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Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats

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Abstract

Rationale

Evidence is accumulating that metabotropic glutamate 5 (mGlu5) receptors play an important role in regulating the reinforcing actions of drugs of abuse.

Objectives

We examined the effects of the mGlu5 receptor antagonist MPEP on cocaine consumption and cocaine-enhanced brain reward function in rats.

Methods

Cocaine consumption was measured in rats with 1 h (short-access; ShA) or 6 h (long-access; LgA) daily access to intravenous cocaine (0.25 mg/infusion) self-administration. Cocaine-enhanced brain reward function was measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds.

Results

Cocaine consumption remained stable and unaltered over successive self-administration sessions in ShA rats. In contrast, cocaine consumption progressively “escalated” in LgA rats. MPEP (1–9 mg/kg) dose-dependently decreased responding similarly in ShA and LgA rats. These data suggest that mGlu5 receptors regulate the reinforcing properties of cocaine, and that this action of mGlu5 receptors is independent of the escalation in consumption associated with extended access to cocaine self-administration. MPEP doses (1–9 mg/kg) that decreased cocaine self-administration elevated brain reward thresholds to a similar degree in cocaine- and vehicle-treated rats, indicating that MPEP induced a negative affective state. The additive effects of MPEP and cocaine on thresholds resulted in attenuation of the magnitude of cocaine-induced (10 mg/kg) lowering of ICSS thresholds.

Conclusions

Overall, mGlu5 receptors appear to play an important role in regulating cocaine consumption, and also in regulating brain reward function. Further, it is likely that blockade of mGlu5 receptors may attenuate cocaine consumption, at least in part, by decreasing the baseline activity of brain reward circuitries.

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Acknowledgements

P.J.K. and B.B. contributed equally to this work. Supported by the National Association for Research on Schizophrenia and Depression (NARSAD) (P.J.K.), the Peter F. McManus Charitable Trust (P.J.K.), Fondation pour la Recherche Medicale (B.B.), and grants from Novartis (A.M.) and the National Institute on Drug Abuse (DA04398 to G.F.K. and DA11946 to A.M.). The authors thank Mike Arends for editorial assistance. This is manuscript number 15851-NP from The Scripps Research Institute.

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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

    Paul J. Kenny, Benjamin Boutrel, George F. Koob & Athina Markou

  2. Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

    Fabrizio Gasparini

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  1. Paul J. Kenny
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  2. Benjamin Boutrel
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  3. Fabrizio Gasparini
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  4. George F. Koob
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  5. Athina Markou
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Correspondence to Athina Markou.

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Kenny, P.J., Boutrel, B., Gasparini, F. et al. Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology 179, 247–254 (2005). https://doi.org/10.1007/s00213-004-2069-2

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  • DOI: https://doi.org/10.1007/s00213-004-2069-2

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