TY - JOUR T1 - The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task JF - bioRxiv DO - 10.1101/467308 SP - 467308 AU - Joost Wiskerke AU - Morgan H. James AU - Gary Aston-Jones Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/09/467308.abstract N2 - There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition – the ability to cancel ongoing behavior – is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug seeking behavior are not related to effects on response inhibition.HighlightsOrexin-1 receptor antagonists hold great promise for treatment of drug addictionThese compounds are thought to reduce motivation for drug seekingLess is known about effects of orexin-1 receptor blockade on cognitive functioningWe tested the orexin-1 receptor antagonist SB-334867 in a rat stop signal taskSB-334867 reduced task motivation but had little effect on executive control as measured with response inhibitionAbbreviations5-CSRTTfive choice serial reaction time taskDMH/PFdorsomedial hypothalamus and perifornical areaGoRTGo trial reaction timeICVintra-individual coefficient of variationLHlateral hypothalamusMTmovement timeOxR1 and OxR2orexin-1 and orexin-2 receptorsSBSB-334867, orexin-1 receptor antagonistSSDstop signal delaySSRTstop signal reaction timeSSTstop signal taskWTstop trial wait time ER -