Excitation of locus coeruleus neurons by vasoactive intestinal peptide: evidence for a G-protein-mediated inward...

Vasoactive intestinal polypeptide (VIP) caused a reversible increase in the firing rate of locus coeruleus (LC) neurons. Voltage-clamp at -60 mV revealed that VIP induced an inward current associated with a small increase in conductance. The inward current persisted in the presence of Co2+ (to block Ca2+ channels) or tetrodotoxin (to block fast voltage-dependent Na+ channels). Substitution (80%) of Na+ with choline or Tris reduced the VIP-elicited inward current by approximately 75%. Changing external K+ concentrations did not alter the effect of VIP. The inward current induced by VIP became irreversible after the intracellular administration of GTP gamma S, a hydrolysis-resistant analog of GTP which can cause a prolonged activation of G-proteins. The intracellular application of GDP beta S, which can interfere with G-protein activation, attenuated the effect of VIP. Pertussis toxin, an inactivator of certain G-proteins, did not block the effect of VIP. We conclude that VIP directly excites LC neurons by inducing a largely Na-dependent inward current. As this effect became irreversible in the presence of intracellular GTP gamma S, was attenuated by GDP beta S, and was not eliminated by pertussis toxin, mediation through a pertussis toxin-insensitive G-protein is suggested.