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N-Methyl-D-aspartate (NMDA)-type glutamic acid receptors play a critical role in excitatory synaptic transmission, synaptic plasticity and neuronal development in the central nervous system. During the developmental stage from week 25 of gestation to birth in humans, elongation and branching of axons and dendrites of nerve cells, synapse formation, myelination and realignment of nerve pathways (neural circuits) for acquiring higher neural function actively proceed, and this stage corresponds to postnatal weeks 1 through 2 in mice.1) It is generally recognized that non-synapse-mediated intercellular glutamic acid is largely involved in this process of nerve development. Stimulation of NMDA receptors facilitated radial migration of the cortical plate of excitatory nerve cells 2) and the selective blockade of NMDA receptors disturbed neuronal migration in the cerebral cortex.3)It has been reported that rats injected subcutaneously (s.c.) with phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, at 10 mg/kg once a day during the postnatal development stage (postnatal days 7, 9 and 11) exhibit an increase in spontaneous motor activity, impairment of prepulse inhibition and behavioral changes in respect of learning and cognition after attaining maturation.4-7) When rats neonatally administered PCP were examined for any changes in the binding capacity of NMDA receptors and g-aminobutyrate A (GABA A ) receptors at maturity by autoradiography using In the present study, we investigated brain function from the behavioral, anatomical and neurochemical viewpoints in mice injected with PCP at 10 mg/kg on postnatal days 7, 9 and 11. Especially, we focused on changes in social interaction in PCP-treated mice, and examined the effects of clozapine, an atypical antipsychotic drug, D-cycloserine, an NMDA receptor partial agonist, flumazenil, a benzodiazepine receptor antagonist, and SHC50911, a GABA B receptor antagonist on social interaction deficits in PCP-treated mice. Of note, as far as we are aware, this is the first experimental demonstration that neonatal PCP treatment in mice results in increased sensitivity to PCP, and impaired social interaction behaviors in adulthood, which are accompanied by a decrease in the number of GABAergic interneurons and spine density in the frontal cortex and hippocampus, and abnormal monoamine metabolism in the brain. Neonatal PCP treatment in mice could be regarded as a neurodevelopmental animal model for schizophrenia. MATERIALS AND METHODSMethods. Animals Male mice aged 13 weeks old and female mice aged 13 weeks old Crlj:CD1 (ICR) were mated, and male offspring were used on postnatal day 7. Animals were maintained in a room controlled at 23°C and 55% humidity with a 12-h lighting cycle (lights on: 6:00 a.m.), and 12 ventilations/h. Animals had free access to solid feed (CRF-1; Oriental Yeast Co., Ltd., Tokyo, Japan) from feed- Kakuma-machi, Kanazawa 920-1192, Japan: b Nihon Bioresearch Inc.; 6-104 Majima, Fukuju-cho, Hashima, Gifu 501-6251, Japan: c Narabyouri Research Co.,...

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Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.

1 The atypical antipsychotic pro®le of (R)-(+)-2-amino-4-(4-¯uorophenyl)-5-[1-[4-(4-¯uorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D 4 and 5-hydroxytryptamine (5-HT) 2A receptor antagonist, was examined in rats. 2 Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED 50 3.7 mg kg 71 ), haloperidol (ED 50 0.1 mg kg 71 ) and chlorpromazine (ED 50 0.9 mg kg 71 ), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg 71 , did not exceed 50%. 3 Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg 71 , i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED 50 0.4 mg kg 71 , i.p., and 0.3 mg kg 71 , p.o., respectively), clozapine (ED 50 0.3 mg kg 71 , i.p. and 0.8 mg kg 71 , p.o., respectively), haloperidol (ED 50 0.02 mg kg 71 , i.p. and 0.1 mg kg 71 , p.o., respectively), chlorpromazine (ED 50 0.3 mg kg 71 , i.p. and 3.3 mg kg 71 , p.o., respectively). In contrast, the MAP (3 mg kg 71 , i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not a ected by NRA0045 or clozapine, at the highest dose given (30 mg kg 71 , i.p.). Haloperidol (ED 50 0.3 mg kg 71 , i.p.) and chlorpromazine (ED 50 4.8 mg kg 71 , i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/ mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4 Extracellular single-unit recording studies demonstrated that MAP (1 mg kg 71 , i.v.) decreased the ®ring rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 0.1 mg kg 71 , i.v.), whereas the inhibitory e ects of MAP on A9 dopamine neurones were not a ected by NRA0045, in doses up to 1 mg kg 71 (i.v.). Clozapine completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 1.9 mg kg 71 , i.v.) and on A9 dopamine neurones (ED 50 2.5 mg kg 71 , i.v.). Haloperidol completely reversed the inhibitory e ects of MAP on A10 (ED 50 0.03 mg kg 71 , i.v.) and on A9 dopamine neurones (0.02 mg kg 71 , i.v.). NRA0045, like clozapine, was more potent in reversing the e ects of MAP on A10 than A9 dopamine neurones. 5 Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg 71 , s.c.) was reversed signi®cantly by NRA0045 (3 mg kg 71 , i.p.), clozapine (3 mg kg 71 , i.p.) and haloperidol (0.3 mg kg 71 , i.p.). 6 Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03 ± 0.3 mg kg 71 , i.p.) and clozapine (0.1 ± 1 mg kg 71 , i.p.) signi®cantly and dose-dependently shortened the PCP(1.25 mg kg 71 , i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (...