Drug and Alcohol Dependence 123 (2012) 264–268 Contents lists available at SciVerse ScienceDirect Drug and Alcohol Dependence j ourna l ho me pag e: www.elsevier.com/locate/drugalcdep Short communication The mGlu5 receptor antagonist MTEP attenuates opiate self-administration and cue-induced opiate-seeking behaviour in mice Robyn M. Brown a , Monique R. Stagnitti a , Jhodie R. Duncan a,b , Andrew J. Lawrence a,c,∗ a Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria 3010, Australia b Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria 3010, Australia c Centre for Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia a r t i c l e i n f o Article history: Received 28 July 2011 Received in revised form 2 November 2011 Accepted 3 November 2011 Available online 29 November 2011 Keywords: Reinstatement Morphine Intra-venous self-administration Drug-seeking MGluR5 Opiates Relapse a b s t r a c t 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. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. 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 neu- rotransmitter 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 inconclu- sive, 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 antag- onist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) at or lower than 20 mg/kg, while a dose of 30 mg/kg significantly attenuates ∗ Corresponding author at: Florey Neuroscience Institutes, University of Mel- bourne, Parkville, Victoria 3010, Australia. Tel.: +61 3 8344 0414; fax: +61 3 9348 1707. E-mail address: andrew.lawrence@florey.edu.au (A.J. Lawrence). 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 antag- onist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning disrupts the expression of conditioned reinforce- ment 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 D 1 -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 learn- ing 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 oper- ant 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 0376-8716/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2011.11.002