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

Abstract

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 Ϫ/Ϫ , weighed significantly less than littermate controls (mGluR5 ϩ/ϩ ), despite no difference in ad libitum food intake. After overnight food deprivation, mGluR5Ϫ/Ϫ mice ate significantly less than their mGluR5 ϩ/ϩ controls when refeeding. When on a high fat diet, mGluR5Ϫ/Ϫ 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 ϩ/ϩ , but not mGluR5 Ϫ/Ϫ 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 ϳ30%. 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.

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

“…On the other hand, administration of glutamate agonists directly into the lateral hypothalamus induces binge-type eating in rats, and this effect is blocked by the administration of NMDA receptor antagonists (Khan et al 2004). Peripheral administration of the mGlu5 antagonists MPEP or MTEP reduced food intake in rodents (Bradbury et al 2005;Semenova and Markou 2007), and food BP in rats (Paterson and Markou 2005). And, finally, NMDA receptor antagonists also suppress feeding induced by food deprivation (Stanley et al 1996) and by the infusion of neuropeptide Y (Lee and Stanley 2005).…”

Metabotropic Glutamate 5 Receptor (mGluR5) Antagonists Decrease Nicotine Seeking, But Do Not Affect the Reinforcement Enhancing Effects of Nicotine

“…Metabotropic glutamate receptors include eight subtypes that have been divided into three groups according to G-protein coupling and sequence homology: group I (mGluR1, 5), group II (mGluR2-3), and group III (mGluR4, 6-8;Conn and Pin, 1997). The moderate to high density localization of mGlu5 receptors in the frontal cortex, striatum, nucleus accumbens, and hippocampus , as well as their modulatory role in membrane excitability in these regions (eg Domenici et al, 2003) has made them a target of interest for pharmacotherapeutic intervention in substance dependence (Chiamulera et al, 2001) and obesity (Bradbury et al, 2005). Noncompetitive antagonists of mGluR5 decrease selfadministration of cocaine (Kenny et al, 2005), ethanol (Cowen et al, 2005), and nicotine (Paterson and Markou, 2005;Paterson et al, 2003).…”

Rapid Direct Excitation and Long-Lasting Enhancement of NMDA Response by Group I Metabotropic Glutamate Receptor Activation of Hypothalamic Melanin-Concentrating Hormone Neurons

“…In the present study, we found that metabotropic glutamate receptor activation exerts strong excitatory effects on MCH and hypocretin neurons in the LH, suggesting these receptors may be involved in food intake and energy homeostasis. Supporting this view, mice lacking mGluR5 weigh less than their normal littermates and an mGluR5 antagonist MPEP decreases fasting-induced refeeding in wild but in not mGluR knock-out mice (Bradbury et al, 2005). mGluRs may interact with signals related to energy homeostasis.…”

“…Functional experiments demonstrate that mGluR5 modulates food intake and energy balance (Bradbury et al, 2005). Group III mGluRs inhibit LH neurons .…”