Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness.
Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.



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.



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).



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.



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.



• 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.
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain. carmen.arenas@uv.es.
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Arenas
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain.
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Mateos-García
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain.
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Manzanedo
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain.|Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
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Rodríguez-Arias
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain.|Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
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Aguilar
Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.|Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550, San Juan de Alicante, Alicante, Spain.
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Navarrete
Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.|Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550, San Juan de Alicante, Alicante, Spain.
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Gutiérrez
Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.|Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550, San Juan de Alicante, Alicante, Spain.
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Manzanares
Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibañez, 21, 46010, Valencia, Spain.|Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
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Miñarro
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D012201:Reward; D000077236:Topiramate; D017557:Ventral Tegmental Area / Q000187:drug effects
D000927:Anticonvulsants; D018765:Dopamine Uptake Inhibitors; D000077236:Topiramate; D005632:Fructose; D003042:Cocaine
CPP; Cocaine; Mice; Reward effects; Topiramate; Ventral tegmental area