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The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

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Abstract

Rationale

Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine.

Objectives

The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice.

Methods

Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair.

Results

MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice.

Conclusions

These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission.

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Acknowledgements

The authors would like to thank Mike Arends for editorial assistance, and Bob Lintz and Jessica Chevrette for technical assistance. This is publication number 15014-NP from The Scripps Research Institute. This study was supported by NIDA grant DA11946, Tobacco-Related Disease Research Program Grant 10RT-0074 from the State of California and a Novartis Research Grant to AM. S.S. was supported by Tobacco-Related Disease Research Program Fellowship 10FT-0323.

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Authors and Affiliations

  1. Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

    Neil E. Paterson, Svetlana Semenova & Athina Markou

  2. Nervous System Research, Novartis Pharma AG, 4002, Basel , Switzerland

    Fabrizio Gasparini

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  1. Neil E. Paterson
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  2. Svetlana Semenova
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  3. Fabrizio Gasparini
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  4. Athina Markou
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Correspondence to Athina Markou.

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Paterson, N.E., Semenova, S., Gasparini, F. et al. The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology 167, 257–264 (2003). https://doi.org/10.1007/s00213-003-1432-z

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  • DOI: https://doi.org/10.1007/s00213-003-1432-z

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