title: 5-hydroxytryptamine-mediated neurotransmission modulates spontaneous and vagal-evoked glutamate release in the nucleus of the solitary tract effect of uptake blockade.
abstract: The effect of blockade of either 5-hydroxytryptamine (5-HT)/serotonin transporter (SERT) with citalopram or the organic cation transporter 3 (OCT3)/plasma membrane monoamine transporter (PMAT) with decynium-22 (D-22) on spontaneous and evoked release of 5-HT in the nucleus tractus solitarius (NTS) was investigated in rat brainstem slices treated with gabazine. 5-HT release was measured indirectly by changes in the frequency and amplitude of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) [in the presence of tetrodotoxin (TTX)] and evoked EPSCs. Blockade of 5-HT3 receptors with granisetron reduced, whereas the 5-HT3 agonist phenylbiguanide increased, the frequency of mEPSCs. 5-HT decreased mEPSC frequency at low concentrations and increased frequency at high concentrations. This inhibition was blocked by the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635), which was ineffective on its own, whereas the excitation was reversed by granisetron. The addition of citalopram or D-22 caused inhibition, which was prevented by 5-HT1A blockade. Thus, in the NTS, the spontaneous release of 5-HT is able to activate 5-HT3 receptors, but not 5-HT1A receptors, as the release in their vicinity is removed by uptake. The ineffectiveness of corticosterone suggests that the low-affinity, high-capacity transporter is PMAT, not OCT3. For evoked 5-HT release, only D-22 caused an increase in the amplitude of EPSCs, with a decrease in the paired pulse ratio, and increased the number of spontaneous EPSCs after 20-Hz stimulation. Thus, for the evoked release of 5-HT, the low-affinity, high-capacity transporter PMAT, but not 5-HT transporter (5-HTT)/SERT, is important in the regulation of changes in 5-HT extracellular concentration.
authors.affiliation: Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas (P.S.H., S.W.M.); and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom (P.S.H., A.G.R.).
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Hosford
authors.forename: Steve W
authors.initials: SW
authors.lastname: Mifflin
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Ramage
mesh_terms: D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D055369:Miniature Postsynaptic Potentials; D009474:Neurons / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors; D011724:Pyridazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D015283:Citalopram; D018698:Glutamic Acid; D029362:Organic Anion Transporters, Sodium-Independent; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D011724:Pyridazines; D011804:Quinolines; D012701:Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C114338:organic anion transport protein 3; C100254:pseudoisocyanine; C049853:gabazine