Hcrtr1, also known as OX1R, is a G-protein-coupled receptor. The endogenous ligands for Hcrtr1 are the neuropeptides hypocretin-1/orexin-A. Hcrtr1 is associated with the regulation of motivation, reward, and autonomic functions. It is part of the hypocretin/orexin system, which is crucial for the endogenous sleep-wake regulatory circuitry [1].

Genetic and pharmacological inhibition studies in mice have provided insights into Hcrtr1's role. Hcrtr1 null mice showed a significant reduction in behavioral despair in the forced swim test and tail suspension test, similar to wild-type mice treated with the Hcrtr1 antagonist SB-334867, suggesting an anti-depressant-like effect [4]. In addition, the HCRTR1 gene variant (rs2271933 G > A) has been associated with aggressive behavior, with A/A homozygotes reporting higher aggression in both self-report and interview measures, and being more likely to breach the law [2]. Also, in the context of depression, excessive hypocretin-1 acting on HCRTR1 impairs adult hippocampal neuroplasticity and cognitive function through reducing lactate production and BDNF expression, and HCRTR1 antagonists can reverse these changes [3].

In summary, Hcrtr1 plays a significant role in regulating behaviors such as motivation, reward, aggression, and depression-like behaviors. The use of Hcrtr1 knockout mouse models and pharmacological inhibition has revealed its functions in these biological processes, contributing to our understanding of related diseases like depression and aggression-related disorders [2,3,4].