Serotonin 5-HT2 receptors activate local GABA inhibitory inputs to serotonergic neurons of the dorsal raphe nucleus

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 (EC50: 86 mu M); 5-HT also increased IPSC amplitude. These effects were blocked by the GABA(A) receptor antagonist, bicuculline (10 mu M) 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 mu M) in the DRN. A near maximal concentration of the selective 5-HT,, antagonist, MDL100,907 (30 nM), produced a large reduction (similar to 70%) in the increase in IPSC frequency induced by 100 mu M 5-HT; SB242,084 (30 nM), a selective 5-MT2C antagonist, was less effective (similar to 24% reduction). Combined drug application suppressed the increase in 5-HT-induced IPSC frequency almost completely, suggesting involvement of both 5-HT2A and 5-HT2C receptors. Unexpectedly. the phenethylamine hallucinogen, DOI, a partial agonist at 5-HT2A/2C receptors, caused a greater increase (+334%) in IPSC frequency than did 5-HT 100 mu M (+80%). This result may be explained by an opposing 5-HT1A inhibitory effect since the selective 5-HT1A 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 GPLBAergic interneurons in the DRN via 5-HT,, and, to a lesser extent, 5-HT2C 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. (C) 2000 Elsevier Science B.V. All rights reserved.