Neuroscience
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Pretreatment with anesthetics before but not during hypoxia or ischemia can improve neuronal recovery after the insult. Sevoflurane, a volatile anesthetic agent, improved neuronal recovery subsequent to 10 min of global cerebral ischemia when it was present for 1 h before the ischemia. The mean number of intact hippocampal cornus ammonis 1 (CA1) pyramidal neurons in rats subjected to cerebral ischemia without any pretreatment was 17+/-5 (neurons/mm+/-S. ⋯ However if 2% sevoflurane was present for 1 h before the hypoxia then there was significantly improved recovery, enhanced hypoxic hyperpolarization, and reduced final depolarization. Thus we conclude that sevoflurane preconditioning improves recovery in both in vivo and in vitro models of energy deprivation and that preconditioning enhances the hypoxic hyperpolarization and reduces the hypoxic depolarization. Anesthetic preconditioning may protect neurons from ischemia by altering the electrophysiological changes a neuron undergoes during energy deprivation.
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Acid challenge of the gastric mucosa is signaled to the brainstem. This study examined whether mild gastritis due to dextrane sulfate sodium (DSS) or iodoacetamide (IAA) enhances gastric acid-evoked input to the brainstem and whether this effect is related to gastric myeloperoxidase activity, gastric histology, gastric volume retention or cyclooxygenase stimulation. The stomach of conscious mice was challenged with NaCl (0.15 M) or HCl (0.15 and 0.25 M) administered via gastric gavage. ⋯ HCl-induced gastric volume retention was not altered by IAA but attenuated by DSS pretreatment. Indomethacin (5 mg/kg) failed to significantly alter HCl-evoked expression of c-Fos in the NTS of control, DSS-pretreated and IAA-pretreated mice. We conclude that the gastritis-evoked increase in the gastric acid-evoked c-Fos expression in the NTS is related to disruption of the gastric mucosal barrier, mucosal inflammation, mucosal acid influx and enhanced activation of the afferent stomach-NTS axis.
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The signaling pathway of cyclooxygenase-2 (COX-2) induction following ischemic preconditioning (IPC) in brain remains undefined. To determine role of COX-2 in ischemic preconditioning, we used two in vitro models: mixed cortical neuron/astrocyte cell cultures and organotypic hippocampal slice cultures. We simulated IPC by exposing cell or slice cultures to 1 h or 15 min of oxygen/glucose deprivation (OGD), respectively, 48 h prior to ischemia. ⋯ Cell cultures were treated with an epsilonPKC-specific activating peptide (psiepsilonRACK, 100 nM) for 1 h, and 48 h later were exposed to OGD. epsilonPKC activation increased ERK1/2 phosphorylation and COX-2 induction and conferred neuroprotection similar to IPC. Additionally, inhibition of either epsilonPKC or ERK1/2 activation abolished COX-2 expression and neuroprotection due to ischemic preconditioning. These results demonstrate a crucial role for the epsilonPKC-->ERK1/2-->COX-2 pathway in the induction of neuroprotection via ischemic preconditioning.
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The vertebrate neuromuscular junction (NMJ) is known to be a cholinergic synapse at which acetylcholine (ACh) is released from the presynaptic terminal to act on postsynaptic nicotinic ACh receptors. There is now growing evidence that glutamate, which is the main excitatory transmitter in the CNS and at invertebrate NMJs, may have a signaling function together with ACh also at the vertebrate NMJ. In the CNS, the extracellular concentration of glutamate is kept at a subtoxic level by Na(+)-driven high-affinity glutamate transporters located in plasma membranes of astrocytes and neurons. ⋯ GLT was relatively higher in the slow-twitch muscle soleus than in the fast-twitch muscle extensor digitorum longus, whereas GLAST was relatively higher in extensor digitorum longus than in soleus. The findings show--together with previous demonstration of vesicular glutamate, a vesicular glutamate transporter and glutamate receptors--that mammalian NMJs contain the machinery required for synaptic release and action of glutamate. This indicates a signaling role for glutamate at the normal NMJ and provides a basis for the ability of denervated muscle to be reinnervated by glutamatergic axons from the CNS.
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Cocaine-associated cues acquire incentive motivational effects that manifest as craving in humans and cocaine-seeking behavior in rats. We have reported an increase in neuronal activation in rats, measured by Fos protein expression, in various limbic and cortical regions following exposure to cocaine-associated cues. This study examined whether the conditioned neuronal activation involves glutamate AMPA receptors by measuring coexpression of Fos and AMPA glutamate receptor subunits (GluR1, GluR2/3, or GluR4). ⋯ The No Extinction group exhibited increases in cocaine-seeking behavior and Fos expression in limbic and cortical regions relative to the Extinction group. A large number of Fos immunoreactive cells coexpressed GluR1, GluR2/3, and GluR4, suggesting that an action of glutamate at AMPA receptors may in part drive cue-elicited Fos expression. Importantly, there was an increase in the percentage of cells colabeled with Fos and GluR1 in the anterior cingulate and nucleus accumbens shell and cells colabeled with Fos and GluR4 in the infralimbic cortex, suggesting that within these regions, a greater, and perhaps even different, population of AMPA receptor subunit-expressing neurons is activated in rats engaged in cocaine-seeking behavior.