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To this end, whole animal experiments were carried out in gonadectomized female guinea pigs. Estradiol benzoate (EB; 10 \u03bcg sc) decreased incremental food intake as well as O<jats:sub>2<\/jats:sub>consumption, CO<jats:sub>2<\/jats:sub>production, and metabolic heat production as early as 2 h postadministration. This was associated with increased phosphorylation of nNOS (pnNOS), as evidenced by an elevated ratio of pnNOS to nNOS in the ARC. Administration of the cannabinoid receptor agonist WIN 55,212-2 (3 \u03bcg icv) into the third ventricle evoked hyperphagia as early as 1 h postadministration, which was blocked by EB and restored by the nonselective NOS inhibitor N-nitro-l-arginine methyl ester hydrochloride (l-NAME; 100 \u03bcg icv) when the latter was combined with the steroid. Whole cell patch-clamp recordings showed that 17\u03b2-estradiol (E<jats:sub>2<\/jats:sub>; 100 nM) rapidly diminished cannabinoid-induced decreases in miniature excitatory postsynaptic current frequency, which was mimicked by pretreatment with the NOS substrate l-arginine (30 \u03bcM) and abrogated by l-NAME (300 \u03bcM). Furthermore, E<jats:sub>2<\/jats:sub>antagonized endocannabinoid-mediated depolarization-induced suppression of excitation, which was nullified by the nNOS-selective inhibitor N<jats:sup>5<\/jats:sup>-[imino(propylamino)methyl]-l-ornithine hydrochloride (10 \u03bcM). These effects occurred in a sizable number of identified POMC neurons. Taken together, the estradiol-induced decrease in energy intake is mediated by a decrease in cannabinoid sensitivity within the ARC feeding circuitry through the activation of nNOS. These findings provide compelling evidence for the need to develop rational, gender-specific therapies to help treat metabolic disorders such as cachexia and obesity.<\/jats:p>","DOI":"10.1152\/jn.00615.2014","type":"journal-article","created":{"date-parts":[[2014,11,13]],"date-time":"2014-11-13T03:34:48Z","timestamp":1415849688000},"page":"904-914","source":"Crossref","is-referenced-by-count":18,"title":["Role of neuronal nitric oxide synthase in the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis"],"prefix":"10.1152","volume":"113","author":[{"given":"Amanda","family":"Borgquist","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Meza","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Osteopathic Medicine, 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