Neuroscience
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The role of 5-HT receptors in fluoxetine-induced nociception and antinociception in rats was assessed. Formalin produced a typical pattern of flinching and licking/lifting behaviors. Local peripheral ipsilateral, but not contralateral, pre-treatment with fluoxetine (0.3-3 nmol/paw) increased in a dose-dependent fashion 0.5% formalin-induced nociception. ⋯ In marked contrast, the spinal antinociceptive effect of fluoxetine was prevented by the 5-HT1A (WAY-100635, 0.3-1 nmol/rat), 5-HT1B/1D (GR-127935, 0.3-1 nmol/rat), 5-HT1B (SB-224289, 0.3-1 nmol/rat), 5-HT1D (BRL-15572, 0.3-1 nmol/rat) and 5-HT5A (SB-699551, 1-3 nmol/rat), but not by the 5-HT2A (ketanserin, 3-10 pmol/rat), 5-HT2B (RS-127445, 3-10 pmol/rat), 5-HT2C (RS-102221, 3-10 pmol/rat), 5-HT3 (ondansetron, 3-10 nmol/rat), 5-HT4 (GR-113808, 3-100 fmol/rat), 5-HT6 (SB-258585, 3-10 pmol/rat) nor 5-HT7 (SB-269970, 0.3-1 nmol/rat), receptor antagonists. These results suggest that fluoxetine produces nociception at the periphery by activating peripheral 5-HT2A/2B/2C/3/4/6/7 receptors. In addition, intrathecal fluoxetine produces antinociception by activation of spinal 5-HT1A/1B/1D/5A receptors.
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We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine (DA) neurons via inhibiting G protein-coupled inwardly rectifying potassium (GIRK) channels. In this study, we investigated the action of tipepidine on DA D2 receptor-mediated GIRK currents (IDA(GIRK)) and membrane excitability in DA neurons using the voltage clamp and current clamp modes of the patch-clamp techniques, respectively. DA neurons were acutely dissociated from the ventral tegmental area (VTA) in rats and identified by the presence of the hyperpolarization-activated currents. ⋯ Then tipepidine depolarized membrane potential and generated action potentials in the neurons current-clamped. Furthermore, the drug at 40 mg/kg, i.p. increased the number of cells immunopositive both for c-Fos and tyrosine hydroxylase (TH) in the VTA. These results suggest that tipepidine may activate DA neurons in VTA through the inhibition of GIRK channel-activated currents.
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Reactive astrogliosis, a feature of neuro-inflammation is induced by a number of endogenous mediators including cytokines. Despite interleukin-1 beta (IL-1β) stands out as the major inducer of this process, the underlying mechanism and its role on neuronal viability remain elusive. We investigated in human astrocytoma cells and the rat brain striatum, the role of the nuclear factor-kB (NF-kB) intracellular Ca(2+) concentration ([Ca(2+)]i) calmodulin (CaM) and extracellular regulated mitogen-activated protein kinases (ERK1/2) in IL-1β-induced expression of glial fibrillary acidic protein (GFAP) and neuronal apoptosis associated to a brain trauma. ⋯ The GFAP response was also prevented by antagonizing selectively increase in [Ca(2+)]i, CaM activity or inducible nitric oxide synthase expression with respectively ryanodine plus 2-aminoethoxydiphenyl-borate, N-(6-aminohexyl)-5-chloro-1-naphthalensulfonamide hydrochloride and N-[(3-(aminomethyl)-phenyl]methyl]-ethanimidamide dihydrochloride. Data in vivo supported these findings and showed that GFAP expression induced by IL-1β (50 ng/ml) correlated with attenuated glial scar formation and reduced neuronal apoptosis. Our data identified the NF-kB/Ca(2+)-CaM/ERK signaling pathway as a novel in vivo key regulator of IL-1β-induced astrogliosis which may represent a potential target in neurodegeneration.
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Botulinum neurotoxins (BoNTs) may affect the excitability of brain circuits by inhibiting neurotransmitter release at central synapses. There is evidence that local delivery of BoNT serotypes A and E, which target SNAP-25, a component of the release machinery specific to excitatory synapses, can inhibit seizure generation. BoNT serotype B (BoNT/B) targets VAMP2, which is expressed in both excitatory and inhibitory terminals. ⋯ BoNT/B-treated animals also exhibited tactile hyperresponsivity in comparison with vehicle-treated controls. This is the first demonstration that BoNT/B causes a delayed proconvulsant action when infused into the hippocampus. Local infusion of BoNT/B could be useful as a focal epilepsy model.
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Organic cation transporters (OCTs) are expressed mainly in the kidney and liver. OCTs transport intrinsic organic cations, including monoamine, dopamine, serotonine and choline, across the plasma membrane. Here, we demonstrate that OCT2 (SLC22A2) is expressed in cholinergic neurons, motoneurons in the anterior horn of the spinal cord, and is implicated in acetylcholine (Ach) recycling in presynaptic terminals. ⋯ Double immunostaining of muscle sections with anti-OCT2 and alpha-bungarotoxin (BTX) revealed that OCT2 was localized in the neuromuscular junctions (NMJs). Immunoelectron microscopy revealed that OCT2 was localized both in synaptic vesicles (SVs) in presynaptic terminals around the motoneurons (C-terminals) and in SVs in nerve terminals in NMJs. The similarity in the distribution of OCT2 in cholinergic neurons and that of vesicular acetyl choline transporter (VAchT), and the fact that OCT2 can transport choline suggest that OCT2 could work as a low-affinity and high-capacity choline transporter at presynaptic terminals in cholinergic neurons in a firing-dependent manner.