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- emd large-diameter acutely is olated 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 DRQ cells (including type 4) and in 67% of large-diamet er DRG cells, but not other DRG cell types. 2. The increase of I-H by 5-HT was antagonized by spiperone but not cyanopi ndolol, and was mimicked by 5-carboxyamidotryptamine, but not (+)-8 -hydrox ydipropylaminotetralin (8-OH-DPAT) or cyanopindolol. These data suggested t he involvement of 5-HT7 receptors, which were shown to be expressed by medi um-diameter DRG cells using RT-PCR analysis. 3. 5-HT shifted the conductance-voltage relationship of I-H by +6 mV withou t changing peak conductance. The effects of 5-HT on I-H were mimicked and o ccluded by forskolin, but not by inactive 1,9-dideoxy forskolin. 4. At holding potentials negative to -50 mV, 5-HT increased steady-state in ward current and instantaneous membrane conductance (fast current). The 5-H T-induced inward current and fast current were blocked by Cs+ nut not Ba2and reversed at -23 mV, consistent with the properties of tonically activat ed 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 t he voltage dependence of I-H to more depolarized potentials and increases n euronal excitability.