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      The Anticonvulsant Effects of SR 57227 on Pentylenetetrazole-Induced Seizure in Mice

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          Abstract

          Recently, studies have shown that serotonin plays an important role in the control of seizure. However, the specific role of 5-HT receptor subtypes is not yet well described, in particular that of the 5-HT 3 receptor. The present study was aimed to investigate the role of 5-HT 3 receptor on the pentylenetetrazole (PTZ)-induced seizure in mice. Firstly, seizure latency was significantly prolonged by a 5-HT 3 receptor agonist SR 57227 in a dose-dependent manner. Seizure score and mortality were also decreased by SR 57227 in PTZ-treated mice. Furthermore, these anticonvulsant effects of SR 57227 were inhibited by a 5-HT 3 receptor antagonist ondansetron. However, ondansetron alone had no effect on seizure latency, seizure score or mortality at different doses. Immunohistochemical studies have also shown that c-Fos expression was significantly increased in hippocampus (dentate gyrus, CA1, CA3 and CA4) of PTZ-treated mice. Furthermore, c-Fos expression was significantly inhibited by ondansetron in mice treated with PTZ and SR 57227. An ELISA study showed that SR 57227 attenuated the PTZ-induced inhibitory effects of GABA levels in hippocampus and cortex, and the attenuated effects of SR 57227 were antagonized by ondansetron in hippocampus but not cortex. Our findings suggest that activation of 5-HT 3 receptor by SR 57227, which plays an important role on the control of seizure induced by PTZ, may be related to GABA activity in hippocampus. Therefore, 5-HT 3 receptor subtype is a potential target for the treatment of epilepsy.

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          Serotonin and epilepsy.

          Gyorgy Bagdy, Valeria Kecskemeti, Pal Riba … (2007)
          In recent years, there has been increasing evidence that serotonergic neurotransmission modulates a wide variety of experimentally induced seizures. Generally, agents that elevate extracellular serotonin (5-HT) levels, such as 5-hydroxytryptophan and serotonin reuptake blockers, inhibit both focal and generalized seizures, although exceptions have been described, too. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsions. Furthermore, it has been shown that several anti-epileptic drugs increase endogenous extracellular 5-HT concentration. 5-HT receptors are expressed in almost all networks involved in epilepsies. Currently, the role of at least 5-HT(1A), 5-HT(2C), 5-HT(3) and 5-HT(7) receptor subtypes in epileptogenesis and/or propagation has been described. Mutant mice lacking 5-HT(1A) or 5-HT(2C) receptors show increased seizure activity and/or lower threshold. In general, hyperpolarization of glutamatergic neurons by 5-HT(1A) receptors and depolarization of GABAergic neurons by 5-HT(2C) receptors as well as antagonists of 5-HT(3) and 5-HT(7) receptors decrease the excitability in most, but not all, networks involved in epilepsies. Imaging data and analysis of resected tissue of epileptic patients, and studies in animal models all provide evidence that endogenous 5-HT, the activity of its receptors, and pharmaceuticals with serotonin agonist and/or antagonist properties play a significant role in the pathogenesis of epilepsies.
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            The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon.

            Marisela Morales, Floyd E. Bloom (1997)
            The type 3 serotonin receptor (5-HT3R) is a ligand-gated ion channel whose presence in the CNS has been established by radioligand binding, in situ hybridization, and immunohistochemical analysis. To analyze further the role of the 5-HT3R in the CNS, we used in situ hybridization and immunocytochemistry to determine that 5-HT3R-expressing neurons are mainly GABA-containing cells in the rat telencephalon. We determined that 5-HT3R/GABA-containing neurons do not exhibit somatostatin immunoreactivity but often contain cholecystokinin (CCK) immunoreactivity. 5-HT3R-expressing cells with CCK immunoreactivity were observed in the neocortex, olfactory cortex, hippocampus, and amygdala. The 5-HT3R/CCK interneurons represent between 35 and 66% of the total population of CCK-containing cells in the neocortex. Further characterization of the 5-HT3R/GABAergic neurons was based on their calcium-binding protein immunoreactivity and showed that these neurons lack parvalbumin (PV) and represent a subpopulation of calbindin (CB)-containing interneurons that were preferentially present in the CA1-CA3 subfield of the hippocampus. Although some 5-HT3R/GABAergic neurons with calretinin (CR) were found in the neocortex, olfactory cortex, hippocampus, and amygdala, these neurons were more often present in the agranular insular and piriform cortices. We conclude that the neuronal expression of the 5-HT3R is selective within the GABA neuron population in the rat telencephalon. These 5-HT3R-expressing interneurons might contain CCK, CB, and CR. We suggest that serotonin through the 5-HT3R may regulate GABA and CCK neurotransmission in the telencephalon.
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              In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors.

              G Mengod, Pau Celada, Francesc Artigas … (2004)
              Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors. Here we report that the physiological stimulation of the raphe nuclei excites local, putatively GABAergic neurons in the prelimbic and cingulate areas of the rat PFC in vivo. These excitations had a latency of 36 +/- 4 ms and a duration of 69 +/- 9 ms and were blocked by the i.v. administration of the 5-HT3 receptor antagonists ondansetron and tropisetron. The latency and duration were shorter than those elicited through 5-HT2A receptors in pyramidal neurons of the same areas. Double in situ hybridization histochemistry showed the presence of GABAergic neurons expressing 5-HT3 receptor mRNA in PFC. These cells were more abundant in the cingulate, prelimbic and infralimbic areas, particularly in superficial layers. The percentages of GAD mRNA-positive neurons expressing 5-HT3 receptor mRNA in prelimbic cortex were 40, 18, 6 and 8% in layers I, II-III, V and VI, respectively, a distribution complementary to that of cells expressing 5-HT2A receptors. Overall, these results support an important role of 5-HT in the control of the excitability of apical dendrites of pyramidal neurons in the medial PFC through the activation of 5-HT3 receptors in GABAergic interneurons.
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                Author and article information

                Contributors
                Andrej A. Romanovsky: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 1 April 2014
                Volume: 9
                Issue: 4
                Electronic Location Identifier: e93158
                Affiliations
                [1 ]Second hospital of Jilin University, Changchun, China
                [2 ]National Engineering Laboratory for Druggable Gene and Protein Screening Northeast Normal University, Changchun, China
                [3 ]First hospital of Jilin University, Changchun, China
                [4 ]China-Japan Union Hospital, Changchun, China
                St. Joseph's Hospital and Medical Center, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BJL RJC. Performed the experiments: LW ZHS YZ DYS JZ YNS JYL XD CHL PW. Analyzed the data: XYZ BJL RJC. Wrote the paper: BJL RJC.

                Article
                Publisher ID: PONE-D-13-50479
                DOI: 10.1371/journal.pone.0093158
                PMC ID: 3972186
                PubMed ID: 24690630
                SO-VID: c93a86a2-f46e-432b-969a-15a4c36d66f7
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 30 November 2013
                Date accepted : 28 February 2014
                Page count
                Pages: 6
                Funding
                This work was supported by Natural Science Foundation of China (31171123; 31300850; 81328011). The project was supported by Program for New Century Excellent Talents in University (NCET-13-0715); Jilin Provincial Department of Human Resources and Social Security Project ([2012]39); and Jilin Science and Technology Agency funding (20110726; 20140414039GH; 20130303095YY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Serotonin
                Subject: Neurochemicals
                Subject: Proteins
                Subject: Immunology
                Subject: Neuroscience
                Subject: Behavioral Neuroscience
                Subject: Cellular Neuroscience
                Subject: Learning and Memory
                Subject: Molecular Neuroscience
                Subject: Research and Analysis Methods
                Subject: Histochemistry and Cytochemistry Techniques
                Subject: Immunohistochemistry Techniques
                Subject: Immunohistochemical Analysis
                Subject: Immunologic Techniques
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse Models
                Subject: Specimen Preparation and Treatment
                Subject: Mechanical Treatment of Specimens
                Subject: Specimen Disruption
                Subject: Electroporation

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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