2-Methyl-6(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward as assessed by acquisition, extinction, and reinstatement of conditioned place preference in the rat

Kam, Elizabeth L. van der; Vry, Jean De; Tzschentke, Thomas

doi:10.1016/j.ejphar.2008.12.042

Cited by 48 publications

(48 citation statements)

References 31 publications

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“…Hence, NMDA-R antagonists have been examined for their efficacy, with some success in treating opiate addiction (Herman et al 1995;Krupitsky et al 2002;Comer and Sullivan 2007). MPEP and related mGluR5 antagonists have been proposed as an alternate therapy, which may be analogous to methadone treatment in that these compounds appear to partially substitute for the primary rewarding effects of opiates (van der Kam et al 2009b;Rutten et al 2011). AMPA-Rs and glial glutamate transporters have also proven important in animal models of addiction, but many of the compounds targeting these substrates have not yet been approved for use in humans.…”

Section: Resultsmentioning

confidence: 99%

“…For example, NMDA-R and AMPA-R antagonists increase rates of heroin self-administration and produce behavioral effects consistent with a decrease in opiate reward (Semenova et al 1999;Xi and Stein 2002). Similar to its substitution-like effects in the CPP model, MPEP pretreatment reduces rates of heroin selfadministration (van der Kam et al 2007), and rats will self-administer this mGluR5 antagonist intravenously (van der Kam et al 2009b). Collectively, these observations suggest that effects on the acquisition of CPP or the self-administration of opiates, or in general, experimental phases in which the opiate drug is "on board," can be most parsimoniously explained by effects on primary reward.…”

Section: Conditioned Reinforcementmentioning

confidence: 99%

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Glutamate Mechanisms Underlying Opiate Memories

Peters

Vries

2012

Cold Spring Harbor Perspectives in Medicine

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Correspondence: tj.devries@vumc.nlAs the major excitatory neurotransmitter in the brain, glutamate plays an undisputable integral role in opiate addiction. This relates, in part, to the fact that addiction is a disorder of learning and memory, and glutamate is required for most types of memory formation. As opiate addiction develops, the addict becomes conditioned to engage in addictive behaviors, and these behaviors can be triggered by opiate-associated cues during abstinence, resulting in relapse. Some medications for opiate addiction exert their therapeutic effects at glutamate receptors, especially the NMDA receptor. Understanding the neural circuits controlling opiate addiction, and the locus of glutamate's actions within these circuits, will help guide the development of targeted pharmacotherapeutics for relapse.

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Section: Resultsmentioning

confidence: 99%

Section: Conditioned Reinforcementmentioning

confidence: 99%

Glutamate Mechanisms Underlying Opiate Memories

Peters

Vries

2012

Cold Spring Harbor Perspectives in Medicine

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“…The deletion of mGluR5 results in marked deficits in responding to the reinforcing and locomotor stimulating effects of cocaine [7] . Furthermore, the administration of the noncompetitive selective mGluR5 antagonist 2-methyl-6 (phenyethynyl) pyridine (MPEP) decreased the self-administration and/or relapse of nicotine [8,9] , cocaine [10,11] , ethanol [12][13][14] , and heroin [15,16] . MTEP, another antagonist of mGluR5, also can attenuate opiate selfadministration and opiate-seeking behavior in mice [17] .…”

Section: Introductionmentioning

confidence: 99%

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

et al. 2014

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Aim: Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats. Methods: Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming. Results: Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities. Conclusion: Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.Keywords: heroin; addiction; relapse; mGluR5; MPEP; the nucleus accumbens; striatum Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1485Sinica ( -1492 doi: 10.1038/aps.2014 published online Nov 17 2014 Original Article IntroductionRelapse is the most important manifestation of heroin addiction following prolonged periods of abstinence [1] . Relapse arises from intense craving that can be triggered by a single drug-taking experience or exposure to an environmental stimulus [2] . The pre-clinical literature indicates that longterm drug-induced alterations in glutamatergic transmission within the NAc may underlie relapse to drug-seeking behavior following the re-exposure to drugs and drugassociated stimuli during abstinence of the drug [3,4] . Type 5 metabotropic glutamate receptor (mGluR5) as a postsynaptic element is abundantly present throughout in the NAc, where it is positively coupled to NMDA receptor function and mediates various forms of synaptic plasticity [5,6] . The deletion of mGluR5 results in marked deficits in responding to the reinforcing and locomotor stimulating effects of cocaine [7] . Furthermore, the administration of the noncompetitive selective mGluR5 antagonist 2-methyl-6 (phenyethynyl) pyridine (MPEP) decreased the self-administration and/or relapse of nicotine [8,9] , cocaine [10,11] , ethanol [12][13][14] , and heroin [15,16] . MTEP, another antagonist of mGluR5, also can attenuate opiate selfadministration and opiate-seeking behavior in mice [17] . These data indicate mGluR5 plays a...

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“…Rats were pretreated with caffeine, nicotine or ethanol for 14 days, and subjected to Zoletil® conditioned place preference (CPP) and self-administration (SA). The CPP and SA tests are two of the most widely used animal models of drug addiction, that measure the rewarding (CPP) and reinforcing effects (SA) of addictive drugs (Shippenberg and Koob, 2002;van der Kam et al, 2009). In addition, the locomotor activity (ambulatory behavior) during the conditioning phase of the CPP was also evaluated.…”

Section: Introductionmentioning

confidence: 99%