Szabo B, Fröhlich R, Illes P
Pharmakologisches Institut, Albert-Ludwigs-Universität, Freiburg, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Apr;353(5):557-63. doi: 10.1007/BF00169176.
alpha 2-Adrenoceptor agonists inhibit the firing of locus coeruleus (LC) neurons. It was recently observed that the alpha-adrenoceptor agonists clonidine, rilmenidine and cirazoline, when injected intravenously in anaesthetized rats pretreated with the irreversible alpha 2-adrenoceptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), excite the LC. The effect was attributed to activation of I1 imidazoline receptors. The aim of the present experiments was to characterize the direct effect of alpha 2-adrenoceptor and I1 imidazoline receptor agonists on LC neurons. Electrical activity of LC neurons was extracellularly recorded in midpontine slices prepared from the rat brain. Concentration-response curves were obtained for the alpha 2-agonist noradrenaline and the mixed I1/alpha 2-receptor agonists clonidine, rilmenidine and moxonidine in slices without treatment and in slices treated with 6-chloro-N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F86466) or EEDQ, alpha 2-adrenoceptor antagonists with low affinity for I1 and I2 imidazoline receptors, respectively. All four agonists concentration-dependently reduced the firing rate of the neurons, with full inhibition at higher concentrations. SK&F86466 shifted the concentration-response curves of the agonists to the right; the calculated antagonist dissociation constants are compatible with an effect of the agonists on alpha 2-adrenoceptors. EEDQ completely prevented the inhibition by the agonists. Neither in SK&F86466- nor in EEDQ-treated slices was an excitation by clonidine, rilmenidine and moxonidine observed. We conclude that the LC neurons do not possess functional I1 (and also no I2) imidazoline receptors. The effects of noradrenaline, clonidine, rilmenidine and moxonidine on the neurons can be fully explained with an interaction with inhibitory alpha 2-adrenoceptors (probably of the alpha 2D subtype). The excitation of the LC by imidazoline receptor agonists under in vivo conditions, hence, is not a direct effect on the neurons of the LC.
α2 -肾上腺素能受体激动剂可抑制蓝斑（LC）神经元的放电。最近观察到，在经不可逆α2 -肾上腺素能受体拮抗剂N -乙氧羰基-2 -乙氧基-1,2 -二氢喹啉（EEDQ）预处理的麻醉大鼠中静脉注射α -肾上腺素能受体激动剂可乐定、利美尼定和西拉唑啉时，会兴奋蓝斑。该效应归因于I1咪唑啉受体的激活。本实验的目的是表征α2 -肾上腺素能受体和I1咪唑啉受体激动剂对蓝斑神经元的直接作用。在从大鼠脑制备的脑桥中部切片中细胞外记录蓝斑神经元的电活动。在未处理的切片以及用6 -氯-N -甲基-2,3,4,5 -四氢-1H - 3 -苯并氮杂䓬（SK&F86466）或EEDQ处理的切片中，分别获得了α2 -激动剂去甲肾上腺素以及I1/α2 -受体混合激动剂可乐定、利美尼定和莫索尼定的浓度-反应曲线，SK&F86466和EEDQ分别是对I1和I2咪唑啉受体亲和力低的α2 -肾上腺素能受体拮抗剂。所有四种激动剂均浓度依赖性地降低神经元的放电率，在较高浓度时完全抑制。SK&F86466使激动剂的浓度-反应曲线右移；计算出的拮抗剂解离常数与激动剂对α2 -肾上腺素能受体的作用相符。EEDQ完全阻止了激动剂的抑制作用。在SK&F86466处理的切片和EEDQ处理的切片中均未观察到可乐定、利美尼定和莫索尼定的兴奋作用。我们得出结论，蓝斑神经元不具有功能性I1（也没有I2）咪唑啉受体。去甲肾上腺素、可乐定、利美尼定和莫索尼定对神经元的作用可以通过与抑制性α2 -肾上腺素能受体（可能是α2D亚型）的相互作用得到充分解释。因此，在体内条件下咪唑啉受体激动剂对蓝斑的兴奋作用并非对蓝斑神经元的直接作用。
