Endogenous 5-HT, released by MDMA through serotonin transporter- and secretory vesicle-dependent mechanisms, reduces hippocampal excitatory synaptic transmission by preferential activation of 5-HT1B receptors located on CA1 pyramidal neurons.
A multitude of different serotonin (5-HT) receptor types are expressed in the hippocampus, but the identity of receptors actually mediating the physiological response to endogenous 5-HT has not been determined. We combined pharmacologically induced release of 5-HT with patch-clamp recordings on disinhibited rat CA1 minislices to determine effects of endogenous 5-HT on the excitability of pyramidal neurons and synaptic transmission among them. We found that application of 5-HT releasers, 3,4-methylenedioxy-methamphetamine (MDMA) or p-methylthioamphetamine, at concentrations ranging from 2 to 50 microm, reduced the excitatory synaptic transmission between CA1 pyramidal neurons without altering their basal electrical properties. This effect of MDMA was blocked by the selective 5-HT1B antagonist GR 55562, was dependent on endogenous 5-HT content and was mediated by presynaptically located, pertussis-toxin sensitive mechanisms. We found no other MDMA effects in our preparation, which indicates that the release of endogenous 5-HT preferentially stimulates 5-HT1B receptors on CA1 pyramidal neurons. Therefore, 5-HT1B receptor activation may represent a predominant component of the physiological response to endogenous 5-HT in the CA1. The high sensitivity of the 5-HT1B receptor-mediated reduction of polysynaptic excitatory responses to the extracellular 5-HT level enabled us to study mechanisms of the 5-HT releasing action of MDMA. Block of the serotonin transporter (SERT) with citalopram slowed the time course and reduced overall 5-HT release by MDMA. Depletion of vesicular 5-HT, by inhibition of vesicular monoamine transporter type 2 with tetrabenazine prevented the release. Thus although the SERT reversal contributes, a direct vesicle-depleting action is essential for MDMA release of 5-HT.
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D009431:Neural Conduction / Q000187:drug effects; D037342:Pertussis Toxin / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D022142:Secretory Vesicles / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044302:Receptor, Serotonin, 5-HT1B; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D037342:Pertussis Toxin; D018817:N-Methyl-3,4-methylenedioxyamphetamine