Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice

Although originally developed as an antidepressant, long- term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via miniosmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.