Neuroscience
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Intraperitoneal injection of the endotoxin lipopolysaccharide produces an inflammation accompanied by immune system activation and secretion of cytokines that stimulate the hypothalamo-pituitary-adrenal (HPA) axis to release the anti-inflammatory corticosterone. Upstream in HPA axis are neuroendocrine corticotropin-releasing hormone neurons in the paraventricular nucleus whose multipeptidergic phenotype changes during inflammation: coexisting corticotropin-releasing hormone and cholecystokinin mRNAs are up-regulated whereas neurotensin mRNA expression is induced de novo. These changes may be mediated by prostaglandins released from perivascular and microglial cells in response to circulating cytokines. ⋯ Because indomethacin also elevated circulating corticosterone, animals were adrenalectomized and corticosterone replaced. Results showed that i.p. indomethacin administration suppressed lipopolysaccharide effects in a phenotype non-specific manner: one injection was sufficient to prevent both the increase in corticotropin-releasing hormone and cholecystokinin mRNAs expression and the induction of neurotensin mRNA expression. Therefore, neuroendocrine corticotropin-releasing hormone neurons with different peptidergic phenotypes appear to respond as a whole in the acute phase response to systemic infection.
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Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been extensively evaluated for toxicity in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. However, little is known about its action on the CNS. In this report, we show that prenatal and neonatal exposure to BPA in mice leads to the enhancement of the dopamine D1 receptor-dependent rewarding effect induced by a psychostimulant methamphetamine. ⋯ Additionally, chronic BPA exposure produced a significant increase in levels of the dopamine D1 receptor mRNA in the whole brain. In contrast, no change in protein levels of methamphetamine-targeted proteins, dopamine transporter or the type 2 vesicle monoamine transporter in the brain was observed by prenatal and neonatal exposure to BPA. The present data provide the first evidence that prenatal and neonatal exposure to BPA can potentiate the central dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity of methamphetamine-induced pharmacological actions related to psychological dependence on psychostimulants.
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We describe the thorough characterisation of a new transgenic mouse line overexpressing the 695-amino acid isoform of human amyloid precursor protein harbouring the Swedish double familial Alzheimer's disease mutation. This line, referred to as TAS10, exhibits neuropathological features and cognitive deficits that are closely correlated to the accumulation of Abeta in their brain and that are reminiscent of those observed in AD. ⋯ Morphometric studies demonstrate that the synapse to neuron ratio is higher in transgenics than in control mice at 12 months, but this ratio decreases as they age and synapse size increases. Thus, this mouse model exhibits a close correlation of amyloid burden with behavioural deficits and ultrastructural abnormalities and so represents an ideal system to study the mechanisms underlying the impact of amyloid pathology on CNS function.
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This study examined the role of spinal GABAergic, serotoninergic and alpha(2) adrenergic receptors in the antinociception produced by the microinjection of equi-antinociceptive doses of selective opioid receptor agonists in the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars alpha (NGCpalpha) of the rat. Rats were pretreated with intrathecal administration of either the GABA(A) receptor antagonist bicuculline, the GABA(B) receptor antagonist CGP35348, the serotonin(1/2) receptor antagonist methysergide, the alpha(2) adrenergic receptor antagonist yohimbine or saline. Ten minutes later, either the delta(1) opioid receptor agonist [D-Pen(2,5)]enkephalin (DPDPE), delta(2) opioid receptor agonist [D-Ala(2),Glu(4)]deltorphin (DELT) or mu opioid receptor agonist [D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) was microinjected into the NRM, NGCpalpha or sites in the medulla outside these two regions. ⋯ Intrathecal pretreatment with methysergide or bicuculline did not antagonize the antinociception produced by microinjection of DELT into either the NRM or the NGCpalpha. The increase in tail-flick latency produced by microinjection of DAMGO in the NRM was antagonized by intrathecal pretreatment with methysergide or CGP35348, but not by bicuculline or yohimbine. Taken together, these results support the hypothesis that the antinociception produced by activation of delta(1), delta(2) or mu opioid receptors in the rostral ventromedial medulla is mediated by different neural substrates.
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Different isoforms of a vesicular glutamate transporter (VGLUT) mediate glutamate uptake into synaptic vesicles of excitatory neurons. There is agreement that the VGLUTs are differentially expressed in brain, and that two isoforms, VGLUT1 and VGLUT2, are localized to excitatory axon terminals in the cerebellar cortex. While granule cells express solely VGLUT1, there is no report about the VGLUT(s) of the unipolar brush cell (UBC), the second type of glutamatergic interneuron residing in the cerebellar granular layer. ⋯ Moreover, CR(+) dendritic brushes were contacted by mossy terminals provided with both transporters, while mGluR1alpha(+) dendritic brushes were contacted by mossy terminals immunopositive for VGLUT1 and immunonegative for VGLUT2. These data indicate that the two UBC subsets use different modalities of vesicular glutamate storage and form separate networks. We consider it possible that expressions of CR with VGLUT1/VGLUT2 and mGluR1alpha(+) with VGLUT1 in the two subsets of vestibulocerebellar UBCs are determined by specific vestibular inputs, carried by groups of primary and/or secondary vestibular afferents.