dendritic arborization, the number of spines, and functional responses [6,7,8,9,10,11,12]; increased and sustained amygdala activity, the brain region responsible for the processing of emotions, was demonstrated, suggesting an altered connectivity among all of these brain areas [7,13,14,15] Many of these regions express high levels of glucocorticoid receptors and are regulated by the HPA axis through the action of stress hormones on transcriptional programs [16,17]. This systems biology approach helped revealing the involvement of many oGPCRs in the neurobiology of affective disorders, uncovering alternative potential therapeutic targets
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