{Reference Type}: Journal Article
{Title}: Hypocretin-1 receptor antagonism improves inhibitory control during the Go/No-Go task in highly motivated, impulsive male mice.
{Author}: Metha J;Ji Y;Braun C;Nicholson JR;De Lecea L;Murawski C;Hoyer D;Jacobson LH;
{Journal}: Psychopharmacology (Berl)
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 18
{Factor}: 4.415
{DOI}: 10.1007/s00213-024-06628-3
{Abstract}: <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.