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

Abstract

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 μM); 5-HT also increased IPSC amplitude. These effects were blocked by the GABA A receptor antagonist, bicuculline (10 μM) 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 μ-agonist, markedly suppressed the increase in IPSC frequency induced by 5-HT (100 μM) in the DRN. A near maximal concentration of the selective 5-HT 2A antagonist, MDL100,907 (30 nM), produced a large reduction (∼70%) in the increase in IPSC frequency induced by 100 μM 5-HT; SB242,084 (30 nM), a selective 5-HT 2C antagonist, was less effective (∼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 μM (+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.