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

Abstract

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.

Alpha 1‐adrenoceptors in rat dorsal raphe neurons: regulation of two potassium conductances.

“…Similar results have been obtained in experiments from spinal neurons in culture (Legendre et al 1988). Our results differ from other reports on neurons in the dorsal raphe that indicate that the major excitatory effects of phenylephrine in the dorsal raphe is not calcium dependent (Aghajanian, 1985;Freedman & Aghajanian, 1987). The calcium dependence of the a1-mediated inward current appears to only involve external calcium.…”

“…In addition, amphetamine, an agent that releases noradrenaline, caused a depolarization that was blocked by prazosin, indicating that the release of endogenous noradrenaline increased the excitability of dorsal raphe neurons (Pan & Williams, 1989). The most commonly reported ionic mechanism that mediates the depolarization induced by a1-adrenoceptor activation is a decrease in potassium conductance (Yoshimura et al 1985;Fukuda, Minami, Nabekura & Oomura, 1987;Freedman & Aghajanian, 1987;McCormick & Prince, 1988; Legendre, Dupouy & Vincent, 1988;McCormick, 1992;Larkman & Kelly, 1992). There are several additional reports of noradrenaline acting on various conductances, ranging from an inhibition of the transient potassium conductance (Aghajanian, 1985;Wang, Wettwer, Gross & Ravens, 1991) to both augmentation (Freedman & Aghajanian, 1987) and depression.…”

Somatodendritic autoreceptor regulation of serotonergic neurons: dependence on l‐tryptophan and tryptophan hydroxylase‐activating kinases

“…This increase in autoinhibition may be mediated only in part by impulse‐flow‐dependent 5‐HT release. In addition, the rate of 5‐HT synthesis could be increased because increased calcium influx at higher firing rates together with phenylephrine‐induced calcium release from intracellular stores (Freedman & Aghajanian, 1987) can activate TPH via CaMKII and PKA. The evidence that autoinhibition is partly dependent on impulse‐flow‐dependent 5‐HT release is consistent with microdialysis studies in vivo showing that extracellular 5‐HT is reduced considerably by TTX (Matos et al ., 1996; Tao et al ., 2000; Adell et al ., 2002).…”

Neurotensin Excitation of Serotonergic Neurons in the Dorsal Raphe Nucleus of the Rat In Vitro

“…The neurotensin receptor is a member of the G protein-coupled receptor family and is coupled to the inositol phosphate (Goedert et al, 1984;Amar et al, 1986Amar et al, , 1987Snider et al, 1986;Kanba and Richelson, 1987), CAMP (Bozou et al, 1986) and cGMP second messenger systems Kanba and Richelson, 1987;Stauch Slusher et al, 1994). As the noradrenergic excitation of the serotonergic neurons in the DRN is known to result from the stimulation of al -adrenoceptors (VanderMaelen and Aghajanian, 1983;Yoshimura et al, 1985;Freedman and Aghajanian, 1987;Pan et af., 1994), which are also coupled to the inositol phosphate second messenger pathway (Brown ef al., 1984;Janowsky et al, 1984;Minneman and Johnson, 1984;Schoepp et al, 1984;Kemp and Downes, 1986), we investigated the possible interactions between phenylephrine, an al-adrenoceptor agonist, and neurotensin on serotonergic neurons. Some of these results were presented at the 24th annual meeting of the American Society for Neuroscience in 1994.…”