Neuroscience
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Recent studies have shown the existence of a specific antagonistic interaction between adenosine A2a receptors and dopamine D2 receptors in the brain. This A2a-D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine. In the present study quantitative receptor autoradiography and brain microdialysis were combined to demonstrate a powerful antagonistic A2a-D2 interaction in the ventral striopallidal system. ⋯ The infusion of (2-p-carboxyethyl)phenylamino-5'-N-carboxamidoadenosine in the nucleus accumbens induced the same postsynaptic changes as the D2 antagonist raclopride, i.e. an increase in pallidal GABA extracellular levels, without changing those levels in the nucleus accumbens. Furthermore, the coinfusion in the nucleus accumbens of low concentrations of (2-p-carboxyethyl) phenylamino-5'-N-carboxamido-adenosine and raclopride, which were ineffective when administered alone, induced a significant increase in pallidal gamma-aminobutyric acids extracellular levels. These results suggest that A2a agonists, alone or in combination with D2 antagonists, could be advantageous antischizophrenic drugs, as blockage of D2 receptors in the ventral striopallidal system appears to be associated with the antipsychotic activity of neuroleptics but not with their extrapyramidal motor-side effects.
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During brain development, the microtubule-associated protein tau presents a transient state of high phosphorylation. We have investigated the developmental distribution of the phosphorylated fetal-type tau in the developing rat cortex and in cultures of embryonic cortical neurons, using antibodies which react with tau in a phosphorylation-dependent manner. The phosphorylated fetal-type tau was present in the developing cortex at 20 days but not at 18 days of embryonic life and was not detected before four to five days in neuronal culture. ⋯ The timing of appearance of phosphorylated tau in the cortex, by comparison with the expression of other developmental markers, indicates that phosphorylated tau is present at a high level only during the period of intense neuritic outgrowth and that it disappears during the period of neurite stabilization and synaptogenesis, concomitantly to the expression of adult tau isoforms. In control cultures and in cultures treated with colchicine, the phosphorylated tau was not associated to cold-stable and to colchicine-resistant microtubules. These in vivo results suggest that the high expression of phosphorylated tau species is correlated with the presence of a dynamic microtubule network during a period of high plasticity in the developing brain.
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We have recently reported the cloning of a mouse kappa opioid receptor cDNA. Following transfection of the kappa receptor cDNA into COS-1 cells, a receptor is expressed with the pharmacological specificity of a kappa opioid receptor. To further analyse its functional properties, we have stably expressed the kappa opioid receptor in undifferentiated PC-12 cells, a pheochromocytoma clonal cell line, which do not endogenously express this receptor. ⋯ Kappa opioid receptors are thought to be important in pain pathways, learning and memory deficits, and seizure activity. A major physiological action of the dynorphins, the endogenous ligands of the kappa receptor, is thought to be inhibition of neurotransmitter release at presynaptic terminals. N-type calcium channels may be important in neurotransmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)
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Arachidonic acid (20:4) is a component of membrane lipids that has been implicated as a messenger both in physiological and pathophysiological processes, including ischemic injury and synaptic plasticity. In order to clarify direct trophic or toxic effects of arachidonic acid on central neurons, primary cultures of rat hippocampal neurons were exposed to arachidonic acid under chemically-defined conditions. Arachidonic acid present in the culture medium at concentrations over 5 x 10(-6) M showed profound toxicity, whereas at lower concentrations (10(-6) M) it significantly supported the survival of hippocampal neurons. ⋯ At lower concentrations (10(-7)-10(-6) M), arachidonic acid promoted neurite elongation, which was not inhibited by nordihydroguaiaretic acid or indomethacin. Overall, arachidonic acid has both trophic and toxic actions on cultured hippocampal neurons, part of which involves its metabolism by lipoxygenases. The mechanisms and the physiological significance of these effects are discussed.
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Activation of neurons in the rostral ventral medulla, by electrical stimulation or microinjection of glutamate, produces antinociception. Microinjection of opioid compounds in this region also has an antinociceptive effect, indicating that opioids activate a medullary output neuron that exerts a net inhibitory effect on nociception. When given systemically in doses sufficient to produce antinociception, morphine produces distinct, opposing responses in two physiologically identifiable classes of rostral medullary neurons. "Off-cells" are activated, and have been proposed to inhibit nociceptive transmission. "On-cells" are invariably depressed, and may have a pro-nociceptive role. ⋯ Off-cells were activated following DAMGO microinjections, but only in experiments in which the tail flick reflex was inhibited. Both reflex inhibition and neuronal effects were reversed following systemic administration of naloxone. These observations thus confirm the role of the on-cell as the focus of direct opioid action within the rostral medulla, and strongly support the proposal that disinhibition of off-cells is central to the antinociception actions of opioids within this region.