Opioid transmission and dysregulated prefrontal cortex (PFC) activity have both been implicated in the inhibitory-control deficits associated with addiction and binge-type eating disorders. What remains unknown, however, is whether endogenous opioid transmission within the PFC modulates inhibitory control. Here, we compared intra-PFC opioid manipulations with a monoamine manipulation (d-amphetamine), in two sucrose-reinforced tasks: progressive ratio (PR), which assays the motivational value of an incentive, and differential reinforcement of low response rates (DRLs), a test of inhibitory control. Intra-PFC methylnaloxonium (M-NX, a limited diffusion opioid antagonist) was given to rats in a 'low-drive' condition (2-h food deprivation), and also after a motivational shift to a 'highdrive' condition (18-h food deprivation). Intra-PFC DAMGO (D-[Ala2,N-MePhe4, Gly-ol]-enkephalin; a μ-opioid agonist) and damphetamine were also tested in both tasks, under the low-drive condition. Intra-PFC M-NX nearly eliminated impulsive action in DRL engendered by hunger, at a dose (1 μg) that significantly affected neither hunger-induced PR enhancement nor hyperactivity. At a higher dose (3 μg), M-NX eliminated impulsive action and returned PR breakpoint to low-drive levels. Conversely, intra-PFC DAMGO engendered 'high-drive-like' effects: enhancement of PR and impairment of DRL performance. Intra-PFC d-amphetamine failed to produce effects in either task. These results establish that endogenous PFC opioid transmission is both necessary and sufficient for the expression of impulsive action in a high-arousal, high-drive appetitive state, and that PFC-based opioid systems enact functionally unique effects on food impulsivity and motivation relative to PFC-based monoamine systems. Opioid antagonists may represent effective treatments for a range of psychiatric disorders with impulsivity features.

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