Serotonin modulation of cell excitability and of [3H]GABA and [3H]D-aspartate efflux in primary cultures of rat cortical neurons

Abstract The effects of 5-hydroxytryptamine (5-HT) on neuronal excitability, evaluated as depolarization-induced firing rate, and on amino acid release, measured as electrically-evoked [ 3 H]GABA and [ 3 H] d -aspartate efflux, were investigated in rat primary cortical neuronal cultures. 5-HT displayed a concentration-dependent, bimodal effect on neuronal excitability: at 3–10 μM it increased excitability through 5-HT 2A receptors, and was blocked by the selective 5-HT 2A antagonist MDL 100907, whereas at 30–100 μM it reduced excitability through 5-HT 1A receptors, and was, in turn, blocked by the selective 5-HT 1A antagonist WAY 100135. The electrically-evoked [ 3 H]GABA efflux was concentration-dependently inhibited by 5-HT (pEC 50  = 4.74) and such inhibition was prevented by WAY 100135, but not by GR 55562, a selective 5-HT 1D/B receptor antagonist. Conversely, 5-HT concentration-dependently increased stimulus-evoked [ 3 H] d -aspartate efflux (pEC 50  = 4.71). The increase was facilitated by methiothepin and was reversed into inhibition by ICS 205930, a selective 5-HT 3 receptor antagonist. In the presence of ICS 205930, the inhibition induced by 5-HT was prevented by the selective 5-HT 1D/B receptor antagonist GR 55562, but not by WAY 100135. These findings suggest that 5-HT inhibits GABA release through 5-HT 1A receptors and exerts a dual modulation on glutamate release, mostly facilitatory (through 5-HT 3 receptors) but also inhibitory (through 5-HT 1D/B receptors), leading to a prevalently positive modulation of the excitatory signal by amino acid neurotransmitter containing neurons.