| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
1. We established the in vivo method of monitoring in real-time extracellular glutamate levels in rat medial prefrontal cortex by employing the microdialysis technique and then examined the effect of different types of antipsychoic drugs on prefrontal glutamate release. The atypical antipsychotic drugs such as clozapine, olanzapine and risperidone at at least one dose, but not the typical antipsychotic haloperidol, attenuated high K^+-induced extracellular glutamate levels in the medial prefrontal cortex. This finding suggests that acute administration of atypical antipsychotics may inhibit prefrontal glutamatergic activity.
2. Since atypical antipsychotic drugs selectively attenuated the expression of the immediate-early gene arc in the medial prefrontal cortex and nucleus accumbens of phencyclidine-treated rats, this animal model of schizophrenia may be useful for elucidating the sites of action of these drugs. However, alteration of dopaminergic neurotransmission may not contribute t
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o the mechanism of action of atypical antipsychotic drugs in regard to their ability to attenuate phencyclidine-induced arc expression.
3. Taken together with previous reports from other laboratories, acute administration of clozapine, risperidone and olanzapine may increase the release of dopamine, norepinephrine and acetylcholine in rat prefrontal cortex. These atypical antipsychotics may decrease prefrontal glutamate release at at least one dose, whereas risperidone, but not clozapine or olanzapine, may facilitate serotonin release. Haloperidol may have minimal effect on the prefrontal release of either neurotransmitters.
4. By means of the ability to induce the region-specific release of dopamine, norepinephrine and acetylcholine, antipsychotic drugs may be classified into three types: I. dominantly prefrontal type such as clozapine, II. Non-dominantly prefrontal type such as risperidone, and III. Dominantly subcortical type such as haloperidol. The former two types are atypical antipsychotics in regard to the clinical effects, although the type II drugs at high doses lack their atypicality. Less
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