Hcrtr1, also known as OX1R, is a G-protein-coupled receptor. It is the receptor for the neuropeptides hypocretin-1/orexin-A. Hcrtr1 is involved in multiple physiological processes, including the regulation of motivation, reward, and autonomic functions. It is part of the hypocretin/orexin system which is crucial for the regulation of the sleep-wake cycle and is implicated in the etiology of narcolepsy [1].

In genetic models, Hcrtr1 null mice showed a significant reduction in behavioral despair in the forced swim test and tail suspension test, suggesting its role in modulating depression-like behaviors [4]. In addition, an Hcrtr1 gene variant (rs2271933 G > A) was associated with aggressive behavior, higher reward sensitivity in males, and different responses to stressful life events in a gender-dependent manner [2,5]. In a high-fat diet-induced depression-like phenotype in rats, the Hcrtr1 antagonist SB334867 could reverse adverse effects on body weight, depressive-like behavior, and anxiety-like mood, indicating Hcrtr1's involvement in the link between high-fat diet and emotional dysfunctions [3]. Also, in sheep, the C589T locus of Hcrtr1 was associated with seasonal reproduction and litter size [6].

In summary, Hcrtr1 plays important roles in regulating behaviors such as aggression, reward-seeking, and depression-like behaviors. Its involvement in diet-related emotional dysfunctions and in the reproductive traits of sheep has also been demonstrated. The use of gene knockout mouse models and genetic variant studies has provided valuable insights into its functions in these biological processes and disease-related conditions.

References:

1. Sun, Yu, Tisdale, Ryan K, Kilduff, Thomas S. 2021. Hypocretin/Orexin Receptor Pharmacology and Sleep Phases. In Frontiers of neurology and neuroscience, 45, 22-37. doi:10.1159/000514963. https://pubmed.ncbi.nlm.nih.gov/34052813/

2. Harro, Jaanus, Laas, Kariina, Eensoo, Diva, Mäestu, Jarek, Veidebaum, Toomas. 2019. Orexin/hypocretin receptor gene (HCRTR1) variation is associated with aggressive behaviour. In Neuropharmacology, 156, 107527. doi:10.1016/j.neuropharm.2019.02.009. https://pubmed.ncbi.nlm.nih.gov/30742846/

3. Dong, Jingyi, Zhang, Jinghui, Cheng, Shangping, Zhang, Yuyan, Lu, Jing. 2024. A high-fat diet induced depression-like phenotype via hypocretin-HCRTR1 mediated inflammation activation. In Food & function, 15, 8661-8673. doi:10.1039/d4fo00210e. https://pubmed.ncbi.nlm.nih.gov/39056112/

4. Scott, Michael M, Marcus, Jacob N, Pettersen, Ami, Elmquist, Joel K, Lutter, Michael. 2011. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. In Behavioural brain research, 222, 289-94. doi:10.1016/j.bbr.2011.02.044. https://pubmed.ncbi.nlm.nih.gov/21377495/

5. Pulver, Aleksander, Kiive, Evelyn, Kanarik, Margus, Harro, Jaanus. 2020. Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender. In Brain research, 1746, 147013. doi:10.1016/j.brainres.2020.147013. https://pubmed.ncbi.nlm.nih.gov/32652147/

6. Zhu, Mengting, Zhang, Hongmei, Yang, Hua, Fang, Chenhui, Xie, Mengting. 2022. Polymorphisms and association of GRM1, GNAQ and HCRTR1 genes with seasonal reproduction and litter size in three sheep breeds. In Reproduction in domestic animals = Zuchthygiene, 57, 532-540. doi:10.1111/rda.14091. https://pubmed.ncbi.nlm.nih.gov/35104000/