Serotonin 5-HT(2) receptors activate local GABA inhibitory inputs to serotonergic neurons of the dorsal raphe nucleus

Brain Res. 2000 Aug 4;873(1):34-45. doi: 10.1016/s0006-8993(00)02468-9.


The purpose of the present study was to characterize the synaptic currents induced by bath-applied serotonin (5-HT) in 5-HT cells of the dorsal raphe nucleus (DRN) and to determine which 5-HT receptor subtypes mediate these effects. In rat brain slices, 5-HT induced a concentration-dependent increase in the frequency of inhibitory postsynaptic currents (IPSCs) in 5-HT neurons recorded intracellularly in the ventral part of the DRN (EC(50): 86 microM); 5-HT also increased IPSC amplitude. These effects were blocked by the GABA(A) receptor antagonist, bicuculline (10 microM) and by the fast sodium channel blocker, TTX, suggesting that 5-HT had increased impulse flow in local GABAergic neurons. DAMGO (300 nM), a selective mu-agonist, markedly suppressed the increase in IPSC frequency induced by 5-HT (100 microM) in the DRN. A near maximal concentration of the selective 5-HT(2A) antagonist, MDL100,907 (30 nM), produced a large reduction ( approximately 70%) in the increase in IPSC frequency induced by 100 microM 5-HT; SB242,084 (30 nM), a selective 5-HT(2C) antagonist, was less effective ( approximately 24% reduction). Combined drug application suppressed the increase in 5-HT-induced IPSC frequency almost completely, suggesting involvement of both 5-HT(2A) and 5-HT(2C) receptors. Unexpectedly, the phenethylamine hallucinogen, DOI, a partial agonist at 5-HT(2A/2C) receptors, caused a greater increase (+334%) in IPSC frequency than did 5-HT 100 microM (+80%). This result may be explained by an opposing 5-HT(1A) inhibitory effect since the selective 5-HT(1A) antagonist, WAY-100635, enhanced the 5-HT-induced increase in IPSCs. These results indicate that within the DRN-PAG area there may be a negative feedback loop in which 5-HT induces an increase in IPSC frequency in 5-HT cells by exciting GABAergic interneurons in the DRN via 5-HT(2A) and, to a lesser extent, 5-HT(2C) receptors. Increased GABA tone may explain the previous observation of an indirect suppression of firing of a subpopulation of 5-HT cells in the DRN induced by phenethylamine hallucinogens in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Afferent Pathways / physiology
  • Analgesics, Opioid / pharmacology
  • Animals
  • Electrophysiology
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • In Vitro Techniques
  • Indophenol / analogs & derivatives*
  • Indophenol / pharmacology
  • Male
  • Neural Inhibition / physiology*
  • Neurons / physiology*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Raphe Nuclei / cytology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiology*
  • Rats
  • Receptors, Serotonin / physiology*
  • Serotonin / pharmacology
  • Serotonin / physiology*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • gamma-Aminobutyric Acid / physiology*


  • Analgesics, Opioid
  • Piperazines
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • dimethoxy-4-indophenyl-2-aminopropane
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Serotonin
  • Indophenol
  • gamma-Aminobutyric Acid
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide