D'Souza MS, Markou A. Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) microinfusions into the nucleus accumbens shell or ventral tegmental area attenuate the reinforcing effects of nicotine in rats. Neuropharmacology 61: 1399-1405

Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Neuropharmacology (Impact Factor: 5.11). 08/2011; 61(8):1399-405. DOI: 10.1016/j.neuropharm.2011.08.028
Source: PubMed


Systemic administration of the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was previously shown to selectively attenuate nicotine self-administration without affecting food-maintained responding in rats. Glutamatergic neurotransmission in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) shell plays an important role in the reinforcing effects of nicotine. To determine the brain sites that may mediate the systemic effects of MPEP on nicotine self-administration, the present study investigated the effects of MPEP microinfusions into the VTA or the NAcc shell on nicotine and food self-administration in separate groups of rats. Administration of low MPEP doses (0, 0.5, 1, and 2 μg/0.5 μl/side) microinfused into the NAcc shell had no effect on nicotine self-administration, whereas higher MPEP doses (0, 10, 20, and 40 μg/0.5 μl/side) microinfused into the NAcc shell dose-dependently attenuated nicotine self-administration without affecting food-maintained responding. Microinfusions of MPEP into the VTA (0, 10, 20, and 40 μg/0.5 μl/side) significantly decreased both nicotine and food self-administration at 20 μg/0.5 μl/side but did not affect responding for either reinforcer at 40μg/0.5 μl/side. This lack of effect of 40 μg/0.5 μl/side MPEP on either nicotine or food self-administration when administered into the VTA may be attributable either to actions of MPEP at presynaptic mGlu5 receptors or at targets other than mGlu5 receptors. Importantly, anatomical control injections 2mm above the NAcc shell or the VTA using the most effective MPEP dose in the two regions did not result in attenuation of nicotine self-administration. In conclusion, MPEP microinfusions in the VTA or NAcc shell attenuates the reinforcing effects of nicotine possibly via blockade of mGlu5 receptors located in these regions.

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Available from: Athina Markou, May 21, 2015
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    • "However, a large body of evidence suggests GLU as a possible mediator of nicotine's excitatory effects and its stimulatory action on mesocorticolimbic DA transmission . Intra-VTA injections of GLU antagonists strongly attenuate several important effects of nicotine, including locomotor activation (Kelsey et al. 2002), self-administration (Kenny et al. 2009; D'Souza and Markou 2011), DA cell excitation (Svensson et al. 1998; Erhardt et al. 2002), NAcc DA release (Fu et al. 2000; Sziraki et al. 2002), and druginduced reinstatement of lever pressing (Bespalov et al. 2005). While nicotine-induced increases in extracellular GLU levels have been reported in microdialysis studies (Fu et al. 2000), the low temporal resolution of this technique limits examination of rapid GLU fluctuations induced by nicotine in awake animals. "
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    ABSTRACT: Although numerous data suggest that glutamate (GLU) is involved in mediating the neural effects of nicotine, direct data on nicotine-induced changes in GLU release are still lacking. Here we used high-speed amperometry with enzyme-based GLU and enzyme-free GLU-null biosensors to examine changes in extracellular GLU levels in the ventral tegmental area (VTA) and nucleus accumbens shell (NAcc) induced by intravenous nicotine in a low, behaviorally active dose (30 μg/kg) in freely moving rats. Using this approach, we found that the initial nicotine injection in drug-naive conditions induces rapid, transient, and relatively small GLU release (~90 nM; latency ~15 s, duration ~60 s) that is correlative in the VTA and NAcc. Following subsequent nicotine injections within the same session, this phasic GLU release was supplemented by stronger tonic increases in GLU levels (100-300 nM) that paralleled increases in drug-induced locomotor activation. GLU responses induced by repeated nicotine injections were more phasic and stronger in the NAcc than in VTA. Therefore, GLU is phasically released within the brain's reinforcement circuit following intravenous nicotine administration. Robust enhancement of nicotine-induced GLU responses following repeated injections suggests this change as an important mediator of sensitized behavioral and neural effects of nicotine. This article is protected by copyright. All rights reserved.
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    • "Specifically, mGlu5 is predominantly located post-synaptically [29], [30] in areas such as the hippocampus, cerebral cortex, nucleus accumbens (NAcc), lateral septum and the dorsal striatum [29], [31]. Moreover, mGlu5 has been implicated in drug-taking behaviour; a reduction in mGlu5 signalling reliably decreases drug-taking and drug-seeking behaviour for alcohol [32]–[34], cocaine [35], METH [36], [37], opiates [38] and nicotine [39], [40]. A reduction in the acquisition of conditioned place preference (CPP) for cocaine [41], [42] and morphine [43], as well as reduced expression of CPP for morphine [44], ethanol [45] and amphetamine [46] has also been reported following mGlu5 antagonist administration. "
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    ABSTRACT: Methamphetamine (METH) is a highly addictive psychostimulant with no therapeutics registered to assist addicts in discontinuing use. Glutamatergic dysfunction has been implicated in the development and maintenance of addiction. We sought to assess the involvement of the metabotropic glutamate 5 receptor (mGlu5) in behaviours relevant to METH addiction because this receptor has been implicated in the actions of other drugs of abuse, including alcohol, cocaine and opiates. mGlu5 knockout (KO) mice were tested in intravenous self-administration, conditioned place preference and locomotor sensitization. Self-administration of sucrose was used to assess the response of KO mice to a natural reward. Acquisition and maintenance of self-administration, as well as the motivation to self-administer METH was intact in mGlu5 KO mice. Importantly, mGlu5 KO mice required more extinction sessions to extinguish the operant response for METH, and exhibited an enhanced propensity to reinstate operant responding following exposure to drug-associated cues. This phenotype was not present when KO mice were tested in an equivalent paradigm assessing operant responding for sucrose. Development of conditioned place preference and locomotor sensitization were intact in KO mice; however, conditioned hyperactivity to the context previously paired with drug was elevated in KO mice. These data demonstrate a role for mGlu5 in the extinction and reinstatement of METH-seeking, and suggests a role for mGlu5 in regulating contextual salience.
    PLoS ONE 07/2013; 8(7):e68371. DOI:10.1371/journal.pone.0068371 · 3.23 Impact Factor
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    • "Extensive evidence implicates mGluR 5 and other postsynaptic G q -coupled receptors in the activation of diacylglycerol lipase a involved in 2-AG formation (Jung et al, 2005), although the relative influence of volitional vs forced nicotine administration on these and related G q coupled receptors have not been investigated. It is conceivable, however, that diminished 2-AG formation has a role in the attenuation of nicotine SA behavior induced by mGluR 5 antagonists (D'Souza and Markou, 2011; Tronci and Balfour, 2011). "
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