Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking

https://doi.org/10.1016/j.ejphar.2004.07.056Get rights and content

Abstract

Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.

Introduction

Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and cocaine-induced hyper-locomotion (Chiamulera et al., 2001). The role of mGlu5 receptors in the self-administration of drugs other than cocaine has been recently investigated. For example, MPEP reduces nicotine self-administration in rats and mice without affecting food self-administration (Paterson et al., 2003). In contrast, MPEP does not affect the effects of nicotine on brain stimulation reward in rats (Harrison et al., 2002). Furthermore, Popik and Wrobel (2002) demonstrated that MPEP can attenuate both the acquisition and expression of morphine-induced conditioned place preference without impairing locomotor activity and acquisition of learning and memory retrieval (Popik and Wrobel, 2002). In contrast, a lack of effect of MPEP in reducing the expression of conditioned place preference produced by nicotine, d-amphetamine, ethanol, and morphine is shown in another study (McGeehan and Olive, 2003). Finally, the oral administration of MPEP does not affect d-amphetamine-induced locomotor activity in mice (Spooren et al., 2000).

The present series of experiments aimed to clarify the importance of mGlu5 receptors in a range of behavioural paradigms that reflect different aspects of addiction. Furthermore nicotine, cocaine and natural reinforcers were studied to provide clarification of the relative contribution of mGlu5 receptors in the mediation of their effects.

Accordingly, the effects of the selective mGlu5 receptor antagonist MPEP were investigated on intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behaviour. To test whether MPEP effects would generalise to other drugs of abuse or natural reinforcers, the mGlu5 receptor antagonist was also tested for its effects on cocaine and food self-administration. In addition, MPEP was tested on the acute locomotor stimulant effects of nicotine and on the expression of behavioural sensitisation to nicotine. Finally, to clarify that MPEP was not causing non-selective behavioural disruption its effects on motor coordination using the Rotarod test were also examined.

Section snippets

Animals

Male Wistar rats (Charles River, Germany) were individually housed in a temperature-controlled environment with lights on from 0600 to 1800 h. Water was continuously available and animals were maintained at a constant body weight (240–260 g). All experiments were performed under a Project License obtained according to Italian law (art. 7, Legislative Decree no. 116, 27 January 1992), which acknowledged the European Directive 86/609/EEC.

Apparatus

Sixteen operant chambers were used to perform the

Effect of MPEP (1, 3, 10 mg/kg i.v.) on nicotine-triggered relapse to nicotine-seeking behaviour

MPEP (1, 3 and 10 mg/kg i.v.) was administered 5 min before starting the relapse session. Responding was measured throughout the session up to 120 min (Fig. 1). MPEP (1, 3 and 10 mg/kg i.v.) slightly modified responding during the first 30-min cue-component approaching significance [F(4,35)=2.5, P=0.06]. Furthermore, MPEP did not affect inactive-lever presses during the first 30-min cue-component [F(4,35)=1.08, P=0.38]. In contrast, the acute systemic administration of nicotine (0.15 mg/kg

Discussion

The results of the present study indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine-seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration.

Conclusion

The present results clearly showed an involvement of mGlu5 receptors in nicotine taking behaviour and in the reinstatement of nicotine-seeking behaviour. In addition, antagonism at mGlu5 receptors also reduced significantly cocaine-taking behaviour. The effects observed in the present study are likely to be mediated via complex glutamate-dopamine interactions in the mesocorticolimbic system where glutamatergic afferents from subcortical/cortical areas and dopaminergic afferents from the ventral

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