D₂-like dopamine receptors depolarize dorsal raphe serotonin neurons through the activation of nonselective cationic conductance

The dorsal raphe (DR) receives a prominent dopamine (DA) input that has been suggested to play a key role in the regulation of central serotoninergic transmission. DA is known to directly depolarize DR serotonin neurons, but the underlying mechanisms are not well understood. Here, we show that activation of D₂-like dopamine receptors on DR 5-HT neurons elicits a membrane depolarization and an inward current associated with an increase in membrane conductance. The DA-induced inward current (I_DA) exhibits a linear I-V relationship and reverses polarity at around -15 mV, suggesting the involvement of a mixed cationic conductance. Consistent with this notion, lowering the extracellular concentration of sodium reduces the amplitude of I_DA and induces a negative shift of its reversal potential to approximately -45 mV. This current is abolished by inhibiting G-protein function with GDPβS. Examination of the downstream signaling mechanisms reveals that activation of the nonselective cation current requires the stimulation of phospholipase C but not an increase in intracellular calcium. Thus, pharmacological inhibition of phospholipase C reduces the amplitude of I _DA. In contrast, buffering intracellular calcium has no effect on the amplitude of I_DA. Bath application of transient receptor potential (TRP) channels blockers, 2-aminoethoxydiphenyl borate and SKF96365 [1-(β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole], strongly inhibits I_DA amplitude, suggesting the involvement of TRP-like conductance. These results reveal previously unsuspected mechanism by which D₂-like DA receptors induce membrane depolarization and enhance the excitability of DR 5-HT neurons.