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

Abstract

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.

Hippocampus Contributions to Food Intake Control: Mnemonic, Neuroanatomical, and Endocrine Mechanisms

“…Hsu, Kanoski, and colleagues have recently shown that vHP GLP-1R activation potently reduced food intake in rats, with ~40% reduction in 24hr chow intake and ~50% reduction in 24hr Western diet intake (68). These intake reducing effects are physiologically relevant to normal feeding, as vHP administration of the selective GLP-1R antagonist, exendin-(9–39), increased food intake.…”

“…Extensive direct projections are also observed from the vCA1 and vSub neurons to the mPFC (infralimbic and prelimbic subregions) (53, 85), which has recently been linked to reward-driven feeding via D1R (8) and opioid receptor signaling (9). Nucleus accumbens core and shell neurons, other key targets of VTA dopamine signaling, receive substantial innervation from the vSub (86–88).…”

“…Basic science investigation of the systems neuroscience of feeding behavior has historically, and nearly exclusively, focused on neurons in the arcuate hypothalamic nucleus, and to a lesser extent, on neurons in other hypothalamic nuclei and the caudomedial medulla. Recent studies have expanded focus beyond these common targets, focusing attention on additional hindbrain, midbrain, and forebrain regions, including the parabrachial nucleus (5), ventral tegmental area (VTA) (6, 7), medial prefrontal cortex (mPFC) (8, 9), amygdala and extended amygdala (10), and nucleus accumbens (11–13). Neuroanatomically interconnected with several of these regions is the hippocampus; a forebrain structure historically associated with mnemonic control.…”

Feeding-modulatory effects of mu-opioids in the medial prefrontal cortex: a review of recent findings and comparison to opioid actions in the nucleus accumbens

“…In addition to driving feeding itself, μ-OR stimulation in vmPFC also robustly amplifies responding in a sucrose-reinforced progressive ratio (PR) task and promotes ‘impulsiveness-like’ deficits in differential reinforcement of low response rates task (DRL) (Selleck et al 2015). Together, these effects indicate that cortical μ-OR stimulation increases the motivational value of food and energizes food-seeking repertoires, as well as disrupting inhibitory control over food-seeking.…”

“…Conversely, activation of the Acb via AMPA receptor stimulation (possibly arising from glutamatergic PFC projections) inhibits feeding, partly through descending inhibitory control over the hypothalamus, but also through the recruitment of non-food-directed behaviors. The incoherent engagement of these parallel ‘feeding-driver’ and ‘feeding-limiter’ pathways by opioid signaling could result in disorganized, impulsive food-seeking behaviors, such as those engendered by μ-OR stimulation in ventromedial PFC (Mena et al 2011; Selleck et al 2015). Fig.…”