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The mGlu5 receptor antagonist MTEP attenuates opiate self-administration and cue-induced opiate-seeking behaviour in mice

https://doi.org/10.1016/j.drugalcdep.2011.11.002Get rights and content

Abstract

The mGlu5 receptor (mGluR5) has been implicated in the rewarding effect of various drugs of abuse and drug-seeking behaviour. In the present study we investigated the impact of antagonism of mGluR5 with the selective negative allosteric, modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on operant self-administration of morphine as well as cue-induced drug-seeking in adult CD1 mice. Administration of MTEP (20 mg/kg, i.p.) attenuated operant responding for morphine (0.1 mg/kg/infusion) and cue-induced morphine-seeking after a period of forced abstinence. Collectively, these data implicate mGluR5 in the reinforcing effects of opiates and support the proposition that mGluR5 is a potential therapeutic target for treatment of drug addiction.

Introduction

Opiates represent the single largest contribution to illicit drug-related mortality and morbidity worldwide and remain a major clinical problem for society (Darke et al., 2007). Over the last two decades, a body of evidence has accumulated implicating the neurotransmitter l-glutamate in the both the rewarding effects of various drugs of abuse and drug-seeking behaviour (Kalivas et al., 2009, Duncan and Lawrence, 2011). The metabotropic glutamate type 5 receptor (mGluR5), has been implicated the actions of many drugs of abuse such as alcohol (Cowen et al., 2005, Bird et al., 2008), nicotine (Kenny et al., 2003) and cocaine (Chiamulera et al., 2001, Bird et al., 2010, Novak et al., 2010).

The evidence obtained thus far regarding the role of mGluR5 in the rewarding effects of opiates remains somewhat inconclusive, with the majority of data obtained from the conditioned place preference (CPP) paradigm. Opiate reward, as measured by CPP, remains unaffected by doses of the less-selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) at or lower than 20 mg/kg, while a dose of 30 mg/kg significantly attenuates morphine-induced CPP in C57/Bl6 mice (Popik and Wrobel, 2002, McGeehan et al., 2004). This latter finding is supported by the observation that centrally administered MPEP reduces morphine-induced CPP in ICR mice (Aoki et al., 2004). In addition, an operant study has reported modest attenuation of heroin self-administration by MPEP (van der Kam et al., 2007).

More recently, evidence has been forthcoming which implicates mGluR5 in associative reward learning processes more generally. Thus, systemic administration of the more selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning disrupts the expression of conditioned reinforcement by food delivery (O’Connor et al., 2010). This suggests a critical role for mGluR5 in the acquisition of incentive properties by a conditioned stimulus (CS) (O’Connor et al., 2010). In support is the finding that mice with knockdown of mGluR5 in striatal D1-expressing neurons exhibit diminished cue-induced cocaine-seeking, as well as impaired incentive learning (Novak et al., 2010). Hence, mGluR5 may play a central role in associative reward learning processes (Novak et al., 2010) in addition to the rewarding properties of drugs of abuse.

The objective of the present study was to assess the role of mGluR5 in the reinforcing properties of opiates, as well as cue-induced opiate-seeking behaviour as assessed by the operant self-administration paradigm. MPEP has been found to have numerous off-target effects at high concentrations (Lea and Faden, 2006), therefore, the more recently developed mGluR5 antagonist MTEP was chosen for this study. MTEP shows greater selectivity for the mGluR5 and greater bioavailability (Anderson et al., 2002, Cosford et al., 2003), and is therefore less likely to have off-target effects.

Section snippets

Methods

Singly housed adult male CD1 mice 12–20 weeks of age (n = 17) were implanted with indwelling venous cannulae and trained to self-administer morphine (0.1 mg/kg/infusion, fixed ratio (FR) 1) for 10 days as previously described (Brown et al., 2009). Daily sessions were 2 h in length and a time out period of 10 s occurred after each infusion. 9 mice were randomly selected to assess the impact of MTEP (20 mg/kg, i.p.) on self-administration of morphine at this dose. After 3 days of stable responding

Results

As shown in Fig. 1a, mice readily self-administered morphine at a dose of 0.1 mg/kg/infusion and MTEP significantly decreased this responding. Analysis by two-way ANOVA of lever-pressing data revealed a significant interaction between lever × treatment (F(1,28) = 9.55, p < 0.001). Subsequent Student–Newman–Keuls (SNK) post hoc analyses revealed that this was due to the significantly enhanced responding on the active (morphine) lever versus the inactive lever within vehicle treatment (q = 8.22, p < 0.001).

Discussion

To our knowledge, this is the first study to examine the impact of mGluR5 antagonism by the selective negative allosteric modulator MTEP on opiate self-administration and opiate-seeking behaviour in mice. At the dose tested MTEP markedly attenuated responding for morphine and cue-induced morphine-seeking behaviour after a period of abstinence, suggesting a role for mGluR5 in regulating opiate reward and opiate-seeking behaviour. This role appears to be facilitatory as antagonism attenuated

Acknowledgements

These studies were supported by the National Health & Medical Research Council of Australia (project grant 566736) of which AJL is a Principal Research Fellow and RMB is an Early Career Research Fellow. Financial support from the Pratt/Besen Foundations is also gratefully acknowledged. This work was also supported by the Victorian Government's Operational Infrastructure Support Program.

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