The atypical neuroleptics, clozapine and olanzapine, have superior therapeutic efficacy against the negative symptoms of schizophrenia, compared with the typical neuroleptics. Recently, it has been suggested that the ability of clozapine and olanzapine to induce Fos expression in the medialClozapine, a prototype atypical antipsychotic compound, is effective not only against the positive, but also against the negative symptoms of schizophrenia (Claghorn et al. 1987;Kane et al. 1988) which are usually resistant to typical neuroleptics. The mechanisms underlying this action, although investigated intensively, remain to be established. Recent studies involving the Fos protein have demonstrated that clozapine induces a much larger increase in the number of neurons that exhibit Fos-like immunoreactivity (LI) in the medial prefrontal cortex (mPFC) than do typical neuroleptics (Deutch and Duman 1996; Fink-Jensen and Kristensen 1994; Fink-Jensen et al. 1995;Guo et al. 1995;Kurokawa et al. 1997;Robertson and Fibiger 1992;Robertson et al. 1994;Wan et al. 1995). This regionally specific clozapine effect sets it apart from typical neuroleptics.Although simple neuronal depolarization or increase in firing rate per se are not enough to induce c-fos in many neurons, other factors such as phenotype of neuronal cell are also required for c-fos expression, Fos protein is thought to be a marker of activated neurons in specified subset of neurons (Sagar et al. 1988; Dragunow and Faull 1989;Grant et al. 1992;Sharp et al. 1993). Therefore, it can be postulate that clozapine may enhance neuronal activity in the mPFC. In connection with the hypothesis that hypofrontality may be responFrom the Department of Neuropsychiatry (KO, TH, YL, HS, SK), Okayama University Medical School, Shikata-cho Okayama, Japan; and Takaoka Hospital (YF), Nishi-imazyuku Himeji, Japan.Address correspondence to: Dr. T. Hamamura, Department of Neuropsychiatry, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama, 700-8558 Japan.Received November 9, 1999; revised February 8, 2000; accepted February 17, 2000. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 2 Clozapine-and Olanzapine-induced Fos in mPFC 163 sible for the negative or deficit symptoms of schizophrenia (Weinberger 1988), the preferential induction of Fos-LI in the mPFC is postulated to be one of the mechanisms by which clozapine reduces the negative symptoms of schizophrenia (Robertson et al. 1994). If this is the case, it is important to determine the neuropharmacological mechanisms by which clozapine induces Fos expression in the mPFC. Although clozapine is known to have an affinity for various neurotransmitter receptors, such as noradrenergic, dopaminergic, histaminergic, muscarinic and 5-hydroxytryptamine (5-HT) receptors, the precise neuropharmacological action of clozapine that results in the induction of Fos expression in the mPFC is unknown. Since clozapine administration increases the firing rate of noradrenergic cells in the locus coeruleus (LC) and noradrenaline release from...

Lithium has been used widely for the treatment of manic states. Since amphetamines produce effects in humans similar to the symptoms of idiopathic mania, amphetamine administration to animals has been proposed as a model of this condition. To investigate the neurobiologic substrates of the antimanic effects of chronic lithium administration, we investigated its effects on methamphetamine-induced regional Fos protein expression in the rat brain. Chronic lithium administration (14 days; serum lithium concentration, 0.41+/-0.02 mEq/l) significantly reduced the number of neuronal nuclei showing immunoreactivity induced by methamphetamine (2mg/kg) in the prefrontal cortex, caudate/putamen, nucleus accumbens, and central nucleus of the amygdala. These results indicate the structural basis in CNS which is responsible for the antimanic effect of lithium.

These results suggest that the shell region may be one possible target for the antidepressant effects of fluoxetine and reboxetine. Furthermore, the difference in their clinical effects may depend on their different target sites of action.

Acute administration of typical and atypical antipsychotics has been reported to induce regionally distinct patterns of c-Fos expression in the rat forebrain. Furthermore, atypical index, the difference in the extent of increased Fos-like immunoreactivity (Fos-LI) in the nucleus accumbens (NAc) shell versus the dorsolateral striatum (DLSt), has been proposed to classify antipsychotics into typical or atypical antipsychotics. The present study was conducted to investigate the atypical properties of 24 antipsychotics that are used in Japan and blonanserin, a novel 5-HT2A and D2 receptor antagonist. We systematically examined the effects of the drugs on Fos-LI in the NAc and DLSt in the rat brain using immunohistochemistry and calculated the atypical index, comparing with those of haloperidol and clozapine. Floropipamide, oxypertine, nemonapride, pimozide and mosapramine, as well as clozapine, olanzapine, quetiapine and risperidone, showed high positive atypical index. Zotepine, perospirone, sulpiride, moperone, sultopride, thioridazine, carpipramine, clocapramine and blonanserin showed moderate ones. In contrast, fluphenazine, bromperidol, timiperone, spiperone, propericiazine, perphenazine, chlorpromazine and levomepromazine had negative atypical index like haloperidol. These results suggest that not only so-called atypical antipsychotics, but also several conventional drugs, possess atypical properties.

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