Gene association studies in humans have linked the α5 subunit gene CHRNA5 to an increased risk for nicotine dependence. In the CNS, nicotinic acetylcholine receptors (nAChRs) that contain the α5 subunit are expressed at relatively high levels in the habenulo-interpeduncular system. Recent experimental evidence furthermore suggests that α5-containing receptors in the habenula play a key role in controlling the intake of nicotine in rodents. We have now analysed the subunit composition of hetero-oligomeric nAChRs in the habenula of postnatal day 18 (P18) C57Bl/6J control mice and of mice with deletions of the α5, the β2, or the β4 subunit genes. Receptors consisting of α3β4*1 clearly outnumbered α4β2*-containing receptors not only in P18 but also in adult mice. We found low levels of α5-containing receptors in both mice (6%) and rats (2.5% of overall nAChRs). Observations in β2 and β4 null mice indicate that although α5 requires the presence of the β4 subunit for assembling (but not of β2), α5 in wild-type mice assembles into receptors that also contain the subunits α3, β2, and β4.
This study explores the role of cyclic AMP in electrically evoked [3H]noradrenaline release and in the α2‐adrenergic modulation of this release in chick sympathetic neurons. Along with an increase in stimulation‐evoked tritium overflow, applications of forskolin enhanced the formation of intracellular cyclic AMP. Both effects of forskolin were potentiated by the phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine. The forskolin‐induced increase in overflow was abolished by the Rp‐diastereomer of cyclic AMP‐thioate, an antagonist at cyclic AMP‐dependent protein kinases, and 1,9‐dideoxy‐forskolin, an inactive analogue at adenylyl cyclase, had no effect on the evoked overflow. A 24‐h pretreatment with either cholera toxin or forskolin reduced the subsequent forskolin‐induced accumulation of cyclic AMP and inhibited the stimulation‐evoked release. Basal cyclic AMP production, however, remained unaltered after forskolin treatment and was enhanced after 24 h of cholera toxin exposure. The α2‐adrenergic agonist bromoxidine did not affect the formation of cyclic AMP stimulated by forskolin but reduced electrically evoked release. However, effects of bromoxidine on 3H overflow were attenuated by forskolin as well as by 8‐bromo‐cyclic AMP. Effects of bromoxidine on [3H]noradrenaline release were paralleled by an inhibition of voltage‐activated Ca2+ currents, primarily through a delayed time course of current activation. This effect was abolished when either forskolin or 8‐bromo‐cyclic AMP was included in the pipette solution. Both substances, however, failed to affect Ca2+ currents in the absence of bromoxidine. These results suggest that the signaling cascade of the α2‐adrenergic inhibition of noradrenaline release involves voltage‐activated Ca2+ channels but not cyclic AMP. Elevated levels of cyclic AMP, however, antagonize this α2‐adrenergic reduction, apparently through a disinhibition of Ca2+ channels.
Abstract:The mechanisms by which the cognition enhancer linopirdine may affect transmitter release were investigated in cultures of rat superior cervical ganglion neurons. Overflow of previously incorporated rH]noradrenaline evoked by 10 pM UTP or 0.1 pM bradykinin was enhanced by linopirdine at 2 3 pM, overflow evoked by 25 mM K+, 100 pM nicotine, or 300 pM ATP was enhanced by linopirdine at 210 pM, and overflow due to 40 mM K+ or electrical field stimulation was not altered by linopirdine. Ba2+ (0.3 mM) augmented the same types of stimulation-evoked overflow to a similar extent as linopirdine. K+ (25 mM), nicotine (100 pM), and ATP (300 pM) triggered transmitter release in a partially tetrodotoxin-resistant manner, and the release-enhancing action of linopirdine was lost in the presence of tetrodotoxin (1 pM). Linopirdine (1 0 pM) raised spontaneous tritium outflow and reduced currents through muscarinic Kf ( K, ) channels with a similar time course. The secretagogue action of linopirdine was concentration-and Ca2+-dependent and abolished by tetrodotoxin (1 pM) or Cd2+ (100 pM). Linopirdine (10 p l d ) added to the partial inhibition of K , channels by 1 or 3 mM Ba2+ but not to the complete inhibition by 10 mM Ba2+. Likewise, the secretagogue action of 1 and 3 mM, but not that of 10 mM, Ba2+ was enhanced by linopirdine. These results indicate that linopirdine facilitates and triggers transmitter release via blockade of K , channels and suggest that these K+ channels are located at neuronal somata rather than at presynaptic sites. Key Words: Linopirdine-Ba'+-Rat superior cervical ganglion neurons-Muscarinic K+ channels-Noradrenaline release.
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