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Antagonist WAY (antagonist + way)
Selected AbstractsFenfluramine Blocks Low-Mg2+ -Induced Epileptiform Activity in Rat Entorhinal CortexEPILEPSIA, Issue 8 2000K. Gentsch Summary: Purpose: The entorhinal cortex (EC) represents the main input structure to the hippocampus and seems to be critically involved in temporal lobe epilepsy. Considering that the EC receives a strong serotonergic projection from the raphe nuclei and expresses a high density of serotonin (5-HT) receptors, the effect of the 5-HT,releasing drug fenfluramine (FFA) on epileptiform activity generated in the EC was investigated in an in vitro model of epilepsy. Methods: The experiments were performed on 43 horizontal slices containing the EC, the subiculum, and the hippocampal formation obtained from 230,250 g adult Wistar rats. Using extracellular recording techniques, we investigated the effect of bath-applied FFA (200 ,mol/L to 1 mmol/L) on epileptiform activity induced by omitting MgSO4 from the artificial cerebrospinal fluid. Results: We demonstrate that FFA reversibly blocks epileptiform activity in the EC. Surprisingly, in the presence of the 5-HT uptake blocker paroxetine, the FFA-induced effect was diminished. Coapplication of the 5-HTIA receptor antagonist WAY 100635 prevented the FFA-induced anticonvulsive effect, suggesting that (a) the FFA-induced suppression of epileptiform activity is mediated by the release of 5-HT from synaptic terminals within the EC rather than by an unspecific effect of FFA and (b) released 5-HT most likely blocks the activity by activation of 5-HTIA receptors. Conclusion: FFA, which is primarily used because of its anorectic activity, might get an additional therapeutic value in the treatment of temporal lobe epilepsy with parahippocampal involvement. [source] Somatodendritic autoreceptor regulation of serotonergic neurons: dependence on l -tryptophan and tryptophan hydroxylase-activating kinasesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2005Rong-Jian Liu Abstract The somatodendritic 5-HT1A autoreceptor has been considered a major determinant of the output of the serotonin (5-HT) neuronal system. However, recent studies in brain slices from the dorsal raphe nucleus have questioned the relevance of 5-HT autoinhibition under physiological conditions. In the present study, we found that the difficulty in demonstrating 5-HT tonic autoinhibition in slice results from in vitro conditions that are unfavorable for sustaining 5-HT synthesis. Robust, tonic 5-HT1A autoinhibition can be restored by reinstating in vivo 5-HT synthesizing conditions with the initial 5-HT precursor l -tryptophan and the tryptophan hydroxylase co-factor tetrahydrobiopterin (BH4). The presence of tonic autoinhibition under these conditions was revealed by the disinhibitory effect of a low concentration of the 5-HT1A antagonist WAY 100635. Neurons showing an autoinhibitory response to l -tryptophan were confirmed immunohistochemically to be serotonergic. Once conditions for tonic autoinhibition had been established in raphe slice, we were able to show that 5-HT autoinhibition is critically regulated by the tryptophan hydroxylase-activating kinases calcium/calmodulin protein kinase II (CaMKII) and protein kinase A (PKA). In addition, at physiological concentrations of l -tryptophan, there was an augmentation of 5-HT1A receptor-mediated autoinhibition when the firing of 5-HT cells activated with increasing concentrations of the ,1 adrenoceptor agonist phenylephrine. Increased calcium influx at higher firing rates, by activating tryptophan hydroxylase via CaMKII and PKA, can work together with tryptophan to enhance negative feedback control of the output of the serotonergic system. [source] Effects of chronic paroxetine treatment on dialysate serotonin in 5-HT1B receptor knockout miceJOURNAL OF NEUROCHEMISTRY, Issue 1 2003A. M. Gardier Abstract The role of serotonin (5-HT)1B receptors in the mechanism of action of selective serotonin re-uptake inhibitors (SSRI) was studied by using intracerebral in vivo microdialysis in conscious, freely moving wild-type and 5-HT1B receptor knockout (KO 5-HT1B) mice in order to compare the effects of chronic administration of paroxetine via osmotic minipumps (1 mg per kg per day for 14 days) on extracellular 5-HT levels ([5-HT]ext) in the medial prefrontal cortex and ventral hippocampus. Basal [5-HT]ext values in the medial prefrontal cortex and ventral hippocampus, ,,20 h after removing the minipump, were not altered by chronic paroxetine treatment in both genotypes. On day 15, in the ventral hippocampus, an acute paroxetine challenge (1 mg/kg i.p.) induced a larger increase in [5-HT]ext in saline-pretreated mutant than in wild-type mice. This difference between the two genotypes in the effect of the paroxetine challenge persisted following chronic paroxetine treatment. Conversely, in the medial prefrontal cortex, the paroxetine challenge increased [5-HT]ext similarly in saline-pretreated mice of both genotypes. Such a challenge produced a further increase in cortical [5-HT]ext compared with that in saline-pretreated groups of both genotypes, but no differences were found between genotypes following chronic treatment. To avoid the interaction with raphe 5-HT1A autoreceptors, 1 µm paroxetine was perfused locally through the dialysis probe implanted in the ventral hippocampus; similar increases in hippocampal [5-HT]ext were found in acutely or chronically treated wild-type mice. Systemic administration of the mixed 5-HT1B/1D receptor antagonist GR 127935 (4 mg/kg) in chronically treated wild-type mice potentiated the effect of a paroxetine challenge dose on [5-HT]ext in the ventral hippocampus, whereas systemic administration of the selective 5-HT1A receptor antagonist WAY 100635 did not. By using the zero net flux method of quantitative microdialysis in the medial prefrontal cortex and ventral hippocampus of wild-type and KO 5-HT1B mice, we found that basal [5-HT]ext and the extraction fraction of 5-HT were similar in the medial prefrontal cortex and ventral hippocampus of both genotypes, suggesting that no compensatory response to the constitutive deletion of the 5-HT1B receptor involving changes in 5-HT uptake capacity occurred in vivo. As steady-state brain concentrations of paroxetine at day 14 were similar in both genotypes, it is unlikely that differences in the effects of a paroxetine challenge on hippocampal [5-HT]ext are due to alterations of the drug's pharmacokinetic properties in mutants. These data suggest that there are differences between the ventral hippocampus and medial prefrontal cortex in activation of terminal 5-HT1B autoreceptors and their role in regulating dialysate 5-HT levels. These presynaptic receptors retain their capacity to limit 5-HT release mainly in the ventral hippocampus following chronic paroxetine treatment in mice. [source] 5-HT1B Receptor-Mediated Regulation of Serotonin Clearance in Rat Hippocampus In VivoJOURNAL OF NEUROCHEMISTRY, Issue 5 2000Lynette C. Daws Abstract: The 5-hydroxytryptamine (5-HT; serotonin) transporter (5-HTT) is important in terminating serotonergic neurotransmission and is a primary target for many psychotherapeutic drugs. Study of the regulation of 5-HTT activity is therefore important in understanding the control of serotonergic neurotransmission. Using high-speed chronoamperometry, we have demonstrated that local application of 5-HT1B antagonists into the CA3 region of the hippocampus prolongs the clearance of 5-HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5-HT1B antagonist cyanopindolol does not produce this effect by increasing release of endogenous 5-HT or by directly binding to the 5-HTT. Dose-response studies showed that the potency of cyanopindolol to inhibit clearance of 5-HT was equivalent to that of the selective 5-HT reuptake inhibitor fluvoxamine. Local application of the 5-HT1A antagonist WAY 100635 did not alter 5-HT clearance, suggesting that the effect of cyanopindolol to prolong clearance is not via a mechanism involving 5-HT1A receptors. Finally, the effect of low doses of cyanopindolol and fluvoxamine to inhibit clearance of 5-HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5-HT1B autoreceptors increases 5-HTT activity. [source] 5-HT1B but not 5-HT6 or 5-HT7 receptors mediate depression of spinal nociceptive reflexes in vitroBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002G Hedo The identity of the serotonin (5-HT) receptors modulating the transmission of segmental C-fibre mediated signals was studied using an in vitro preparation of the hemisected spinal cord from rat pups. Responses to trains of stimuli delivered to a lumbar dorsal root were recorded from the corresponding ventral root. The resulting cumulative depolarization (CD) mediated by unmyelinated fibres was quantified in terms of integrated area. The amplitude of the mono-synaptic reflex was also measured. Serotonergic agents were superfused at known concentrations and their effects on the reflexes evaluated. 5-HT had depressant effects on the CD (EC50 34 ,M). The rank order of potency of agonists for the depression of the CD was 5-carboxamidotryptamine (5-CT)>,-methylserotonin (,-met-5-HT) ,5-HT>42-methylserotonin (2-met-5-HT),8-OH-DPAT. All the agonists including 2-met-5-HT and 8-OH-DPAT had strong depressant effects on the mono-synaptic reflex with the following order of potency: 5-CT>48-OH-DPAT>4,-met-5-HT ,5-HT,2-met-5-HT. The inhibitory effects of 5-HT, ,-met-5-HT and 5-CT were attenuated by the non-specific 5-HT antagonist methiothepin (1 ,M) and by the 5-HT1A/1B antagonist SDZ 21009 (100 nM) but not by the selective 5-HT1A antagonist WAY 100135 (1 ,M). Other antagonists known to block 5-HT2, 5-HT6 and/or 5-HT7 receptors (ketanserin, RO 04-6790, ritanserin and clozapine) did not change the effect of the agonists. The data suggest an important contribution of 5-HT1B receptors to the inhibition of spinal C-fibre mediated nociceptive reflexes but no experimental support was found for the intervention of 5-HT2, 5-HT6 or 5-HT7 receptors in this in vitro model. British Journal of Pharmacology (2002) 135, 935,942; doi:10.1038/sj.bjp.0704526 [source] | |||||||||||||