Particle inhalation-induced lung inflammation acts as an adjuvant to allergens or respiratory viral infection in a process that is mediated by macrophages and epitheliums. The production of interleukin (IL)-4 and IL-13 by activated T cells is involved in the augmentation of Th2-type immune responses to particles, and IL-25 induces the synthesis of IL-4 and IL-13. However, whether IL-13 and IL-25 are directly regulated by particle instillation in the lung has not been studied. The aim of this study was to reveal particle induction of IL-13 and IL-25 in the lung. TiO(2) instillation potently induced the mRNA expression for IL-25 and IL-13 in lung tissue extracts 24 h after treatment, as compared with the sham group. Immunostaining for IL-25 and IL-13 showed strong positivity for macrophages in the inflammatory lung lesions of TiO(2)-treated rats. The alveolar macrophages expressed IL-25 and IL-13 24 h after in vitro stimulation with TiO(2) particles in dose- and time-dependent manners, with maximal induction at 24 and 48 h after stimulation, respectively. The sequence of the rat IL-25 gene is 95% homologous with the mouse IL-25 gene. These findings indicate that alveolar macrophages play an important role in particle-induced lung inflammation via direct induction of IL-13 and IL-25 production.

Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further investigation. In this study, we examined the effects of long-term treatment of risperidone on two serotonin receptor subtypes in brain regions of juvenile rat. Levels of 5-HT 1A and 5-HT 2A receptors in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/ kg). Findings were compared to previously reported changes in 5-HT receptors after risperidone treatment (3.0 mg/kg) in adult rat brain. The three doses of risperidone selectively and dosedependently increased levels of 5-HT 1A receptors in medial prefrontal and dorsolateral frontal cortices of juvenile animals. The higher doses (1.0 and 3.0 mg/kg) of risperidone also increased 5-HT 1A receptor binding in hippocampal CA 1 region of juvenile but not adult rats. In contrast, the three doses of risperidone significantly reduced 5-HT 2A labeling in medial prefrontal and dorsolateral frontal cortices in juvenile as well as in adult animals in an equipotent fashion. 5-HT 1A and 5-HT 2A receptors in other forebrain regions were not altered by repeated risperidone treatment. These findings indicate that there are differential effects of risperidone on 5-HT 1A and 5-HT 2A receptors in juvenile animals, and that the 5-HT system in developing animals is more sensitive than adults to the long-term effects of risperidone.

Levels of ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA), and kainic acid (KA) receptors in forebrain regions of juvenile rats (age 42 days) were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg) and compared findings to those in adult rats treated with risperidone (3.0 mg/kg/day) previously. Risperidone (at 0.3 mg/kg/day) did not alter levels of three ionotropic Glu receptors in all brain regions examined. Risperidone (at 1.0 and 3.0 mg/kg/day) significantly decreased NMDA binding in caudate-putamen of juvenile and adult animals. In contrast, the same two doses of risperidone decreased NMDA receptors in nucleus accumbens of juveniles and not adults. Risperidone (at 1.0 and 3.0 mg/kg/day) increased AMPA receptors in medial prefrontal cortex and caudate-putamen of juvenile animals, whereas risperidone (at 3.0 mg/kg) increased AMPA receptors in caudate-putamen and hippocampus of adults. Kainate receptors were not altered by any dose of risperidone in any brain region examined in developing and mature animals. The findings indicate that risperidone exerts dose-dependent effects on Glu receptor subtypes in developing animals, and that Glu receptor responses to repeated administration of risperidone are different in juvenile animals than adults.

No abstract

The putative gene (ygcM) of Escherichia coli was veri¢ed in vitro to encode the ortholog of 6-pyruvoyltetrahydropterin synthase (PTPS). Unexpectedly, the enzyme was found to convert sepiapterin to 7,8-dihydropterin without any cofactors. The enzymatic product 7,8-dihydropterin was identi¢ed by HPLC and mass spectrometry analyses, suggesting a novel activity of the enzyme to cleave the C6 side chain of sepiapterin. The optimal activity occurred at pH 6.5^7.0. The reaction rate increased up to 3.2-fold at 60^80 ‡C, re£ecting the thermal stability of the enzyme. The reaction required no metal ion and was activated slightly by low concentrations (1^5 mM) of EDTA. The apparent K m value for sepiapterin was determined as 0.92 mM and the V max value was 151.3 nmol/min/ mg. The new catalytic function of E. coli PTPS does not imply any physiological role, because sepiapterin is not an endogenous substrate of the organism. The same activity, however, was also detected in a PTPS ortholog of Synechocystis sp. PCC 6803 but not signi¢cant in Drosophila and human enzymes, suggesting that the activity may be prevalent in bacterial PTPS orthologs. ß

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB-1020 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane HCl). EB-1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB-1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB-1020 dose-dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB-1020 dose-dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6-hydroxydopamine (100 μg intracisternally) as neonates; a well-established animal model for attention-deficit hyperactivity disorder (ADHD). These data suggest that EB-1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD.

Changes in representative dopamine (D(1), D(2), and D(4)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D(1) receptors in the medial and lateral caudate-putamen (22% and 23%, respectively) and increased 5HT(1A) receptor binding in the medial-prefrontal (26%) and dorsolateral-frontal cortex (30%). No changes in D(1) or 5HT(1A) receptors were detected in other brain regions. These findings suggest that downregulation of striatal D(1) receptors and upregulation of cortical 5HT(1A) receptors may contribute to PCP-induced impairment of cognitive functions in rats. Subchronic PCP treatment did not alter levels of D(2), D(4), and 5HT(2A) receptors in all brain regions examined, which suggests a minimal role for these receptors in mediating subchronic actions of PCP in adult rats.

Asenapine, a new pyschopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has a unique human receptor binding signature with strong affinity for dopaminergic, alpha-adrenergic, and, in particular, serotonergic receptors raising the possibility of interactions with glutamatergic receptors. Changes in ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA) receptors and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were quantified after repeated administration of multiple doses of asenapine (0.03, 0.1, or 0.3 mg/kg, subcutaneous, twice/day) or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP), and processed for in vitro receptor autoradiography. Four weeks of treatment with 0.03, 0.1, or 0.3 mg/kg of asenapine significantly (P < 0.01) decreased binding of [3H]MK-801 to NMDA/MK-801 modulatory sites in NAc (by 27%, 29%, and 26%, respectively), medial CPu (by 25%, 28%, and 24%), and lateral CPu (by 24%, 31%, and 26%). In contrast, the same doses of asenapine did not alter binding of [3H]glycine to NMDA/glycine modulatory sites in any of the brain regions examined. [3H]AMPA binding to AMPA receptors was selectively and significantly (P < 0.001) elevated in hippocampal CA(1) (41%) and CA(3) (40%) regions but only at the highest dose tested. These results indicate that chronic treatment with asenapine has region-specific and dose-dependent effects on ionotropic Glu-receptor subtypes in rat forebrain, which might contribute to the unique psychopharmacologic properties of asenapine.