Neuropharmacology
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Sharp waves and ripples (SWRs) are a basic endogenous network activity of the hippocampus. Growing evidence from in vivo studies suggests that this activity plays a crucial role in the process of memory consolidation. Generation of SWR activity requires an intricate interaction between pyramidal cells and specific classes of GABAergic interneurons. ⋯ Most of the opposite drug effects on SWRs were also observed at higher concentrations. The present finding demonstrates a crucial involvement of the α5GABA(A)Rs in the SWR activity suggesting that distinct facets of the GABA(A)R-mediated transmission are implicated in particular features of the SWRs activity. In addition, the present results are consistent with the known opposite effects of the two drugs on memory performance.
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The volatile anesthetics enhance GABAergic inhibitory transmission at synaptic and extrasynaptic sites at central neurons. In the present study, we investigated the effects of three volatile anesthetics (isoflurane, enflurane and sevoflurane) on synaptic and extrasynaptic GABA(A) receptor responses using mechanically dissociated rat hippocampal CA1 neurons in which functional native nerve endings (boutons) were retained. The extrasynaptic GABA(A) receptors were activated by exogenous GABA application while synaptic ones were assessed by miniature and evoked inhibitory postsynaptic currents (mIPSCs and eIPSCs, respectively). ⋯ For GABAergic eIPSCs, both isoflurane and enflurane decreased the evoked response amplitude and increased the failure rate (Rf), while sevoflurane decreased the amplitude without affecting Rf. These results suggest that isoflurane and enflurane at the clinically relevant concentrations predominantly act on GABAergic presynaptic nerve endings to decrease action potential dependent GABA release. It was concluded that these anesthetics have heterogeneous effects on mIPSCs and eIPSCs with different modulation of synaptic and extrasynaptic GABA(A) receptors.
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Diminished GABAergic and glycinergic inhibition in the spinal dorsal horn contributes significantly to chronic pain of different origins. Accordingly, pharmacological facilitation of GABAergic inhibition by spinal benzodiazepines (BDZs) has been shown to reverse pathological pain in animals as well as in human patients. Previous studies in GABA(A) receptor point-mutated mice have demonstrated that the spinal anti-hyperalgesic effect of classical BDZs is mainly mediated by GABA(A) receptors containing the α2 subunit (α2-GABA(A) receptors), while α1-GABA(A) receptors, which mediate the sedative effects, do not contribute. ⋯ When non-sedative doses of HZ166 and gabapentin, a drug widely used in the clinical management of neuropathic pain, were compared, the efficacies of both drugs against CCI-induced pain were similar. At doses producing already maximal antihyperalgesia, HZ166 was devoid of sedation and motor impairment, and showed no loss of analgesic activity during a 9-day chronic treatment period (i.e. no tolerance development). These findings provide further evidence that compounds selective for α2- and α3-GABA(A) receptors might constitute a novel class of analgesics suitable for the treatment of chronic pain.
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Peripheral ischemia is commonly associated with an increase in tissue ATP concentration and a decrease in tissue pH. Although in vitro data suggest that low tissue pH can affect ATP-binding affinities to P2 receptors, the mechanistic relationship between ATP and low pH on peripheral nociception has not been fully examined. This study was designed to investigate the potential role of an acidified environment on intraplantar αβmeATP-induced peripheral pain responses in rats. ⋯ Moreover, amiloride injection significantly reduced low pH-induced facilitation of αβmeATP-mediated MA, but not TH. These results demonstrate that low tissue pH facilitates ATP-mediated MA via the activation of P2X receptors and ASICs, whereas TH induced by ATP under low pH conditions is mediated by the P2Y1 receptor and TRPV1, but not ASIC. Thus distinct mechanisms are responsible for the development of MA and TH under conditions of tissue acidosis and increased ATP.
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Chronic stress and alterations in the serotonergic system are key predisposing factors to the development of major depression. Tryptophan hydroxylase (TPH) is the key enzyme in the biosynthesis of serotonin (5-HT). The effects of chronic stress on TPH activity remain uncertain. ⋯ On the other hand, TPH activity was significantly decreased in the brainstem and cortical regions of C57BL/6J mice following both acute and chronic stress. Conversely, no significant stress-induced change in BALB/c TPH activity was observed. Together these data highlight the differential serotonergic response of BALB/c and C57BL/6J mice to acute and chronic restraint stress and may offer insight into the observed differences in their stress-related phenotypes.