Gamma-amino butyric acid (GABA)A receptor stimulation in the nucleus accumbens shell produces intense hyperphagia in rats and increases Fos expression in the lateral hypothalamus. To explore the involvement of hypothalamic orexin/hypocretin- or melanin concentrating hormone-immunoreactive neurons in this effect, the GABAA agonist, muscimol (0, 50 ng), was infused directly into the nucleus accumbens shell of rats; 90 min later, their brains were collected and subsequently processed for immunohistochemistry. A group exposed to a novel environment was included to evaluate the specificity of Fos expression changes with regard to general arousal. Alternating sections through the hypothalamus were double-stained for orexin/hypocretin-Fos or melanin concentrating hormone-Fos combinations. Intra-accumbens shell muscimol treatment significantly increased the percentage of orexin/hypocretin-containing neurons expressing Fos in the lateral, but not medial, portion of the perifornical/lateral hypothalamic area. Regardless of treatment condition, greater percentages of orexin/hypocretin-containing neurons in the medial portion of the hypothalamus expressed Fos relative to cells located more laterally. None of the manipulations increased Fos expression in melanin concentrating hormone-immunoreactive neurons. Muscimol treatment also markedly increased Fos expression in the arcuate nucleus, which connects reciprocally to the lateral/perifornical hypothalamic area. Thus, orexin/hypocretin-containing neurons in lateral sectors of the hypothalamus, along with cells in the arcuate nucleus, display phasic increases in Fos expression after an orexigenic pharmacological manipulation of the nucleus accumbens shell, but to a lesser degree after the heightened arousal associated with exposure to a novel environment.