Serotonergic modulation of hyperpolarization-activated current in acutely isolated rat dorsal root ganglion neurons

1. The effect of serotonin (5-HT) on the hyperpolarization-activated cation current (I(H)) was studied in small-, medium- and large-diameter acutely isolated rat dorsal root ganglion (DRG) cells, including cells categorized as type 1, 2, 3 and 4 based on membrane properties. 5-HT increased I(H) in 91% of medium-diameter DRG cells (including type 4) and in 67% of large-diameter DRG cells, but not other DRG cell types. 2. The increase of I(H) by 5-HT was antagonized by spiperone but not cyanopindolol, and was mimicked by 5-carboxyamidotryptamine, but not (+)-8-hydroxydipropylaminotetralin (8-OH-DPAT) or cyanopindolol. These data suggested the involvement of 5-HT₇ receptors, which were shown to be expressed by medium diameter DRG cells using RT-PCR analysis. 3. 5-HT shifted the conductance-voltage relationship of I(H) by + 6 mV without changing peak conductance. The effects of 5-HT on I(H) were mimicked and occluded by forskolin, but not by inactive 1,9-dideoxy forskolin. 4. At holding potentials negative to -50 mV, 5-HT increased steady-state inward current and instantaneous membrane conductance (fast current). The 5-HT-induced inward current and fast current were blocked by Cs⁺ but not Ba²⁺ and reversed at -23 mV, consistent with the properties of tonically activated I(H). 5. In medium-diameter neurons recorded from in the current clamp mode, 5-HT depolarized the resting membrane potential, decreased input resistance and facilitated action potential generation by anode-break excitation. 6. The above data suggest that in distinct subpopulations of DRG neurons, 5-HT increases cAMP levels via activation of 5-HT₇ receptors, which shifts the voltage dependence of I(H) to more depolarized potentials and increases neuronal excitability.