1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine and nisoxetine

Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA+NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA+NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA+NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA+NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA+NE reuptake (with GBR+NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

Topics: Animals; Area Under Curve; Behavior, Animal; Bupropion; Catecholamines; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Fluoxetine; Male; Mice; Mice, Inbred C57BL; Motor Activity; Norepinephrine; Norethandrolone; Piperazines; Telemetry; Thermogenesis; Time Factors; Weight Loss

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 mini-osmotic 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.

Topics: Animals; Behavior, Animal; Body Weight; Bupropion; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Eating; Energy Metabolism; Fluoxetine; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Motor Activity; Neurotransmitter Uptake Inhibitors; Norepinephrine; Obesity; Piperazines; Time Factors