Delayed estrogen actions diminish food consumption without changing food approach, motor activity, or hypothalamic activation elicited by corticostriatal µ-opioid signaling.

Mu-opioid receptor (µ-OR) signaling in forebrain sites including nucleus accumbens (Acb) and ventromedial prefrontal cortex (vmPFC) modulates reward-driven feeding and may play a role in the pathophysiology of disordered eating. In preclinical models, intra-Acb or intra-vmPFC µ-OR stimulation causes overeating and vigorous responding for food rewards. These effects have been studied mainly in male animals, despite demonstrated sex differences and estrogen modulation of central reward systems. Hence, the present study investigated sex differences and estrogen modulation of intra-Acb and intra-vmPFC µ-OR-driven feeding behaviors. First, the dose-related effects of intra-Acb and intra-vmPFC infusions of the µ-OR-selective agonist, DAMGO, were compared among intact female, ovariectomized (OVX) female, and intact male rats. The DAMGO feeding dose-effect function was flattened in intact females relative to the robust, dose-dependent effects observed in OVX females and intact males. Thus, in intact females, intra-Acb DAMGO failed to elevate food intake relative to vehicle, while intra-vmPFC DAMGO elevated food intake, but to a smaller degree compared to males and OVX females. Next, to explore the possible role of estrogen in mediating the diminished DAMGO response observed in intact females, OVX rats were given intra-Acb or intra-vmPFC infusions of DAMGO either immediately after a subcutaneous injection of 17-beta-estradiol 3-benzoate (EB; 5 µg/0.1 mL) or 24 h after EB injection. Intra-Acb DAMGO effects were not changed at the immediate post-EB time point. At the delayed post-EB timepoint, significant lordosis was noted and the duration of intra-Acb DAMGO-driven feeding bouts was significantly reduced, with no change in the number of bouts initiated, locomotor hyperactivity, or Fos immunoreactivity in hypothalamic feeding and arousal systems. Similarly, EB failed to alter the motor-activational effects of intra-vmPFC DAMGO while reducing feeding. These findings indicate that delayed, presumably genomically mediated estrogen actions modulate the µ-OR-generated motivational state by reducing consummatory activity while sparing goal-approach and general arousal/activity. The results additionally suggest that EB regulation of consummatory activity occurs outside of forebrain-µ-OR control of hypothalamic systems.

Delayed but not immediate effects of estrogen curtail gamma-aminobutyric acid-mediated feeding responses elicited from the nucleus accumbens shell.

The present study investigated immediate versus delayed effects of estrogen replacement in ovariectomized (OVX) rats on hyperphagia elicited by gamma-aminobutyric acid (GABA)-A-agonist (muscimol) infusions into the nucleus accumbens shell (AcbSh). First, because intra-AcbSh muscimol-induced feeding has never been explored in OVX rats, a dose-effect curve was generated and compared to sham-operated males, the current point of reference in the literature. Muscimol (5, 10, 25, and 50 ng) increased food intake in both sexes, and both sexes reached the same asymptotic level of intake. Nevertheless, slopes of the linearized dose-effect functions for males and OVX females differed significantly, with females starting at a lower baseline and exhibiting a steeper slope. Next, the behavioral profiles of a behaviorally active, but nonmaximal intra-AcbSh muscimol dose (25 ng), were examined in a separate group of OVX females at two time-points: immediately after injecting 17ß-estradiol 3-benzoate (EB) subcutaneously (5 µg), and 24 hr post-EB. Delayed, but not immediate, EB pretreatment suppressed, but did not eliminate, muscimol-driven food intake. However, EB did not change nonfood-directed behaviors such as locomotion or rearing. These results demonstrate that feeding mediated by intra-AcbSh GABA-A receptors is delimited by delayed, but not rapid, effects of estradiol. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Eating driven by the gustatory insula: contrasting regulation by infralimbic vs. prelimbic cortices.

Subregions within insular cortex and medial prefrontal cortex (mPFC) have been implicated in eating disorders; however, the way these brain regions interact to produce dysfunctional eating is poorly understood. The present study explored how two mPFC subregions, the infralimbic (IL) and prelimbic (PRL) cortices, regulate sucrose hyperphagia elicited specifically by a neurochemical manipulation of the agranular/dysgranular region of gustatory insula (AI/DI). Using intra-AI/DI infusion of the mu-opioid receptor (µ-OR) agonist, DAMGO (1 µg), sucrose hyperphagia was generated in ad-libitum-maintained rats, while in the same rat, either the IL or prelimbic (PRL) subregion of mPFC was inactivated bilaterally with muscimol (30 ng). Intra-IL muscimol markedly potentiated AI/DI DAMGO-induced sucrose hyperphagia by increasing eating bout duration and food consumption per bout. In contrast, PRL attenuated intra-AI/DI DAMGO-driven sucrose intake and feeding duration and eliminated the small DAMGO-induced increase in feeding bout initiation. Intra-IL or -PRL muscimol alone (i.e., without intra-AI/DI DAMGO) did not alter feeding behavior, but slightly reduced exploratory-like rearing in both mPFC subregions. These results reveal anatomical heterogeneity in mPFC regulation of the intense feeding-motivational state engendered by µ-OR signaling in the gustatory insula: IL significantly curtails consummatory activity, while PRL modestly contributes to feeding initiation. Results are discussed with regard to potential circuit-based mechanisms that may underlie the observed results.

Dissociable control of µ-opioid-driven hyperphagia vs. food impulsivity across subregions of medial prefrontal, orbitofrontal, and insular cortex.

This study explored potentially dissociable functions of mu-opioid receptor (µ-OR) signaling across different cortical territories in the control of anticipatory activity directed toward palatable food, consumption, and impulsive food-seeking behavior in male rats. The µ-OR agonist, DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin), was infused into infralimbic cortex (ILC), prelimbic cortex (PrL), medial and lateral ventral orbitofrontal cortices (VMO, VLO), and agranular/dysgranular insular (AI/DI) cortex of rats. Intra-ILC DAMGO markedly enhanced contact with a see-through screen behind which sucrose pellets were sequestered; in addition, rats having received intra-ILC and intra-VMO DAMGO exhibited locomotor hyperactivity while the screen was in place. Upon screen removal, intra-ILC and -VMO-treated rats emitted numerous, brief sucrose-intake bouts (yielding increased overall intake) interspersed with significant hyperactivity. In contrast, intra-AI/DI-treated rats consumed large amounts of sucrose in long, uninterrupted bouts with no anticipatory hyperactivity pre-screen removal. Intra-PrL and intra-VLO DAMGO altered neither pre-screen behavior nor sucrose intake. Finally, all rats were tested in a sucrose-reinforced differential reinforcement of low rates (DRL) task, which assesses the ability to advantageously withhold premature responses. DAMGO affected (impaired) DRL performance when infused into ILC only. These site-based dissociations reveal differential control of µ-OR-modulated appetitive/approach vs. consummatory behaviors by ventromedial/orbitofrontal and insular networks, respectively, and suggest a unique role of ILC µ-ORs in modulating inhibitory control.

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.

GABA-Mediated Inactivation of Medial Prefrontal and Agranular Insular Cortex in the Rat: Contrasting Effects on Hunger- and Palatability-Driven Feeding.

A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-mediated inactivation of two frontal regions in rats, the agranular/dysgranular insular cortex (AIC) and the ventromedial prefrontal cortex (vmPFC). Food and water intake, feeding microstructure, and general motor activity were measured under two motivational conditions: food-deprived rats given standard chow or ad libitum-fed rats given a palatable chocolate shake. Muscimol infusions into the AIC diminished intake, total feeding duration, and average feeding bout duration for the palatable-food condition only but failed to alter exploratory-like behavior (ambulation or rearing). In contrast, intra-vmPFC muscimol infusions did not alter the overall intake of chow or chocolate shake. However, these infusions markedly increased mean feeding bout duration for both food types and produced a modest but significant reduction of exploratory-like behavior. The lengthening of feeding-bout duration and reduction in rearing were mimicked by intra-vmPFC blockade of AMPA-type but not NMDA-type glutamate receptors. Neither water consumption nor the microstructure of water drinking was affected by inactivation of either site. These results indicate a regional heterogeneity in frontal control of feeding behavior. Neural processing in AIC supports palatability-driven feeding but is not necessary for intake of a standard food under a food-restriction condition, whereas ventromedial prefrontal cortex, and AMPA signaling therein, modulates the duration of individual feeding bouts regardless of motivational context. Results are discussed in the context of regionally heterogeneous frontal modulation of two distinct components of feeding behavior: reward valuation based upon taste perception (AIC) vs switching between ingestive and non-ingestive (eg, exploratory-like) behavioral repertoires (vmPFC).

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.

Sweetened-fat intake sensitizes gamma-aminobutyric acid-mediated feeding responses elicited from the nucleus accumbens shell.

BACKGROUND: There is much interest in exploring whether reward-driven feeding can produce druglike plasticity in the brain. The gamma-aminobutyric acid (GABA) system in the nucleus accumbens (Acb) shell, which modulates hypothalamic feeding systems, is well placed to "usurp" homeostatic control of feeding. Nevertheless, it is unknown whether feeding-induced neuroadaptations occur in this system. METHODS: Separate groups of ad libitum-maintained rats were exposed to daily bouts of sweetened-fat intake, predator stress, or intra-Acb shell infusions of either d-amphetamine (2 or 10 µg) or the µ-opioid agonist D-[Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO, 2.5 µg), then challenged with intra-Acb shell infusion of the GABAA agonist, muscimol (10 ng). RESULTS: Exposure to sweetened fat robustly sensitized muscimol-induced feeding. Sensitization was present 1 week after cessation of the palatable feeding regimen but had abated by 2 weeks. Rats exposed to sweetened fat did not show an altered feeding response to food deprivation. Repeated intra-Acb shell infusions of DAMGO (2.5 µg) also sensitized intra-Acb shell muscimol-driven feeding. However, neither repeated intra-Acb shell d-amphetamine infusions (2 or 10 µg) nor intermittent exposure to an aversive stimulus (predator stress) altered sensitivity to muscimol. CONCLUSIONS: Palatable feeding engenders hypersensitivity of Acb shell GABA responses; this effect may involve feeding-induced release of opioid peptides. Heightened arousal, aversive experiences, or increased catecholamine transmission alone are insufficient to produce the effect, and a hunger-induced feeding drive is insufficient to reveal the effect. These findings reveal a novel type of food-induced neuroadaptation within the Acb; possible implications for understanding crossover effects between food reward and drug reward are discussed.

Induction of hyperphagia and carbohydrate intake by µ-opioid receptor stimulation in circumscribed regions of frontal cortex.

Frontal cortical regions are activated by food-associated stimuli, and this activation appears to be dysregulated in individuals with eating disorders. Nevertheless, frontal control of basic unconditioned feeding responses remains poorly understood. Here we show that hyperphagia can be driven by µ-opioid receptor stimulation in restricted regions of ventral medial prefrontal cortex (vmPFC) and orbitofrontal cortex. In both ad libitum-fed and food-restricted male Sprague Dawley rats, bilateral infusions of the µ-opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) markedly increased intake of standard rat chow. When given a choice between palatable fat-enriched versus carbohydrate-enriched test diets, intra-vmPFC DAMGO infusions selectively increased carbohydrate intake, even in rats with a baseline fat preference. Rats also exhibited motor hyperactivity characterized by rapid switching between brief bouts of investigatory and ingestive behaviors. Intra-vmPFC DAMGO affected neither water intake nor nonspecific oral behavior. Similar DAMGO infusions into neighboring areas of lateral orbital or anterior motor cortex had minimal effects on feeding. Neither stimulation of vmPFC-localized δ-opioid, κ-opioid, dopaminergic, serotonergic, or noradrenergic receptors, nor antagonism of D1, 5HT1A, or α- or ß-adrenoceptors, reproduced the profile of DAMGO effects. Muscimol-mediated inactivation of the vmPFC, and intra-vmPFC stimulation of κ-opioid receptors or blockade of 5-HT2A (5-hydroxytryptamine receptor 2A) receptors, suppressed motor activity and increased feeding bout duration-a profile opposite to that seen with DAMGO. Hence, µ-opioid-induced hyperphagia and carbohydrate intake can be elicited with remarkable pharmacological and behavioral specificity from discrete subterritories of the frontal cortex. These findings may have implications for understanding affect-driven feeding and loss of restraint in eating disorders.

Increases in food intake or food-seeking behavior induced by GABAergic, opioid, or dopaminergic stimulation of the nucleus accumbens: is it hunger?

RATIONALE: Previous work has shown that stimulation of GABAergic, opioid, or dopaminergic systems within the nucleus accumbens modulates food intake and food-seeking behavior. However, it is not known whether such stimulation mimics a motivational state of food deprivation that commonly enables animals to learn a new operant response to obtain food. OBJECTIVES: In order to address this question, acquisition of lever pressing for food in hungry animals was compared with acquisition in non-food-deprived rats subjected to various nucleus accumbens drug treatments. METHODS: All animals were given the opportunity to learn an instrumental response (a lever press) to obtain a food pellet. Prior to training, ad lib-fed rats were infused with the gamma-aminobutyric acid (GABA)A agonist muscimol (100 ng/0.5 microl per side) or the mu-opioid receptor agonist D-Ala2, N-me-Phe4, Gly-ol5-enkephalin (DAMGO, 0.25 microg/0.5 microl per side), or saline into the nucleus accumbens shell (AcbSh). The indirect dopamine agonist amphetamine (10 microg/0.5 microl per side) was infused into the AcbSh or nucleus accumbens core (AcbC) of ad lib-fed rats. An additional group was food deprived and infused with saline in the AcbSh. Chow and sugar pellet intake responses after drug treatments were also evaluated in free-feeding tests. RESULTS: Muscimol, DAMGO, or amphetamine did not facilitate acquisition of lever pressing for food, despite clearly increasing food intake in free-feeding tests. In contrast, food-deprived animals rapidly learned the task. CONCLUSIONS: These findings suggest that pharmacological stimulation of any of these neurochemical systems in isolation is insufficient to enable acquisition of a food-reinforced operant task. Thus, these selective processes, while likely involved in control of food intake and food-seeking behavior, appear unable to recapitulate the conditions necessary to mimic the state of negative energy balance.

Effects of selective dopamine D1 or D2 receptor blockade within nucleus accumbens subregions on ingestive behavior and associated motor activity.

Two anatomically and neurochemically distinguishable regions of the nucleus accumbens (Acb), the core and the shell, have been shown to differentially regulate feeding behavior. Nevertheless, despite the well-known role of Acb dopamine in the modulation of motivated behaviors, there have been no studies directly comparing the effects of acute dopamine receptor blockade in the Acb core versus the Acb shell on feeding. In this study, D1- or D2-selective dopamine receptor antagonists were infused bilaterally into the Acb core or shell of hungry rats, whereupon feeding, drinking, and spontaneous motor activity were monitored. Both the D1 antagonist SCH 23390 (0, 1, and 2 microg/0.5 microl) and the D2 antagonist raclopride (0, 1, and 2 microg/0.5 microl) markedly suppressed ambulation and rearing when infused into either the Acb core or shell. Total food intake and latency to begin feeding were unaffected by either drug in either site. SCH 23390 in the Acb shell, and raclopride in the Acb core or shell, significantly decreased the total number of feeding bouts. In the Acb core, raclopride produced a small but statistically significant increase in overall feeding duration. Dopamine receptor blockade in either site tended to increase mean feeding bout duration. Measures of drinking behavior were generally unaffected. Hence, dopamine receptor blockade in either the Acb core or shell of hungry rats suppressed spontaneous motor activity and shifted the structure of feeding towards longer bout durations, but did not alter the total amount of food consumed. In the Acb shell, the effects of D1 receptor blockade tended to be of greater magnitude than the effects of D2 receptor blockade, although major differences between core and shell effects were not observed. These results are discussed with regard to current theories of dopaminergic control of feeding behavior, and with reference to the functional heterogeneity of Acb subregions.