Due to the nature of processing within the accumbens shell (AccSh) and the presence of orexin receptors and varicosities within the AccSh, we hypothesized that orexin A may partly regulate feeding behavior and locomotor activity via signaling in this site. To test this hypothesis, male Sprague-Dawley rats were implanted with guide cannulae directed to the medial portion of the AccSh. Orexin A (0, 100, 500, and 1000 pmol, in 0.5 microl artificial cerebrospinal fluid) was infused into the AccSh and feeding behavior and locomotor activity were monitored. The effect of pretreatment with an orexin 1 receptor antagonist (SB334867A) on orexin A-induced feeding and locomotor activity was assessed. Orexin A augmented feeding in the 0-1 h and 1-2 h post-infusion interval (P = 0.0058 and P = 0.025, respectively) and stimulated locomotor activity in the 30-60 min, 60-90 min, and 90-120 min post-infusion intervals (P <or= 0.0001, P = 0.0056 and P = 0.046, respectively). Orexin A-induced feeding was significantly attenuated by preadministration of SB334867A in the 0-1 h post-infusion time interval (P = 0.03). Orexin A-induced locomotor activity was not affected by SB334867A. These data support the hypothesis that the AccSh is a site of orexin A modulation of feeding behavior and locomotor activity.