The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

Abstract

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, consistent with other recent findings. 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.

Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system

“…fentanyl, nor any effect on lever pressing for sucrose in fentanyl experienced rats 9 . This is consistent with previous studies demonstrating no effect of systemic SB on general locomotor activity in either an open field apparatus 5,12 or a cognitive task requiring motor engagement 50 . Moreover, here we found that SB treatment had no effect on inactive lever responding during cued reinstatement tests across all treatment groups, further supporting a selective effect of SB on motivated, drug-seeking behaviors.…”

Intermittent self‐administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system

“…fentanyl, nor any effect on lever pressing for sucrose in fentanyl experienced rats 9 . This is consistent with previous studies demonstrating no effect of systemic SB on general locomotor activity in either an open field apparatus 5,12 or a cognitive task requiring motor engagement 50 . Moreover, here we found that SB treatment had no effect on inactive lever responding during cued reinstatement tests across all treatment groups, further supporting a selective effect of SB on motivated, drug-seeking behaviors.…”

Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System

“…in a counterbalanced fashion 30 minutes prior to BE testing. This dose of SB was selected based on previous studies indicating that this dose reliably affects motivated reward seeking, including for food ( Fragale et al, 2019 ; James et al, 2019a , 2019b ; Barson, 2020 ; Mohammadkhani et al, 2020 ; Wiskerke et al, 2020 ). The drug and vehicle were prepared as described previously ( Smith et al, 2009 ).…”