Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/ fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 lCi of iodinated LPS ( 125 I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-a, IL-1b and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). 125I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-a, IL-1b and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1b was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

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Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPYtransgenic rat has provided a unique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacological studies. Locomotor activity and baseline behavior on the elevated plus maze were normal in transgenic subjects. Two robust phenotypic traits were observed. (i) Transgenic subjects showed a markedly attenuated sensitivity to behavioral consequences of stress, in that they were insensitive to the normal anxiogenic-like effect of restraint stress on the elevated plus maze and displayed absent fear suppression of behavior in a punished drinking test. (ii) A selective impairment of spatial memory acquisition was found in the Morris water maze. Control experiments suggest these traits to be independent. These phenotypic traits were accompanied by an overexpression of prepro-NPY mRNA and NPY peptide and decreased NPY-Y1 binding within the hippocampus, a brain structure implicated both in memory processing and stress responses. Data obtained using this unique model support and extend a previously postulated anti-stress action of NPY and provide novel evidence for a role of NPY in learning and memory.anxiety ͉ amygdala N europeptide Y (NPY) (1) is highly expressed in the mammalian brain. Its pharmacological administration into the central nervous system reduces experimental anxiety in a wide range of animal models (2-5), but its involvement in memory function is less clear. NPY receptors cloned to date all belong to the superfamily of G protein-coupled receptors but differ in their ligand affinity profiles. The NPY-Y1 receptor (6-8) requires the intact NPY sequence for recognition and activation, and seems to be the subtype mediating anti-anxiety actions of NPY (3-5, 9, 10). The Y2 receptor subtype is also activated by C-terminal fragments of NPY, such as NPY 13-36 (11). The highest number of NPY-binding sites, predominantly of the Y2 subtype, is found within the hippocampus. Activation of Y2 receptors within this structure has been shown to suppress hippocampal glutamatergic transmission through presynaptic mechanisms (12, 13), but the behavioral consequences of Y2 signaling in this area are unclear.In agreement with anti-stress effects observed following central administration of NPY, a role for endogenous NPY in control of stress and anxiety-related behaviors is suggested by several findings. Acute physical restraint, which promotes experimental anxiety (14), suppresses NPY mRNA and peptide levels within the amygdala and cortex. In contrast, repeated exposure to the same stressor once daily for 10 days leads to a complete behavioral and endocrine habituation, accompanied by an up-regulation of amygdala NPY expression (15). We have therefore proposed that an up-regulation of NPY expression may contribute to the behavioral adaptation to stress. This extends a hypothesis that NPY may act to ''buffer'' behavioral effects of st...

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The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY)inNeuropeptide Y (NPY) is a 36-amino acid peptide that is widely distributed in the central nervous system (CNS). Intracerebroventricular (ICV) administration of NPY stimulates food intake (Clark et al. 1985;Levine and Morley 1984;Stanley and Leibowitz 1984), modulates cognition (Flood et al. 1987;Redrobe et al. 1999), inhibits neuronal excitability (Colmers and Bleakman 1994) and has anticonvulsant effects (Vezzani et al. 1999). NPY modulates the secretion of various hypothalamic neuropeptides, stimulates the corticotrophic axis (Krysiak et al. 1999;Small et al. 1997) and has potent inhibitory effects on gonadotrophic and somatotrophic axes (Catzeflis et al. 1993). In addition, NPY is thought to play a role in the pathophysiology of certain mood disorders and in the mechanism of action of antidepressant drugs (Heilig et al. 1988;Caberlotto et al. 1998 (Michel et al. 1998).Clinical studies have demonstrated decreased NPY levels in the cerebrospinal fluid (CSF) (Heilig and Widerlov 1990) and plasma (Nilsson et al. 1996) of depressed patients, when compared with healthy control subjects. In addition, NPY levels have been shown to be negatively correlated to scores of anxiety in clinically depressed patients (Heilig and Widerlov 1990), suggesting a possible link between low levels of NPY and predisposition to anxiety-related or stress-induced depression.Moreover, pre-clinical studies have shown that electroconvulsive shock stimulation increased NPY gene expression (Heilig et al. 1988), as well as the expression of NPY mRNA in distinct brain regions in rats (Caberlotto et al. 1998;Mikkelsen et al. 1994). In addition, chronic antidepressant treatment has been shown to alter NPY and NPY Y 1 -type receptor mRNA levels (Caberlotto et al. 1998), and to reduce NPY Y 2 -type receptor densities in certain brain regions (Widdowson and Halaris 1991). Interestingly, NPY-like immunoreactivity and NPY Y 1 -type receptor binding sites were shown to be decreased or increased, depending on the brain region studied, in the recently developed Flinders Sensitive Line (FSL) rats (Caberlotto et al. 1999), a purported genetic animal model of depression (Overstreet 1993;Overstreet et al. 1995).Additional evidence of a role for NPY in depressive disorders is found in studies using the olfactory bulbectomized (OB) rat model of depression. Sub-chronic ICV administration of NPY attenuated the increase in ambulation, rearing, grooming and defecation scores consistently found when OB animals are tested in the open field (Song et al. 1996). Treatment with NPY also increased noradrenaline (NA) and serotonin (5-HT) levels in the amygdala and hypothalamus (Song et al. 1996). In addition, NPY reversed the supression of lymphocyte proliferation seen following OB (Song et al. 1994). A decrease in lymphocyte proliferation has also been reported in depressed patients (Kronfol and House 1989). Another study demonstrated that OB caused long term...

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Some evidence has suggested the existence and differential distribution of neuropeptide Y (NPY) receptor subtypes in the mammalian brain (Dumont et al., 1990; Aicher et al., 1991). We now report on the extensive characterization and visualization of at least two classes of NPY receptor sites using a highly selective Y1 analog, [Leu31,Pro34]-NPY or [Pro34]-NPY, and a relatively specific Y2 competitor, NPY13-36. Autoradiographic studies using 125I-peptide YY (125I-PYY) clearly reveal that the Y1 receptor subtype is most abundant in various cortical areas, the dentate gyrus of the hippocampal formation, the claustrum, and the reuniens nucleus of the thalamus. In most other regions, 125I-PYY binding is potently inhibited by increasing concentrations of either NPY2-36 or NPY13-36, suggesting a Y2-like profile. Furthermore, binding assays using homogenates from discrete brain regions clearly demonstrate that various NPY fragments and analogs compete for 125I-PYY labeling with profiles indicative of heterogeneity of NPY receptor subtypes, even in the presence of a selective Y1 blocker. Thus, it is likely that, in addition to the Y1 receptor, which is particularly concentrated in cortical areas, the rat brain is enriched with a receptor class (Y2) that can exist under high- or low-affinity states or with additional receptor subtypes that are recognized by 125I-PYY. These findings cannot be explained by the existence of the very recently reported Y3 receptor subtype, since PYY does not possess significant affinity to this site (Grundemar et al., 1991). Further experiments are currently in progress to determine the nature and functional significance of each of these NPY/PYY receptor sites.