Neuroscience
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Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) is a selective agonist for the delta-subunit containing extrasynaptic GABA(A) receptors that will soon enter the U. S. market as a sleep aid [Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler I (2007) The EEG effects of THIP (gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25:1893-1899]. ⋯ Microdialysis perfusion of THIP (100 microM) into the PFH produced a significant reduction in wakefulness with a concomitant increase in non-rapid eye movement or slow wave sleep as compared with artificial cerebrospinal fluid perfusion. REM sleep was unaffected. This is the first study implicating the delta-subunit containing extrasynaptic GABA(A) receptors in PFH in control of sleep-wakefulness in freely behaving rats.
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Using extracellular single unit recordings alone or in combination with neurobiotin juxtacellular labeling and orexin (hypocretin) immunohistochemistry in the mouse, we have recorded a total of 452 neurons in the orexin neuron field of the posterior hypothalamus. Of these, 76 exhibited tonic discharge highly specific to wakefulness, referred to as waking-active neurons. They showed differences from each other in terms of spike shape, activity profile, and response to an arousing sound stimulus and could be classified into three groups on the basis of spike shape as: 1) biphasic broad; 2) biphasic narrow; and 3) triphasic. ⋯ In contrast, the biphasic narrow non-orexin neurons fired in single spikes either prior to, or after, EEG activation during the same transition and responded to the stimulus with a longer latency. The activity of all waking-active neurons preceded the return of muscle tonus at the transition from paradoxical sleep to wakefulness. These data support the view that the activity of orexin and non-orexin waking-active neurons in the posterior hypothalamus plays an important wake-promoting role and that their activity antagonizes cortical deactivation and loss of muscle tone.
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On the basis of numerous studies that have described interactions between the dopaminergic and opioidergic systems, we have investigated whether genetic deletion of dopamine D2 receptors (D2R) might influence the expression of central opioid receptors. The levels of mu, delta, kappa and nociceptin opioid peptide receptors were determined in the brains and spinal cords of D2R knockout mice using quantitative autoradiography. The significant changes in opioid receptor binding found in the brains of heterozygous and homozygous mice were mainly restricted to the basal ganglia. ⋯ Significant increases in nociceptin receptor binding were also observed in homozygous mice in brain areas involved in motor behavior. At the spinal level, only kappa and nociceptin receptor binding showed significant overall differences between genotypes. The functional consequences of these adaptive changes are discussed in relation to the findings of behavioral and neurochemical studies reported to date in D2R knockout mice.
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Src family protein kinases (SFKs) -mediated tyrosine-phosphorylation regulates N-methyl-D-aspartate (NMDA) receptor synaptic function. Some members of the membrane-associated guanylate kinase (MAGUK) family of proteins bind to both SFKs and NMDA receptors, but it is unclear whether the MAGUK family of proteins is required for SFKs-mediated tyrosine-phosphorylation of the NMDA receptors. Here, we showed by co-immunoprecipitation that post-synaptic density (PSD) -93, a member of the MAGUK family of proteins, interacts with the NMDA receptor subunits NR2A and NR2B as well as with Fyn, a member of the SFKs, in mouse cerebral cortex. ⋯ Interestingly, we found that PSD-93 disruption causes reduction of tyrosine-phosphorylated NR2A and NR2B in the same fraction. Moreover, PSD-93 deletion markedly blocked the SFKs-mediated increase in tyrosine-phosphorylated NR2A and NR2B through the protein kinase C pathway after induction with 4-phorbol 12-myristate 13-acetate in cultured cortical neurons. Our findings indicate that PSD-93 appears to mediate tyrosine-phosphorylation of the NMDA receptors and synaptic localization of Fyn.
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Experiments were done in urethane-anesthetized, barodenervated, male Wistar rats. Chemical stimulation of the hypothalamic paraventricular nucleus (PVN) by unilateral microinjections of N-methyl-D-aspartic acid (NMDA) elicited increases in mean arterial pressure (MAP) and greater splanchnic nerve activity (GSNA). The increases in the MAP and GSNA induced by chemical stimulation of the PVN were significantly exaggerated by bilateral microinjections of D(-)-2-amino-7-phosphono-heptanoic acid (D-AP7) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydro-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX) (ionotropic glutamate receptor antagonists) into the medial subnucleus of the nucleus tractus solitarius (mNTS). ⋯ Unilateral microinjections of fluorogold into the mNTS resulted in bilateral retrograde labeling of the PVN neurons. Unilateral microinjections of biotinylated dextran amine into the PVN resulted in anterograde labeling of axons and terminals in the mNTS bilaterally and the labeled terminals exhibited vesicular glutamate transporter-2 immunoreactivity. These results indicated that 1) a tonically active glutamatergic bilateral projection from the PVN to the mNTS exists; 2) bilateral blockade of ionotropic glutamate receptors in the mNTS exaggerates the increases in MAP and GSNA, but not heart rate, to the chemical stimulation of the PVN; and 3) this projection may serve as a restraint mechanism for excitatory cardiovascular effects of PVN stimulation.