Neuroscience
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Withdrawal from opiates in dependent subjects produces strongly aversive psychological and autonomic responses which contribute to the chronic ingestion of opiates and the high incidence of relapse after withdrawal. A variety of evidence indicates that hyperactivity of noradrenergic locus coeruleus (LC) neurons is an important brain substrate of opiate withdrawal. In particular, only a few agents have been found to be clinically useful in alleviating these symptoms and treating opiate dependence, all of which potently attenuate the activation of noradrenergic neurons in the LC evoked by opiate withdrawal. ⋯ Two results from our laboratory led us to study the effect of enhanced serotonergic neurotransmission on withdrawal-induced LC hyperactivity: (i) a substantial part of such LC hyperactivity is mediated by an excitatory amino acid input to the locus coeruleus, and (ii) 5-HT selectively attenuates excitation of LC neurons mediated by excitatory amino acids. Here, we report that agents which increase serotonergic neurotransmission attenuate the hyperactivity of LC neurons induced by naloxone-precipitated withdrawal from chronic morphine exposure in rats. The 5-HT releaser/uptake blocker, d-fenfluramine, as well as the 5-HT reuptake blockers fluoxetine or sertraline, significantly attenuated the withdrawal-induced hyperactivity of LC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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We examined the effects of the 5-hydroxytryptamine2 receptor agonist, (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, on spontaneous and evoked discharge of locus coeruleus neurons in the rat. Extracellular recordings were obtained from single locus coeruleus neurons while (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane was injected systemically or locally into the locus coeruleus. Systemic, but not local, administration of (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane decreased spontaneous discharge of locus coeruleus neurons in a dose-dependent manner while simultaneously increasing responses evoked by somatosensory stimulation, consistent with previous studies using 5-hydroxytryptamine2 agonists. ⋯ Both of these effects could be completely reversed by systemic administration of the 5-hydroxytryptamine2 receptor antagonist, ketanserin. Furthermore, we report that: (i) the (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced decrease in spontaneous firing was blocked by local infusion of the GABA antagonists bicuculline or picrotoxin into the locus coeruleus, but not by local infusion of the alpha-2 adrenoceptor antagonist, idazoxan; and (ii) the enhancement of locus coeruleus sensory responses after high-intensity stimulation was blocked by local application of the selective antagonist of N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid, but not by local infusion of the preferential antagonist of non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione. Together, these results lead us to propose that systemic 5-hydroxytryptamine2 agonists influence locus coeruleus indirectly, causing tonic activation of a GABAergic input to the locus coeruleus, and facilitating sensory inputs that act via excitatory amino acid receptors within locus coeruleus.
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The effect of medetomidine, a highly selective alpha-2-adrenoceptor agonist, on noxious stimulation-induced expression of immediate-early genes was studied in the central nervous system of the rat. The expressions of c-JUN, JUN B, c-FOS FOS B and KROX-24 proteins were investigated by immunocytochemistry following the application of formalin (5%, 50 microliters) into the plantar skin of one hindpaw. Medetomidine (100 or 300 micrograms/kg i.p.) was administered 12 min or 5 min before the application of formalin. ⋯ It is concluded that the expression of immediate-early gene encoded proteins is more strongly suppressed by alpha-2-adrenoceptor agonists in spinal and parabrachial than in medial thalamic neurons. The increased expression of immediate-early genes in medical thalamus following atipamezole treatment may be explained by increased release of noradrenaline and the consequent activation of alpha-1- and beta-adrenoceptors. Compared with the previously reported effects of behaviorally equipotent doses of morphine, the suppression of c-FOS expression in the spinal cord was stronger following medetomidine than that following morphine.(ABSTRACT TRUNCATED AT 400 WORDS)
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The central nervous system responds to diverse neurologic injuries with a vigorous activation of astrocytes. While this phenomenon is found in many different species, its function is obscure. Understanding the molecular profile characteristic of reactive astrocytes should help define their function. ⋯ Based on the synopsis of studies presented, a number of issues become apparent that deserve a more extensive analysis. Among them are the relative contribution of microglia and astrocytes to early wound repair, the characterization of astroglial subpopulations, the specificity of the astroglial response in different diseases as well as the analysis of reactive astrocytes with techniques that can resolve fast physiologic processes. Differences between reactive astrocytes in vivo and primary astrocytes in culture are discussed and underline the need for the development and exploitation of models that will allow the analysis of reactive astrocytes in the intact organism.
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In this study we have described the ontogeny of immunoreactivity for calcitonin gene-related peptide, substance P and glutamate in primary sensory neurons, and for serotonin in the sacral spin cord, of fetal sheep (n = 37) from 56 to 140 days of gestation (term = 146 days). A few fine, varicose fibres immunoreactive for calcitonin gene-related peptide were present in Lissauer's tract, the dorsolateral funiculus and in laminae I and V in the dorsal horn of the spinal cord at 56-61 days of gestation. At this age, two groups of intensely staining immunoreactive cells were present in the motoneuron pool in laminae VIII and IX in the ventral horn of the spinal cord. ⋯ Immunoreactivity for glutamate and neuropeptides appeared in the cells and fibres of dorsal root ganglia at 97-100 days. In the skin, immunoreactivity for calcitonin gene-related peptide and substance P was present at 85 days, some time after its appearance in the cord. Fibres immunoreactive for serotonin appeared in lamina I, at the neck of the dorsal horn and in the ventral horn at 83 days of gestation.(ABSTRACT TRUNCATED AT 400 WORDS)