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).