Abstract
Most psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.
Highlights
Most psychiatric disorders are characterized by deficits in the ability to interact socially with others
Dopamine cells within the ventral tegmental area (VTA) contain receptors for, and respond to, peptides associated with social motivation including oxytocin, galanin, and neurotensin, and the neurons that produce these peptides are located in hypothalamic regions that express growth hormone secretagogue receptor (GHSR), providing another route through which ghrelin may influence social behavior[15,20,21,22,23,24,25]
The most notable finding from our experiments is that the GHSR, and GHSR in the VTA, is important for behaviors linked to social motivation
Summary
Most psychiatric disorders are characterized by deficits in the ability to interact socially with others. Mice receiving chronic infusions of the ghrelin receptor antagonist JMV2959 for 4 weeks show longer latencies to approach unfamiliar mice[14], highlighting the importance of GHSR signaling in modulating social interactions, as increased latencies could suggest decreased motivation to interact with a conspecific.
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