Stimulation of nitric oxide-cGMP pathway excites striatal cholinergic interneurons via protein kinase G activation

Conflicting data have been collected so far on the action of nitric oxide ( NO) on cholinergic interneurons of the striatum. In the present in vitro el ectrophysiological study, we reported that intracellularly recorded striata l cholinergic interneurons are excited by both hydroxylamine and S-nitroso- N-acetylpenicillamine, two NO donors. This excitation persisted unchanged i n the presence of glutamate, dopamine, and substance P receptor antagonists as well as after blockade of tetrodotoxin (TTX) and calcium channel-sensit ive transmitter release, suggesting that NO produces its effects by modulat ing directly resting ion conductances in the somatodendritic region of stri atal cholinergic cells. The depolarizing effect of hydroxylamine was greatl y reduced by lowering external concentrations of sodium ions (from 126 to 3 8 mM) and did not reverse polarity in the voltage range from -120 to -40 mV . The sodium transporter blockers bepridil and 3',4'-dichlorobenzamil were conversely ineffective in preventing NO-induced membrane depolarization. In tracellular cGMP elevation is required for the action of hydroxylamine on s triatal cholinergic cells, as demonstrated by the findings that the membran e depolarization produced by this pharmacological agent was prevented by ba th and intracellular application of two inhibitors of soluble guanylyl cycl ase and was mimicked and occluded by zaprinast, a cGMP phosphodiesterase in hibitor. Finally, intracellular Rp-8-Br-cGMPS, a protein kinase G (PKG) inh ibitor, blocked the hydroxylamine-induced membrane depolarization of cholin ergic interneurons, whereas both okadaic acid and calyculin A, two protein phosphatase inhibitors, enhanced it, indicating that intracellular PKG and phosphatases oppositely regulate the sensitivity of striatal cholinergic in terneurons to NO. The characterization of the cellular mechanisms involved in the regulation of striatal interneuron activity is a key step for the un derstanding of the role of these cells in striatal microcircuitry.