Hindawi Publishing Corporation Journal of Obesity Volume 2013, Article ID 457047, 9 pages http://dx.doi.org/10.1155/2013/457047 Research Article High-Fat Diet-Induced Alterations in the Feeding Suppression of Low-Dose Nisoxetine, a Selective Norepinephrine Reuptake Inhibitor Nicholas T. Bello, 1, 2 Amy L. Walters, 1 Jessica L. Verpeut, 1, 2 and Priscila P. Cunha 1 1 Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, e State University of New Jersey, 84 Lipman Drive, New Brunswick, NJ 08901, USA 2 Graduate Program in Endocrinology and Animal Biosciences, Rutgers, e State University of New Jersey, 84 Lipman Drive, New Brunswick, NJ 08901, USA Correspondence should be addressed to Nicholas T. Bello; ntbello@aesop.rutgers.edu Received 19 October 2012; Accepted 17 December 2012 Academic Editor: Alfredo Halpern Copyright © 2013 Nicholas T. Bello et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Central noradrenergic pathways are involved in feeding and cardiovascular control, physiological processes altered by obesity. e present studies determined how high-fat feeding and body weight gain alter the sensitivity to the feeding suppression and neural activation to a selective norepinephrine reuptake inhibitor, nisoxetine. Acute administration of nisoxetine (saline: 0, 3, 10, and 30 mg/kg; IP) resulted in a dose-dependent reduction in the 24 h refeeding response in male Sprague Dawley rats maintained on standard chow. In a similar fashion, nisoxetine resulted in reductions in blood pressure and a compensatory increase in heart rate. From these studies, the 3 mg/kg dose was subthreshold. In a separate experiment, however, 10 wk exposure to a high-fat diet (60% fat) resulted in weight gain and signi�cant feeding suppression following administration of nisoxetine (3 mg/kg) compared with animals fed a control diet (10% fat). Nisoxetine (3mg/kg) also resulted in greater neural activation, as measured by c-Fos immunohistochemistry, in the arcuate nucleus of the hypothalamus in animals exposed to the high-fat diet. Such data indicate acute nisoxetine doses that suppress food intake can impact cardiovascular measures. It also suggests that the feeding suppression to a low-dose nisoxetine is enhanced as a result of high-fat diet and weight gain. 1. Introduction Obesity is a risk factor for cardiovascular disease [1, 2]. Central noradrenergic pathways are involved in regulating cardiovascular function, as well as in the control of food intake [3, 4]. Norepinephrine (NE) levels and sympathetic activity are responsive to stressors and glycemic �uctuations [5–7]. Central-acting pharmacological compounds that have actions on norepinephrine and other biogenic amines are currently used (e.g., phentermine and related formulations) or have the potential (e.g., tesofensine and bupropion/ naltrexone) to treat obesity [8, 9]. However, elevations in heart rate and blood pressure are adverse effects that are oen associated with the long-term use of these medications [10, 11]. erefore, understanding how central-acting noradrenergic compounds impact feeding behavior and related neural structures can provide more targeted approaches for the treatment of obesity. Nisoxetine (3-[2-methoxyphenoxy]-N-methyl-3-phenyl- 1-propanamine) is a highly selective central-acting nore- pinephrine reuptake inhibitor originally developed as an antidepressant [12, 13]. In vitro studies with nisoxetine revealed that norepinephrine levels were 1,000-fold higher than serotonin (5-hydroxytryptamine; 5HT) levels and 300- fold higher than dopamine levels [13, 14]. Aer studies sug- gested it did not have the desired antidepressant effect [15], nisoxetine has been used instead as a pharmacological tool to discriminate the involvement of the noradrenergic system. Radiolabeled nisoxetine is also used to identify