The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats

Paterson, Neil E.; Markou, Athina

doi:10.1007/s00213-004-2070-9

Cited by 146 publications

(123 citation statements)

References 42 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…Glutamatergic systems have also received attention for their effects on eating behavior (e.g., Parsons et al 2005). For example MPEP, a metabotropic glutamate receptor 5 antagonist, has been shown to decrease the BPs for standard food, and intravenously self-administered cocaine or nicotine (Paterson and Markou 2005). Recently, we have shown that memantine (MEM), which blocks glutamatergic N-methyl-D-aspartate (NMDA) receptors, also decreased intake of both highly palatable food and standard food pellets by baboons, but only increased the latency to the first meal when the standard diet was available (Bisaga et al submitted).…”

Section: Introductionmentioning

confidence: 99%

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

2008

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Rationale-Procedures for studying the effects of medications on satiation will assist the development of obesity medications.Objectives-Develop a procedure for measuring satiation during consumption of bland and highly palatable food, and determine the effect of acute intramuscular administration of dexfenfluramine (DFEN), which increases serotonin levels, and memantine (MEM), which blocks N-methyl-Daspartate receptors.Methods-A modified progressive ratio (PR) procedure was used to track changes in reinforcing strength when a food was consumed. The response requirement increased after each reinforcement, and reinforcing strength was estimated using the breakpoint (BP), which was the last completed response cost. There was one preferred food (sweet candy) and one chow pellet PR session per week. During each session, 4 male and 4 female adult baboons experienced three 1-hr PR trials, separated by 30 min. Chow pellets were available at all other times. We examined the BP for 1 to 20 candies or chow pellets. Drug effects were examined when baboons had access to 1 and 10 candies/pellets.Results-Breakpoints for candy were greater than for pellets. Varying the pellet/candy pieces per delivery, produced an inverted U-shaped function on the first trial, i.e., maximal BP was observed for 3 items, and the BP for multiple items, but not a single item, decreased across trials, i.e., BP decreased with food intake and satiation. DFEN and MEM decreased responding with the greatest effects at 10 deliveries suggesting that DFEN and MEM enhanced satiation.Conclusion-Drugs that enhance satiation for several types of food may be particularly effective for decreasing food intake.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2008

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“…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). Many of these studies suggest that mGlu5 receptors mediate drug reinforcement and reward-related learning (see also Bäckström and Hyytiä, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies by Markou and colleagues (Harrison et al, 2002;Paterson and Markou, 2005;Paterson et al, 2003) suggest that the mGluR5 system may mediate primary reinforcement by nicotine, without impinging upon the reinforcement enhancing effects of drug administration. For example, administration of a selective antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), decreased nicotine self-administration in rats and mice and decreased the motivation to take nicotine as measured on a progressive ratio schedule (Paterson and Markou, 2005). In contrast, MPEP did not alter nicotine's ability to lower intracranial self-stimulation thresholds (Harrison et al, 2002), suggesting the mGlu5 systems may not mediate the reinforcement enhancing effects of nicotine.…”

Section: Introductionmentioning

confidence: 99%

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

Palmatier

Liu

Donny

et al. 2007

Neuropsychopharmacol

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Nicotine self-administration models typically evaluate the effects of smoking cessation aides on 'primary reinforcement' engendered by nicotine. However, the more recently described reinforcement enhancing effects of the drug are not always included in experimental analyses of potential therapeutics. We evaluated the effects of pretreatment with noncompetitive antagonists of the metabotropic glutamate 5 receptor (mGluR5) on each reinforcement-related effect of nicotine using a model in which a reinforcing visual stimulus (VS) and nicotine infusions were concurrently available. Five groups (2-lever, VS-only, NIC + VS, NIC-only, or SAL-only) were instrumented for self-administration. The 2-lever group could earn a nicotine infusion (0.06 mg/kg per infusion free base) for meeting the schedule on one lever (eg right), or VS for meeting the schedule on the other lever (eg left). The VS-only group could earn VS or saline under similar contingencies. Remaining rats could press one lever to earn both reinforcers (NIC + VS), nicotine infusions (NIC-only), or saline infusions (SAL-only); the other lever was 'inactive'. Responding on the VS lever in the 2-lever group was greater than that of the VS-only group, reflecting the reinforcement-enhancing effect of nicotine. Pretreatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) decreased nicotine intake as well as the enhanced responding for the concurrently available VS. In follow-up studies, replacing nicotine via experimenter-administered infusions sustained the drugs reinforcement enhancing effect; neither MPEP nor MTEP decreased the enhancing effects of nicotine. These findings are consistent with other studies suggesting that mGlu5 receptors mediate nicotine seeking, but do not alter the reinforcement enhancing effects of nicotine.

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“…The EVH1 domain exhibits a high degree of similarity across Homer isoforms and is essential for Homer interactions with a proline-rich sequence (PPSPF) displayed by proteins regulating drug-induced alterations in neuronal morphology, synaptic architecture, and glutamate receptor signaling/intracellular calcium dynamics. Of particular relevance to drug-induced neuroplasticity [e.g., 20,73,74,[78][79][80][81][82][89][90][91][92][93][94][95][96][97][98][99][100][123][124][125][126][127][128][129][130], these proteins include the mGluR1a and mGluR5 subtypes of Group 1 metabotropic glutamate receptors (mGluRs) [34,102,104,107,[131][132][133][134][135][136][137], the NMDA glutamate receptor scaffolding protein Shank [38,132,138,139], the inositol-1,4,5-triphosphate (IP3) receptor, a down-stream mediator of Group1 mGluR signaling [133,[140]…”

Section: Molecular Aspects Of Homer Proteinsmentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

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Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

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The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats

Abstract: The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.

Cited by 146 publications

References 42 publications

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

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

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

Homers regulate drug-induced neuroplasticity: Implications for addiction

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