Abstract
Postganglionic sympathetic neurons and brain noradrenergic neurons use α2A- and α2C-adrenoceptors as presynaptic autoreceptors. The present experiments were carried out in order to see whether they possess presynaptic α2B-autoreceptors as well. Pieces of atria, vasa deferentia, the occipito-parietal cortex and the hippocampus were prepared from either wildtype (WT) mice or mice in which both the α2A- and the α2C-adrenoceptor gene had been disrupted (α2ACKO). The pieces were incubated with 3H-noradrenaline and then superfused and stimulated electrically. In a first series of experiments, single pulses or brief, autoinhibition-poor pulse trains were used for stimulation. The α2-adrenoceptor agonist UK 14,304 (brimonidine) reduced the evoked overflow of tritium in all four tissues from WT mice but did not change it in any tissue from α2ACKO mice. A different pattern was obtained with medetomidine as α2 agonist. Like UK 14,304, medetomidine reduced the evoked overflow of tritium in all four tissues from WT mice and did not affect overflow in brain slices from α2ACKO mice; however, in contrast to UK 14,304, medetomidine reduced evoked overflow also in atrial and vas deferens pieces from α2ACKO mice, although with a lower maximum and potency than in WT preparations. The α-adrenoceptor antagonists rauwolscine, phentolamine, prazosin, spiroxatrine and WB 4101 shifted the concentration-response curve of medetomidine in α2ACKO atria and vasa deferentia to the right. The pKd values of the five antagonists against medetomidine in α2ACKO atria and vasa deferentia correlated with pKd values at prototypical α2B radioligand binding sites but not at α2A or α2C binding sites. In a second series of experiments, autoinhibition-rich pulse trains were used for stimulation. Under these conditions, rauwolscine and phentolamine increased the evoked overflow of tritium from α2ACKO atrial and vas deferens pieces but not from α2ACKO brain slices. The increase was smaller (by 40% in atria and by 70% in the vas deferens) than previously observed in WT preparations (by 200–400%). In a last series of experiments, mRNA for the α2B-adrenoceptor was demonstrated by RT-PCR in thoracolumbar sympathetic ganglia from WT, α2AKO, α2CKO and α2ACKO mice but not from α2BKO mice. The results show that brain noradrenergic neurons express only α2A- and α2C-adrenoceptors as autoreceptors. Postganglionic sympathetic neurons, however, can express α2B-adrenoceptors as presynaptic autoreceptors as well. The α2B-autoreceptors are activated by medetomidine but not by UK 14,304. They are also activated by previously released noradrenaline. The two-α2-autoreceptor hypothesis has to be replaced by a three-autoreceptor hypothesis for postganglionic sympathetic neurons.
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This study was supported by the Deutsche Forschungsgemeinschaft (SFBs 487 und 505).
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Trendelenburg, AU., Philipp, M., Meyer, A. et al. All three α2-adrenoceptor types serve as autoreceptors in postganglionic sympathetic neurons. Naunyn-Schmiedeberg's Arch Pharmacol 368, 504–512 (2003). https://doi.org/10.1007/s00210-003-0829-x
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DOI: https://doi.org/10.1007/s00210-003-0829-x