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NEUROPHARMACOLOGY

Metabotropic Glutamate Receptor mGlu5 Is a Mediator of Appetite and Energy Balance in Rats and Mice

Departments of Neuropharmacology (M.J.B., U.C., D.G., D.C., J.A., M.A.V.) and Chemistry (C.K., L.T., N.D.P.C.), Merck Research Laboratories, San Diego, California; and Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey (A.M.S.)

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.

Address correspondence to: Alison M. Strack, Department of Pharmacology, RY80Y-145, Merck Research Labs, Box 2000, Rahway, NJ 07065. E-mail: alison_strack{at}merck.com

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