Modulation of appetitive motivation by prefrontal cortical mu-opioid receptors is dependent upon local dopamine D1 receptor signaling.

Opioid neurotransmission has been implicated in psychiatric disorders featuring impaired control over appetitive motivation, such as addiction and binge-eating disorder. We have previously shown that infusions of the µ-opioid receptor (µOR) agonist DAMGO into the ventromedial prefrontal cortex (vmPFC) induced hyperphagia, increased motor activity, and augmented sucrose-reinforced responding in the task progressive ratio (PR) task, which assesses the motivational value of an incentive. These effects were not reproduced by intra-PFC infusion of a variety of dopamine (DA) agonists and antagonists, suggesting that manipulation of intra-PFC DA systems alone is not sufficient to reproduce µOR-like effects. Nevertheless, this does not rule out interactions between PFC DA and µ-opioid systems. Here we used intra-vmPFC drug cocktails containing DAMGO and SCH 23390 (a DA D1 receptor antagonist) to determine whether increases in appetitive motivation and motor activity elicited by intra-vmPFC µOR stimulation require intact signaling through vmPFC D1 receptors. Blockade of D1 receptors with SCH 23390 attenuated the enhancement of PR breakpoint, and increases in exploratory-like behavior and feeding initiation elicited by intra-vmPFC µOR stimulation. These results establish that intra-vmPFC D1 signaling is required for the expression of behavioral effects evoked by µOR stimulation within the PFC, and further suggest that D1 tone plays an enabling or permissive role in the expression of µOR -elicited effects. Simultaneous targeting of both µ-opioid and D1 systems may represent a more efficacious treatment strategy (compared to µOR blockade alone) for psychiatric disorders characterized by dysregulated appetitive motivation.

Endogenous Opioid Signaling in the Medial Prefrontal Cortex is Required for the Expression of Hunger-Induced Impulsive Action.

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 'high-drive' condition (18-h food deprivation). Intra-PFC DAMGO (D-[Ala2,N-MePhe4, Gly-ol]-enkephalin; a µ-opioid agonist) and d-amphetamine 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.