Neuroscience
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Effects of i.c.v. and i.t. administration of (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY215490), a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist and MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist on the micturition reflex were evaluated in urethane-anesthetized rats, to determine if glutamatergic mechanisms in brain as well as spinal cord are important for the control of micturition. I.c.v. or i.t. injection of LY215490 in low doses (0.01-0.03 microg) did not change rhythmic bladder or external urethral sphincter (EUS) electromyogram (EMG) activity during continuous cystometrograms (CMGs; 0.21 ml/min), whereas higher doses (0.1-1 microg) markedly suppressed these responses. During single CMGs (0.04 ml/min), 0.1-1 microg i.c.v. or 0.1-10 microg i.t. doses increased volume threshold and pressure threshold for inducing micturition, and decreased bladder contraction amplitude and voiding efficiency. ⋯ Pretreatment i.c.v. with MK-801 in a dose 1.8 microg which alone had little effect on bladder contraction amplitude and EUS EMG activity, markedly enhanced depressant effects of LY215490 (0.03 microg i.c.v.) on these responses. Administration of same doses of drugs by i.t. route did not elicit a similar synergistic interaction. These data indicate that in urethane-anesthetized rats glutamatergic mechanisms in brain and spinal cord are essential for controlling micturition and that interactions between AMPA and NMDA glutamatergic transmission are important at supraspinal but not spinal sites.
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Comparative Study
Direct binding of estradiol enhances Slack (sequence like a calcium-activated potassium channel) channels' activity.
17Beta-estradiol (E2) is a major neuroregulator, exerting both genomic and non-genomic actions. E2 regulation of Slack (sequence like a calcium-activated potassium channel) potassium channels has not been identified in the CNS. We demonstrate E2-induced activation of Slack channels, which display a unitary conductance of about 60 pS, are inhibited by intracellular calcium, and are abundantly expressed in the nervous system. ⋯ ERalpha or ERbeta). Neither E2-induced activation nor the binding intensity of E2 to the Slack channel is blocked by tamoxifen, an ER antagonist/agonist. Thus, E2 activates a potassium channel, Slack, through a non-traditional membrane binding site, adding to known non-genomic mechanisms by which E2 exerts pharmacological and toxicological effects in the CNS.
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Comparative Study
Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis.
The lateral hypothalamic area, containing orexin neurons, is involved in several aspects of autonomic regulation, including thermoregulation and energy expenditure. To determine if activation of lateral hypothalamic area neurons influences sympathetically-regulated thermogenesis in brown adipose tissue, we microinjected bicuculline (120 pmol, 60 nl, unilateral) into the lateral hypothalamic area in urethane/chloralose-anesthetized, artificially-ventilated rats. ⋯ Subsequent microinjections of glycine (30 nmol, 60 nl) to inhibit local neurons in raphe pallidus or in dorsomedial hypothalamus or of glutamate receptor antagonists into dorsomedial hypothalamus promptly reversed the increases in brown adipose tissue sympathetic nerve activity, brown adipose tissue temperature and heart rate evoked by disinhibition of neurons in lateral hypothalamic area. We conclude that neurons in the lateral hypothalamic area can influence brown adipose tissue sympathetic nerve activity, brown adipose tissue thermogenesis and heart rate through pathways that are dependent on the activation of neurons in dorsomedial hypothalamus and raphe pallidus.
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Effects of neuropeptide Y (NPY) on substantia gelatinosa neurons were investigated in adult rat spinal cord slices using blind whole-cell patch-clamp technique. Bath application of NPY (1 microM) induced a membrane hyperpolarization, resulting in a suppression of the dorsal root stimulation-induced action potentials in 24% of the substantia gelatinosa neurons tested. In voltage clamp mode, NPY produced an outward current dose-dependently in about one third of substantia gelatinosa neurons at the holding potential of -60 mV, which was not affected by tetrodotoxin (1 microM). ⋯ In addition, NPY did not affect both of the miniature inhibitory postsynaptic currents and evoked inhibitory postsynaptic currents, mediated by either the GABA or glycine receptor. These findings, taken together, suggest that NPY produces an outward current in substantia gelatinosa neurons through G-protein coupled, and NPY-Y1 receptor-mediated activation of K+ channels without affecting presynaptic components. The inhibition of the synaptic transmission from the primary fibers to the substantia gelatinosa neurons is considered to contribute to the antinociceptive effects of NPY.
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Injury to the adult CNS often involves death of motoneurons, resulting in the paralysis and progressive atrophy of muscle. There is no effective therapy to replace motoneurons in the CNS. Our strategy to replace neurons and to rescue denervated muscles is to transplant dissociated embryonic day 14-15 (E14-15) ventral spinal cord cells into the distal stump of a peripheral nerve near the denervated muscles. ⋯ FK506-treated muscles were significantly more fatigue resistant than naive control muscles. FK506-treated muscles also had significantly stronger motor units than those in SB203580 or saline-treated muscles. These data suggest that a pathway regulated by FK506 improves the function of muscles reinnervated by embryonic neurons placed in peripheral nerve.