Neuroscience
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Mitogen-activated protein kinases are signal transduction mediators that have been implicated in cell survival and cell death. This study characterized the activation of pathways in the hippocampus during reperfusion after global cerebral ischemia, as well as the influence of a regimen of hypothermia that reduces ischemic cell death in the hippocampus. Circulatory arrest was induced in rats by 8 min of asphyxia. ⋯ In contrast, active stress-activated protein kinase/c-Jun N-terminal kinase immunoreactivity was most intense in the CA3 and dentate gyrus regions. These data demonstrate that both extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun N-terminal kinase pathways are activated during the first 24h of reperfusion after global cerebral ischemia, and that hypothermia increases the activation of extracellular signal-regulated kinase relative to stress-activated protein kinase/c-Jun N-terminal kinase. Thus, an increase in extracellular signal-regulated kinase activation may be associated with improved neuronal survival after ischemic injury.
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The mechanism of spinal tolerance to the analgesic effects of opiates is unclear at present. We have reported previously that calcitonin gene-related peptide-like immunoreactivity was significantly increased in primary afferents of the spinal dorsal horn during the development of morphine tolerance, suggesting that changes in the level of pain-related neuropeptides in dorsal root ganglion neurons may be involved [Menard D. P. et al. (1996) J. ⋯ These data suggest that repeated exposure to morphine rather selectively increases calcitonin gene-related peptide- and substance P-like immunoreactivity in cultured dorsal root ganglion neurons. Moreover, the sensitivity to morphine-induced changes is greater in cultured dorsal root ganglion neurons from 10- compared to three-month-old rats. Hence, cultured dorsal root ganglion neurons can provide a model to investigate the cellular and molecular mechanisms underlying alterations in neuropeptide levels following repeated exposure to opiates and their relevance to the development of opioid tolerance.
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A new approach combining fast-scan cyclic voltammetry with iontophoretic dopamine delivery was used in freely behaving rats to evaluate the time-course of dopamine uptake inhibition in nucleus accumbens induced by intravenous cocaine at a dose (1.0mg/kg) known to maintain self-administration behavior. Cocaine significantly increased the decay time of the dopamine response without altering its magnitude or time to peak. An increase in decay time was evident at 2 min, peaked at 6 min (+87%), and decreased to baseline at 18 min after a single cocaine injection. ⋯ Our data provide direct evidence for a phasic change in dopamine uptake induced by intravenous cocaine under behaviorally relevant conditions. The relatively slow and gradual development of dopamine uptake inhibition, which peaks at times when behaving rats self-inject cocaine, is inconsistent with the suggested role of this mechanism in the acute rewarding (euphoric) effects of self-injected cocaine, but supports its role in the activational and motivational aspects of drug-seeking and drug-taking behavior. Because intravenous cocaine enters the brain rapidly and peaks in neural tissue (1-2 min) long before it effectively inhibits dopamine uptake (6 min), it appears that some of the acute psychoemotional ("rush"), behavioral, autonomic, and neuronal effects of this drug, which are apparently resistant to dopamine receptor blockade, are mediated via rapid central or peripheral mechanisms independent of monoamine uptake.
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Brain serotonin has long been implicated in the regulation of body temperature, although its precise role is not completely understood. The present study examined the effects of environmental cooling (4-8 degrees C for 2 or 4h) on the single-unit activity of serotonergic neurons recorded in the medullary raphe nuclei obscurus and pallidus and in the pontine dorsal raphe nucleus of freely moving cats. These neuronal groups have primarily descending projections to the spinal cord and ascending projections to the forebrain, respectively. ⋯ In contrast, none of the dorsal raphe nucleus cells studied (n=14) displayed a significant change in neuronal activity during cold exposure, suggesting that these neurons do not receive afferent input from cold-sensitive cutaneous receptors or participate in thermoregulatory responses evoked by low ambient temperatures. Overall, these results suggest that a subset of medullary serotonergic neurons play a role in physiological mechanisms underlying cold defense (e.g. increases in motor output and/or autonomic outflow). On the other hand, the lack of responsiveness of serotonergic dorsal raphe nucleus neurons to cold exposure does not support a specific role for these cells in thermoregulation.
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Following cholinergic denervation of the hippocampus by medial septal lesions, an unusual neuronal reorganization occurs in which peripheral adrenergic fibers arising from superior cervical ganglia grow into the hippocampus (hippocampal sympathetic ingrowth). Recent studies suggest that a similar process, in which sympathetic noradrenergic axons invade the hippocampus, can occur in Alzheimer's disease patients. In the last few years, the occurrence of apoptotic cell death has been studied in Alzheimer's disease patients and in animal models of this disorder. ⋯ The cytosolic expression of bcl-x was increased in hippocampal sympathetic ingrowth compared to control and cholinergic denervation. The cytosolic activity of caspase-3 appeared to be significantly decreased in hippocampal sympathetic ingrowth and increased in cholinergic denervation groups compared to control and cholinergic denervation/hippocampal sympathetic ingrowth, respectively. From the present results, we suggest that cholinergic denervation may be responsible for pro-apoptotic responses, while hippocampal sympathetic ingrowth may protect neurons from apoptosis in rat dorsal hippocampus.