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Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

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Abstract

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

• Topiramate increases the rewarding properties of cocaine in CPP

• Topiramate alters dopaminergic signaling in the mesolimbic circuit

• Topiramate delays the extinction of cocaine-induced CPP

• TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine

• Results show that it should limit the use of topiramate in cocaine-dependent subjects

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Acknowledgments

We wish to thank to Ana Díaz PhD, responsible for the welfare of experimental animals in our university, to INVASSAT, particularly Teresa Capilla, for laboratory equipment, and Brian Normanly for his editing of the manuscript. This work was supported by the following research grants: Ministerio de Economía y Competitividad, Dirección General de Investigación, PSI2014-51847-R (José Miñarro) and SAF2011-23420 (Jorge Manzanares). Instituto de Salud Carlos III, Redes Temáticas de Investigación Cooperativa en Salud (RECTICS), Red de Trastornos Adictivos (RTA) RD12/0028/0005 (José Miñarro), RD12/0028/0019 (Jorge Manzanares) and Fondos FEDER. Generalitat Valenciana, Conselleria de Educación, PROMETEOII/2014/063.

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Authors and Affiliations

  1. Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain

    M. C. Arenas, A. Mateos-García, C. Manzanedo, M. Rodríguez-Arias, M. A. Aguilar & J. Miñarro

  2. Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain

    M. Rodríguez-Arias, M. A. Aguilar, F. Navarrete, M. S. García Gutiérrez, J. Manzanares & J. Miñarro

  3. Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550, San Juan de Alicante, Alicante, Spain

    F. Navarrete, M. S. García Gutiérrez & J. Manzanares

Authors
  1. M. C. Arenas
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  2. A. Mateos-García
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  3. C. Manzanedo
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  4. M. Rodríguez-Arias
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  5. M. A. Aguilar
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  6. F. Navarrete
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  7. M. S. García Gutiérrez
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  8. J. Manzanares
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  9. J. Miñarro
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Correspondence to M. C. Arenas.

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Arenas, M.C., Mateos-García, A., Manzanedo, C. et al. Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness. Psychopharmacology 233, 3849–3859 (2016). https://doi.org/10.1007/s00213-016-4409-4

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  • DOI: https://doi.org/10.1007/s00213-016-4409-4

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