Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis
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Neuropsychopharmacology (2008) 33, 1287–1297 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis 1 ,1 Sonja K Billes and Michael A Cowley* 1 Division of Neuroscience, Oregon National Primate Research Center/Oregon Health and Science University, Beaverton, OR, USA 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. Neuropsychopharmacology (2008) 33, 1287–1297; doi:10.1038/sj.npp.1301526; published online 8 August 2007 Keywords: dopamine; norepinephrine; bupropion; temperature; locomotor activity; obesity INTRODUCTION extracellular catecholamines (Hoffman et al, 1998). Through blockade of the DA and NE transporters, BUP causes acute Bupropion (BUP) is currently approved for the treatment of s increases in interstitial catecholamine concentrations and depression (Wellbutrin ) and as an aid in smoking s increased feedback inhibition of presynaptic neurons cessation (Zyban ) (Ascher et al, 1995; Foley et al, 2006). (Ascher et al, 1995; Dong and Blier, 2001). Originally associated with a ‘lack of weight gain’, BUP was BUP reduces food intake when administered acutely to recently shown to cause mild (5%) weight loss in clinical rodents (Zarrindast and Hosseini-Nia, 1988; Billes and trials with obese human subjects (Gadde and Xiong, 2007). Cowley, 2007). Because acute coadministration of selective Although BUP is undergoing further clinical studies as a DA + NE reuptake inhibitors produces an additive inhibi- pharmacotherapy for obesity, there are no controlled tory effect on food intake in mice, both catecholamines comprehensive animal studies that assess how chronic probably contribute to the acute hypophagic effect of BUP. BUP affects energy balance. Both DA and NE also appear to contribute to the weight loss Like many antidepressants and the only centrally acting, effect of BUP that has been documented in humans, as FDA-approved long-term obesity treatment, sibutramine s subchronic (7 day) coadministration of DA + NE reuptake (Meridia ), BUP inhibits biogenic amine plasma membrane inhibitors also causes weight loss in mice (Billes and reuptake transporters (Ascher et al, 1995; Stahl et al, 2004; Cowley, 2007). Interestingly, weight loss caused by sub- Kaplan, 2005). By selectively inhibiting the reuptake chronic DA + NE reuptake inhibition in mice occurred in transporters for dopamine (DA) and norepinephrine (NE), the absence of a reduction in food intake, which is also BUP impinges on the primary means for clearance of similar to the observation that chronic BUP administration does not affect caloric intake in humans (Griffith et al, 1983; *Correspondence: Dr MA Cowley, Division of Neuroscience, Harto-Truax et al, 1983). This suggests that catecholamine Oregon National Primate Research Center/Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, reuptake inhibition may cause weight loss by increasing USA, Tel: + 1 503 533 2421, Fax: + 1 503 690 5384, energy expenditure. E-mail: [email protected] Current data in rodents indicate that acute BUP may Received 11 January 2007; revised 27 June 2007; accepted 10 July 2007 increase energy expenditure by increasing temperature Metabolic effect of catecholamines SK Billes and MA Cowley 1288 (Liu et al, 2002, 2004). Because reports on the acute effects Drugs of BUP on temperature are inconsistent, further research is Drugs were prepared fresh on day of use. For intraper- needed to determine if increased thermogenesis might also itoneal (i.p.) administration, BUP (Sigma, St Louis, MO) contribute to increased energy expenditure by BUP and nisoxetine (NIS; Tocris, Ellisville, MO) were dissolved (Zarrindast and Abolfathi-Araghi, 1992; Liu et al, 2002; in sterile nonpyrogenic 0.9% NaCl. GBR12783 (GBR; Tocris) Hasegawa et al, 2005). We and others have shown that acute peripheral BUP also dose dependently stimulates locomotor and GBR + NIS were dissolved in 10% dimethyl sulfoxide and saline. All acutely administered drugs were given i.p. in activity in rodents, an effect that is consistent with a volume of 0.170.02 ml (according to body weight). inhibition of the DA transporter (Soroko et al, 1977; Control mice received vehicle in a corresponding volume. Cooper et al, 1980; Nielsen et al, 1986; Zarrindast and s For subchronic administration (via Alzet minipumps), Hosseini-Nia, 1988; Vassout et al, 1993; Redolat et al, 2005; NIS was dissolved in 10% dimethyl sulfoxide and sterile Mitchell et al, 2006). nonpyrogenic saline. BUP and GBR were dissolved in Obesity is generally regarded as a chronic disease 50% dimethyl sulfoxide and 50% sterile H O. Previously requiring continuous intervention to maintain low body 2 published data were used to determine drug doses that weight (Appolinario et al, 2004; Ioannides-Demos et al, would have a moderate effect on energy balance (Billes and 2005). Chronic (5–21 days) treatment with drugs like BUP can affect receptor expression, intracellular signaling Cowley, 2007). mechanisms, and transporter expression and activity (Frazer and Benmansour, 2002). Thus, chronic BUP Telemetric Transponder Implantation and Locomotor treatment can result in behavioral tolerance and/or Activity and Temperature Measurement sensitization such that the acute effects of BUP on energy Remote biotelemetry was performed using precalibrated balance may differ from BUP’s chronic effects. Studies that s address how chronic DA + NE reuptake inhibition affect sensitive transmitters (PDT-4000 G2 E-Mitter sensors, energy intake and expenditure are necessary to determine Mini Mitter Company, Sun River, OR). Under isoflurane how long-term drug administration affects energy balance. anesthesia, E-Mitters were implanted beneath the inter- There is a conspicuous absence of data on the compre- scapular brown adipose tissue (IBAT) pad between the hensive effects of chronic BUP treatment on energy balance scapulae, and wounds were closed with sutures. Mice were in animal models. It is also unclear how DA and NE allowed 1-week recovery before studies commenced. Signals contribute to the possible metabolic effects of BUP, as no emitted by the E-Mitter transmitters were detected by a studies have examined how chronic administration of receiver positioned underneath the animal’s home cage and converted into activity counts (arbitrary units) by selective DA or NE reuptake inhibitors affects energy s expenditure. Studies comparing the effects of BUP with VitalView software (Mini Mitter) (Harkin et al, 2002). that of selective DA or NE reuptake inhibitors on multiple Locomotor activity counts are a relative measure of gross measures of energy balance (such as food intake, locomotor motor activity. For all experiments, activity counts and activity, thermogenesis, and body weight) are necessary for interscapular temperature measurements were taken every a complete analysis of the effects of drugs like BUP on 6 min. energy balance. The purpose of the present study was to examine the acute and chronic effects of DA + NE reuptake Acute Drug Administration Studies inhibition on energy balance in mice, particularly to shed light on the mechanism of weight loss by drugs like BUP. To Mice were habituated to the behavioral testing paradigm by this aim, we first investigated the effects of acute admin- daily i.p. injection of 0.1 ml sterile saline and 16 h (over- istration of BUP or selective DA and NE reuptake inhibitors night) fasting every third day for at least 2 weeks. Then mice on locomotor activity and interscapular temperature. We were implanted with interscapular PDT-4000