Metabotropic Glutamate Receptor mGlu 5 Is a Mediator of Appetite and Energy Balance in Rats and Mice

The metabotropic glutamate receptor subtype mGlu5 modulates central reward pathways. Many transmitter systems within reward pathways affect feeding. We examined the potential role of mGlu5 in body weight regulation using genetic and pharmacological approaches. Adult mice lacking mGlu5, mGluR5 / , weighed significantly less than littermate controls (mGluR5 / ), despite no difference in ad libitum food intake. After overnight food deprivation, mGluR5 / mice ate significantly less than their mGluR5 / controls when refeeding. When on a high fat diet, mGluR5 / mice weighed less and had decreased plasma insulin and leptin concentrations. The selective mGlu5 antagonist MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine; 15 mg/kg s.c. ] reduced refeeding after overnight food deprivation in mGluR5 / , but not mGluR5 / mice, demonstrating that feeding suppression is mediated via a mGlu5 mechanism. MTEP (1–10 mg/kg) decreased night-time food intake in rats in a dose-related manner. At 10 mg/kg, MTEP injected at 8.5, 4.5, or 0.5 h before refeeding reduced overnight food intake by approximately 30%. Diet-induced obese (DIO) and age-matched lean rats were treated for 12 days with MTEP (3 or 10 mg/kg/day s.c.), dexfenfluramine (3 mg/kg/day s.c.), or vehicle. Daily and cumulative food intakes were reduced in DIO rats by MTEP and dexfenfluramine. Weight gain was prevented with MTEP (3 mg/kg), and weight and adiposity loss was seen with MTEP (10 mg/kg) and dexfenfluramine. Caloric efficiency was decreased, suggesting increased energy expenditure. In lean rats, similar, although smaller, effects were observed. In conclusion, using genetic and pharmacological approaches, we have shown that mGlu5 modulates food intake and energy balance in rodents. Metabotropic glutamate (mGlu) receptors have received considerable attention within the neurobiological sciences as potential therapeutic targets for multiple diseases due to their ability to modulate excitatory glutamate transmission and postsynaptic signaling (Conn and Pin, 1997; Spooren et al., 2001). Eight mGlu receptor subtypes are distinguished by sequence homology and signal transduction pathways. Group II (mGlu2 and 3) and group III (mGlu4, 6, 7, and 8) mGlu receptors couple to G i, whereas group I mGlu receptors (mGlu1 and 5) stimulate hydrolysis of phosphoinositides through interactions with G q/11 (Conn and Pin, 1997). Of the mGlu receptors, mGlu5 is implicated in the potential treatment of neurological and psychiatric disorders, including anxiety, depression, pain, and Parkinson’s disease (Spooren et al., 2001). Additionally, recent work implicates mGlu5 in central reward pathways. Glutamate release into the core of the nucleus accumbens accompanies the behavioral sequelae of cocaine administration in sensitized rats (Pierce et al., 1996). mGlu5 mRNA is expressed in areas implicated in reward pathways, including nucleus accumbens and the hypothalamus (van den Pol et al., 1995; Kerner Funding was provided by Merck Research Laboratories. 1 Current address: Department of Neuroscience, Neurocrine Biosciences, Inc., San Diego, CA. 2 Current address: Sepracor, Inc., Marlborough, MA. 3 Current address: UCLA, Los Angeles, CA. 4 Current address: RW Johnson Pharmaceutical Research Institute, San Diego, CA. 5 Current address: Cypress Bioscience, Inc., San Diego, CA. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.076406. ABBREVIATIONS: mGluR, metabotropic glutamate receptor; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; CB1, cannabinoid receptor 1; SR171416, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide; DIO, diet-induced obese; MTEP, 3-[(2methyl-1,3-thiazol-4-yl)ethynyl]-pyridine; dexfen, dexfenfluramine; VEH, vehicle; ANOVA, analysis of variance; AUC, area under the curve; MTII: melanotan II; AM251, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide. 0022-3565/05/3131-395–402$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 313, No. 1 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 76406/1195212 JPET 313:395–402, 2005 Printed in U.S.A. 395 at A PE T Jornals on A ril 0, 2017 jpet.asjournals. org D ow nladed from et al., 1997); this expression is modulated by repeated exposure to, and withdrawal from, cocaine and amphetamines (Ghasemzadeh et al., 1999; Mao and Wang, 2001). Mice lacking mGlu5 do not demonstrate full locomotor responses to cocaine and do not self-administer cocaine (Chiamulera et al., 2001). Pharmacologically, mGlu5 antagonists appear to modulate addictive behaviors; the mGlu5 selective antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (Gasparini et al., 1999) reduces cocaine administration in mice (Chiamulera et al., 2001), reduces ethanol consumption in rats (Kelley and Berridge, 2002; Bäckström et al., 2004), and blocks the rewarding associations of cocaine in rodents without producing aversion (Popik and Wrobel, 2002; McGeehan and Olive, 2003). In addition, MPEP decreases nicotine selfadministration in rats and mice (Paterson et al., 2003) and reduces cocaine self-administration (Chiamulera et al., 2001). To date, an effect of mGlu5 antagonists on food intake has not been demonstrated. Consistent with the commonalities between different rewards, both glutamate and dopamine receptors in the nucleus accumbens modulate drug-seeking behaviors and food consumption (Taber and Fibiger, 1997). Several transmitter systems interact with mGlu5-containing cellular signaling pathways, including dopaminergic, cannabinoid, and serotonergic systems, and they have the potential to modify reward behavior through interactions at the nucleus accubens and accompanying ventral striatal and mesolimbic dopamine systems (Kelley and Berridge, 2002; Kelley et al., 2002). For instance, group I metabotropic receptors directly modulate rat dopaminergic neurons in ventral midbrain slices (Morikawa et al., 2003). MPEP blocks methamphetamineinduced decreases in striatal dopamine and dopamine metabolites (Golembiowska et al., 2003). These studies demonstrate that multiple reward systems utilize interactions of mGlu5 with dopamine. Additionally, we have recently demonstrated that mGlu5 antagonists may disinhibit serotonin release (Bradbury et al., 2003). As serotonin reuptake inhibitors and releasers acutely decrease appetite (Halford et al., 1998) and chronically decrease body weight, mGlu5-serotonin interactions may similarly modulate reward or feeding pathways. Finally, the cannabinoid receptor 1 (CB1) inverse agonist SR171416 reduces refeeding after food deprivation (Ravinet Trillou et al., 2003), alcohol consumption (Arnone et al., 1997), and neurochemical responses to nicotine (Cohen et al., 2002). Given that appetite is influenced by dopamine-mediated reward systems (Salamone and Correa, 2002), the studies above suggest that mGlu5 has the potential to modulate appetite control through dopamine reward system interactions. Together, the studies described above support mGlu5 involvement in neurotransmitter systems linked to acute reward-based feeding and, in the case of serotonin interactions, with metabolic endpoints as well. Thus, this lends to the notion that mGlu5 antagonists may reduce food intake and decrease weight gain in human populations. Moreover, localization of mGlu5 in the ventromedial hypothalamus (Romano et al., 1995) suggests a potential role for mGlu5 in metabolic regulation of energy balance. These converging lines of evidence led us to test the hypothesis that mGlu5 is an important modulator of feeding and energy balance in rodents. Materials and Methods