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Hypothalamic hypocretin (orexin) neurons provide afferent inputs to DA and NA nuclei and hypocretin-1 receptors (HcrtR1) are implicated in reward and addiction. However, the role of the HcrtR1 in inhibitory control is not well understood.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Objectives<\/jats:title>\n                <jats:p>To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go\/no-go task in mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p><jats:italic>n<\/jats:italic>\u2009=\u200923 male C57Bl\/6JArc mice were trained in a go\/no-go task. Decision tree dendrogram analysis of training data identified more and less impulsive clusters of animals. A HcrtR1 antagonist (BI001, 12.5\u00a0mg\/kg, <jats:italic>per os<\/jats:italic>) or vehicle were then administered 30\u00a0min before go\/no-go testing, once daily for 5 days, under high (food-restricted) and low (free-feeding) motivational states in a latin-square crossover design. Compound exposure levels were assessed in a satellite group of animals.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>HcrtR1 antagonism <jats:italic>increased<\/jats:italic> go accuracy and <jats:italic>decreased<\/jats:italic> no-go accuracy in free-feeding animals overall, whereas it <jats:italic>decreased<\/jats:italic> go accuracy and <jats:italic>increased<\/jats:italic> no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was <jats:italic>increased<\/jats:italic> in response to the antagonist in free-feeding, less impulsive animals, and <jats:italic>decreased<\/jats:italic> in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~\u200966% during the task.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These data indicate that hypocretin signalling plays roles in goal-directed behaviour and inhibitory control in a motivational state-dependant manner. While likely not useful in all settings, HcrtR1 antagonism may be beneficial in improving inhibitory control in impulsive subpopulations.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00213-024-06628-3","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T02:01:23Z","timestamp":1718676083000},"page":"2171-2187","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypocretin-1 receptor antagonism improves inhibitory control during the Go\/No-Go task in highly motivated, impulsive male mice"],"prefix":"10.1007","volume":"241","author":[{"given":"Jeremy","family":"Metha","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijun","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Braun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet R.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"De Lecea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carsten","family":"Murawski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Hoyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2910-8659","authenticated-orcid":false,"given":"Laura H.","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"6628_CR1","unstructured":"Allaire J (2012) RStudio: integrated development environment for R. 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