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Journal of Neuroscience, Vol 7, 3897-3906, Copyright © 1987 by Society for Neuroscience

ARTICLE

Role of phosphoinositide metabolites in the prolongation of afterhyperpolarizations by alpha 1-adrenoceptors in rat dorsal raphe neurons

JE Freedman and GK Aghajanian
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

Afterhyperpolarizations and outward tail currents of rat dorsal raphe neurons were measured by intracellular recording and single-electrode voltage clamping in the brain slice preparation. The alpha 1-agonist phenylephrine, and (in the presence of propranolol) norepinephrine, elicited an increase in the duration, but not of the initial amplitude, of afterhyperpolarizations and associated outward tail currents which followed depolarizing pulses. These effects were antagonized by prazosin, indicating that they were mediated by alpha 1-adrenoceptors. The outward tail currents were sensitive to apamin, a blocker of certain Ca2+-activated K+ currents. A prolongation of afterhyperpolarizations would offset the major excitatory alpha 1 effects, which were associated with suppression of resting K+ currents and of the A-current. Since polyphosphoinositide metabolites have been reported to be second messengers for Ca2+-dependent receptor actions, we compared their effects with those of alpha 1-receptor stimulation on these cells. Intracellular ejection of the putative second messenger myo-inositol-1,4,5-trisphosphate from the recording electrode transiently mimicked the actions of alpha 1-agonists on the afterhyperpolarization. Superfusion with 1 mM LiCl, simulating therapeutic levels of lithium, had no effect on the rate of recovery from inositol trisphosphate ejection. Superfusion with water-soluble phorbol esters (which mimic actions of another phosphoinositide metabolite, 1,2-diacylglycerol) suppressed rather than mimicked the activation of raphe cell firing by phenylephrine; this occurred with a rank-order potency consistent with activation of protein kinase C and was associated with suppression of a slow inward current and of the outward tail current. Our results suggest that phosphoinositide turnover is more likely to mediate modulatory or negative-feedback effects of alpha 1-adrenoceptors than to mediate the major excitatory effects.

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