%0 Journal Article
%T Hypocretin-1 receptor antagonism improves inhibitory control during the Go/No-Go task in highly motivated, impulsive male mice.
%A Metha J
%A Ji Y
%A Braun C
%A Nicholson JR
%A De Lecea L
%A Murawski C
%A Hoyer D
%A Jacobson LH
%J Psychopharmacology (Berl)
%V 0
%N 0
%D 2024 Jun 18
%M 38886189
%F 4.415
%R 10.1007/s00213-024-06628-3
%X <B>BACKGROUND: </B>Motivation and inhibitory control are dominantly regulated by the dopaminergic (DA) and noradrenergic (NA) systems, respectively. 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.<BR><B>OBJECTIVE: </B>To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go/no-go task in mice.<BR><B>METHODS: </B>n = 23 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 mg/kg, per os) or vehicle were then administered 30 min 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.<BR><B>RESULTS: </B>HcrtR1 antagonism increased go accuracy and decreased no-go accuracy in free-feeding animals overall, whereas it decreased go accuracy and increased no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was increased in response to the antagonist in free-feeding, less impulsive animals, and decreased in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~ 66% during the task.<BR><B>CONCLUSIONS: </B>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.