Differential effects of topiramate on prefrontal glutamatergic transmission when combined with raclopride or clozapine.
Treatment with topiramate may improve negative symptoms in schizophrenia when added to typical antipsychotic drugs (APDs) but not to clozapine. Both dopaminergic and glutamatergic transmissions in the medial prefrontal cortex (mPFC) are facilitated by atypical, but not typical, APDs, which is thought to improve negative symptoms and cognitive dysfunction in schizophrenia. Our previous results show that topiramate increases prefrontal dopamine (DA) outflow when added to the D(2/3) receptorantagonist raclopride. Here, using intracellular recording in vitro, we investigated the effects of topiramate on glutamatergic neurotransmission in the rat mPFC, both when given alone and in combination with raclopride or clozapine. Neither topiramate nor raclopride alone had any effect on N-methyl-D-aspartate (NMDA)-induced currents in pyramidal cells of the mPFC. However, the combination of topiramate and raclopride facilitated the NMDA-induced currents, and this effect was blocked by the D1 receptor antagonist SCH23390. Topiramate also facilitated the effect of a submaximal, but inhibited the effect of a maximal, concentration of clozapine on these currents. The effect of combined topiramate and a submaximal concentration of clozapine could be blocked by SCH23390. In addition, combined topiramate and raclopride facilitated excitatory postsynaptic potentials. In contrast, topiramate inhibited clozapine's facilitating effect on these potentials. These data may help explain the improvement of negative symptoms when topiramate is used as adjunctive therapy in schizophrenic patients receiving typical APDs, but they may also shed light on the observed deterioration of symptoms when topiramate is added to full dose clozapine.
Jardemark
Kent E
KE
Karolinska Institutet, Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, S-171 77 Stockholm, Sweden. kent.jardemark@ki.se
Konradsson
Asa
A
Schilström
Björn
B
Marcus
Monica M
MM
Svensson
Torgny H
TH
D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D020891:Raclopride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D000077236:Topiramate
D018492:Dopamine Antagonists; D018696:Neuroprotective Agents; D012702:Serotonin Antagonists; D000077236:Topiramate; D005632:Fructose; D018698:Glutamic Acid; D020891:Raclopride; D016202:N-Methylaspartate; D003024:Clozapine