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.
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The authors thank Juliana Giacomini and Alexius Lampkin for assistance with general laboratory tasks, and Joyce Borde for excellent care of the rat colony.
This work was supported by NIH grant MH074723 from the National Institute for Mental Health (PI: BAB). JCD was supported by the Science and Medicine Research Scholars Advanced Opportunity Fellowship of the University of Wisconsin-Madison. A subset of these data was presented in abstract form at the annual meeting of the Society for Neuroscience, 2018.
The authors have no competing interests.
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Diaz, J.C., Dunaway, K., Zuniga, C. et al. Delayed estrogen actions diminish food consumption without changing food approach, motor activity, or hypothalamic activation elicited by corticostriatal µ-opioid signaling. Neuropsychopharmacol. 48, 1952–1962 (2023). https://doi.org/10.1038/s41386-023-01711-3