The Effect Of Cocaine Self-administration And Priming- And Cue-induced Reinstatement On mGluR5 And MOP Receptor System In Mouse Brain

P Georgiou1, I Kitchen1, S Hourani1, R Maldonado0,2, A Bailey1. 1University of Surrey, Faculty of Health and Medical sciences, GU2 7TE, Guildford, Surrey, UK, 2Universitat Pompeu Fabra, Department of Experimental and Health Sciences, 88 08003, Barcelona, Spain

Cocaine addiction is a chronic relapsing disorder characterised by intense craving for the drug following cessation of drug-taking. Relapse can be triggered by drug-associated cues and re-exposure of the drug itself. The neuronal mechanisms underlying relapse are not well characterised. There is evidence suggesting that the metabotropic glutamate receptor 5 (mGluR5) and the mu-opioid (MOP) receptors may be involved in the neurobiology of relapse1,2. The aim of this study was to assess the regulation of mGluR5 and MOPr density during acquisition, cocaine priming and cue-elicited reinstatement of cocaine-seeking using a new mouse model of reinstatement of cocaine self-administration.

Male CD1 mice (20-25g) were trained to acquire intravenous self-administration of cocaine (1mg/kg/infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. Mice were divided into 3 groups (n=6/group): a) Mice subjected to self-administration of cocaine b) Mice subjected to extinction training following cocaine self-administration, which then underwent testing for reinstatement triggered by cocaine priming injection (10 mg/kg, i.p.) or c) by a light cue associated with cocaine administration. Mice undergoing the same protocols but receiving saline infusion instead of cocaine were used as controls. Animals were killed 2 hours after the completion of the last session in the operant chamber. Quantitative autoradiographic mapping of mGluR5 and MOPr binding was carried out in these brains using of 10nM [3H]MPEP and 4nM [3H]DAMGO respectively.

Two-way ANOVA (drug treatment x protocol), performed in each individual brain region revealed region specific regulation of mGluR5 and MOPr binding. A significant upregulation of mGluR5 binding was identified in the nucleus accumbens core (AcbC) of mice subjected to cocaine priming-elicited reinstatement (p<0.05) but not in mice undergoing cocaine self-administration or cue-induced reinstatement of cocaine-seeking (p>0.05, Newman–Keuls post-hoc test). mGluR5 binding was found to be increased in the lateral septum of cocaine-treated animals (p<0.001, treatment effect). In the basolateral amygdala, cocaine self-administration (p<0.05) and cue-induced reinstatement (p<0.05), but not cocaine priming-induced reinstatement of cocaine-seeking (p>0.05) induced a downregulation of mGluR5 binding (Newman–Keuls post-hoc test).

MOPr autoradiographic binding analysis showed a significant treatment effect in the nucleus accumbens shell (AcbSh), AcbC (p<0.001), lateral and medial caudate putamen (CPuL and CPuM) (p<0.01) and a significant treatment x protocol interaction in the AcbC, CPuL and CPuM (p<0.05). A significant dowregulation of MOPr binding was identified in the AcbSh (p<0.05), AcbC (p<0.01), CPuL (p<0.05), CPuM (p<0.01) of mice subjected to cocaine self-administration or cue-induced reinstatement of cocaine-seeking but not in mice undergoing priming-induced reinstatement of cocaine-seeking (p>0.05) (Newman–Keuls post-hoc test).

These results demonstrate profound brain specific neuroadaptations of the mGluR5 and MOPr systems following cocaine self-administration and/or cue- or priming-induced reinstatement of cocaine-seeking. In addition, the results suggest that cue- and priming-elicited reinstatement induce distinct differential regulation of these receptors in specific brain regions associated with reward, emotions or stress which may be a key neurobiological mechanism involved in the pathophysiology of cocaine addiction and relapse after abstinence.

1. Martin-Fardon et al. (2009), J Pharmacol Exp Ther , 329(3), 1084-90.

2. Tang et al. (2005), J Neurosci, 25(18), 4512–4520