Topiramate antagonizes MK-801 in an animal model of schizophrenia.
The phencyclidine (PCP) model of schizophrenia suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction and its consequences may play an important role in the pathophysiology of this psychiatric disorder. Moreover, the schizophreniform psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, especially negative symptoms and cognitive dysfunction. Because of interest in the PCP model and possible NMDA receptor hypofunction in schizophrenia, animal behaviors elicited by PCP and its analogues have been characterized. These preclinical models may serve to identify candidate compounds that possess therapeutic efficacy in schizophrenia. Ideally, negative symptoms and cognitive dysfunction would also serve as therapeutic targets for these novel medications. In the current study, the ability of topiramate to attenuate the severity of a specific behavior elicited by MK-801 (dizocilpine), a high affinity analogue of PCP was studied in mice. Topiramate was chosen because it addresses two of the predicted pathological consequences of NMDA receptor hypofunction. Specifically, topiramate potentiates GABAergic neurotransmission and antagonizes the excitotoxic actions of glutamate at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) classes of glutamate-gated channels. Topiramate was shown to inhibit MK-801-elicited "popping" behavior in a complex dose-dependent manner.
Deutsch
Stephen I
SI
Mental Health Service Line, Veterans Integrated Service Network 5, 849 International Drive, Suite 275, Linthicum, MD 21090, USA. Stephen.Deutsch@med.va.gov
Rosse
Richard B
RB
Billingslea
Eddie N
EN
Bellack
Alan S
AS
Mastropaolo
John
J
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006213:Hallucinogens / Q000633:toxicity; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000633:toxicity*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000633:toxicity; D012559:Schizophrenia / Q000139:chemically induced / Q000517:prevention & control*; D012565:Schizophrenic Psychology; D000077236:Topiramate
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose; D016291:Dizocilpine Maleate; D010622:Phencyclidine