Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release.
Previously, serotonin (5-HT) was found to induce a marked increase in glutamatergic spontaneous excitatory postsynaptic currents (EPSCs) in apical dendrites of layer V pyramidal cells of prefrontal cortex; this effect was mediated by 5-HT2A receptors, a proposed site of action of hallucinogenic and atypical antipsychotic drugs. Unexpectedly, although the effect of 5-HT was Ca2+-dependent and tetrodotoxin-sensitive, it did not appear to involve the activation of excitatory afferent impulse flow. This paradox prompted us to investigate (in rat brain slices) whether 5-HT was acting through an atypical mode of excitatory transmitter release. We found that the frequency of 5-HT-induced spontaneous EPSCs was fully supported by Sr2+ in the absence of added Ca2+, implicating the mechanism of asynchronous transmitter release which has been linked to the high-affinity Ca2+-sensor synaptotagmin III. Although the early, synchronous component of electrically evoked EPSCs was reduced while 5-HT was being applied, late, nonsynchronous components were enhanced during 5-HT washout and also by the 5-HT2 partial agonist 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI); the effect of DOI was blocked by a selective 5-HT2A antagonist (MDL 100,907). This late, nonsynchronous component was distinct from conventional polysynaptic EPSCs evoked in the presence of the GABAA antagonist bicuculline, but resembled asynchronous glutamatergic excitatory postsynaptic potentials (EPSPs) evoked in the presence of Sr2+. An enhancement of asynchronous EPSCs by a specific neurotransmitter receptor has not been reported previously. The possible role of excessive asynchronous transmission in the cerebral cortex in mediating the hallucinogenic effects of 5-HT2A agonists such as DOI is discussed.
Aghajanian
G K
GK
Departments of Psychiatry and Pharmacology, Yale School of Medicine, Yale University, New Haven, CT 06508, USA. george.aghajanian@yale.edu
Marek
G J
GJ
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002118:Calcium / Q000493:pharmacokinetics; D002135:Calcium-Binding Proteins; D003712:Dendrites / Q000737:chemistry / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005464:Fluorobenzenes / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D007215:Indophenol / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D017966:Pyramidal Cells / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013324:Strontium / Q000493:pharmacokinetics; D050857:Synaptotagmins
D002135:Calcium-Binding Proteins; D005464:Fluorobenzenes; D016166:Free Radical Scavengers; D018756:GABA Antagonists; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C494291:Syt3 protein, rat; C113896:dimethoxy-4-indophenyl-2-aminopropane; D050857:Synaptotagmins; D012701:Serotonin; D018698:Glutamic Acid; D007215:Indophenol; C079049:volinanserin; D002118:Calcium; D001640:Bicuculline; D013324:Strontium