title: Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride.
abstract: Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats. Therefore, we investigated the putative antipsychotic-like activity of topiramate when added to the selective dopamine (DA) D2 receptor antagonist raclopride, using the CAR model in the rat. Extrapyramidal side effect liability of the drug combination was evaluated in parallel by means of the catalepsy test. We also examined the effect of this drug treatment on DA release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis in freely moving animals. Topiramate (40 mg/kg), while ineffective when given alone, significantly augmented the antipsychotic-like effect of raclopride (0.075 mg/kg) on CAR without any concomitant catalepsy. Addition of topiramate to rats treated with raclopride generated a large increase in DA output in the mPFC, whereas no additional effect on the raclopride-induced DA release in the NAC was obtained. These data support the adjunctive use of topiramate in schizophrenia to ameliorate negative symptoms and suggest that this treatment may increase the efficacy, but not the extrapyramidal side effect liability, of the APDs used.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Nanna Svartz Väg 2, 171 77, Stockholm, Sweden.
authors.forename: Amani
authors.initials: A
authors.lastname: Eltayb
authors.forename: Marie-Louise G
authors.initials: ML
authors.lastname: Wadenberg
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D020891:Raclopride / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D014150:Antipsychotic Agents; D000077236:Topiramate; D005632:Fructose; D020891:Raclopride; D004298:Dopamine