Neuroscience
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There appear to be different relationships between mu-opioid receptor densities and the acute and neuroadaptive mu-opioid agonist-induced responses of the multiple opioid neuronal systems, including important pons/medulla circuits. The recent success in creating mu-opioid receptor knockout mice allows studies of mu-opioid agonist-induced pharmacological and physiological effects in animals that express no, one or two copies of the mu-opioid receptor gene. We now report that the binding of mu-opioid receptor ligand, [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin to membrane preparations of the pons/medulla was reduced by half in heterozygous mu-opioid receptor knockout mice and eliminated in homozygous mu-opioid receptor knockout mice. ⋯ These antinociceptive actions were significantly reduced in heterozygous mu-opioid receptor knockout mice, and virtually abolished in homozygous knockout mice. The mu-opioid receptors are the principal molecular targets for endomorphin-induced G-protein activation in the pons/medulla and the antinociception caused by the intracerebroventricular administration of mu-opioid agonists. These data support the notion that there are limited physiological mu-opioid receptor reserves for inducing G-protein activation in the pons/medulla and for the nociceptive modulation induced by the central administration of endomorphin-1 and -2.
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Although the distribution of calcitonin gene-related peptide has been extensively studied in the spinal cord, little is known about the precise subcellular localization of receptors for calcitonin gene-related peptide. The present study was undertaken to localize calcitonin gene-related peptide receptors in both the dorsal and ventral horns of the rat spinal cord. Immunocytochemical localization with specific monoclonal antibodies was performed at the light and electron microscopic levels. ⋯ Motoneurons, on the other hand, were contacted by axonal terminals with presynaptic calcitonin gene-related peptide receptors. These data suggest that (i) dorsal horn neurons are capable of direct primary afferent, calcitonin gene-related peptide receptor-mediated interactions and (ii) neuronal terminals contacting motor horn cells can be influenced through presynaptic paracrine-like calcitonin gene-related peptide receptor-mediated interactions. Thus, calcitonin gene-related peptide can have multiple modulatory effects on spinal cord neurons through site-specific receptors.
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Fos-like immunoreactivity was used to compare the auditory brain stem excitation elicited by bipolar electrical stimulation of the cochlea at various current levels relative to the electrically evoked auditory brain stem response threshold for a 50-micros/phase monophasic pulse. Fos-like immunoreactive cells were labeled in primary auditory brain stem regions. The distribution of labeled cells was restricted to regions known to be cochleotopically related to the stimulated region of the scala tympani. ⋯ These findings support the view that a study of Fos-like immunoreactivity can provide a powerful and quantitative tool for study of the dynamic response characteristics of cells of the central auditory system to electrical stimulation at suprathreshold levels. The data suggest that there is a monotonic increase in the number of neurons responsive to intracochlear electrical stimulation as a function of stimulus level, at least through the upper half of the dynamic range, but that this increase does not result in a complete loss of spatial selectivity. Coupled with previous psychophysical studies, these results suggest that the increase in the number of activated neurons is functionally beneficial, resulting in improved discrimination of changes in the electrical signals.
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Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. ⋯ Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.
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The prefrontal cortex receives dopaminergic inputs from the ventral tegmental area and excitatory inputs from the hippocampus. Both afferent pathways target in close proximity dendritic spines of pyramidal cells in layer V-VI of the prefrontal cortex. In view of the prominent role of dopamine in cognitive functions we examined the effects of ventral tegmental area stimulation on the induction of long-term potentiation in the hippocampal-prefrontal cortex pathway of anesthetized rats. ⋯ However, a recovery to normal long-term potentiation was observed 1 h after tetanic stimulation. In contrast to the effects on long-term potentiation, ventral tegmental area stimulation, when applied at low or high frequency, decreases the amplitude of the hippocampal-prefrontal cortex postsynaptic synaptic response. The present study demonstrates the importance of the integrity of the mesocortical dopaminergic system for long-term potentiation to occur in the hippocampal-prefrontal cortex pathway and suggests a frequency-dependent effect of dopamine on hippocampal-prefrontal cortex transmission.