Garro M A, Pineda J, Giralt M T, Ugedo L
Department of Pharmacology, University of the Basque Country, Faculty of Medicine, Leioa, Vizcaya, Spain.
Pharmacol Toxicol. 1999 Aug;85(2):74-9. doi: 10.1111/j.1600-0773.1999.tb00069.x.
We have investigated the effect of treatments with the muscarinic acetylcholine receptor agonist, pilocarpine, on the sensitivity of central alpha2-adrenoceptors that regulate the firing activity of rat locus coeruleus, the tyrosine hydroxylase activity in the rat cortex, hippocampus and hypothalamus, and the K(+)-evoked release of [3H]noradrenaline from rat cortical and hippocampal synaptosomes. Short-term (4 days), but not acute, treatment with pilocarpine caused a small but statistically significant increase in the inhibitory effect of the alpha2-adrenoceptor agonist clonidine on the firing rate of locus coeruleus neurones, with a decrease in the ED50 of 290% (P<0.001). However, no change in the effect of clonidine on the locus coeruleus was observed after longer pilocarpine (11 days) treatment. In the rat cerebral cortex, but not in hippocampus or hypothalamus, chronic (19 days) treatment with pilocarpine caused a decrease in the inhibitory effect of clonidine on tyrosine hydroxylase activity (55%, P<0.05), but did not change the stimulatory effect of the alpha2-adrenoceptor antagonist idazoxan. Moreover, treatments (4, 11 and 19 days) with pilocarpine did not alter the inhibitory effect of clonidine [10(-8)-10(-5) M] on the K(+)-evoked release of [3H]noradrenaline from rat cortical and hippocampal synaptosomes. These results indicate that administration of pilocarpine slightly potentiates some but not all the functional responses mediated by brain presynaptic alpha2-adrenoceptors. In conclusion, these results do not support the hypothesis that chronic treatments with pilocarpine lead to a suitable model of alpha2-adrenoceptor supersensitivity.
我们研究了用毒蕈碱型乙酰胆碱受体激动剂毛果芸香碱进行治疗，对调节大鼠蓝斑放电活动的中枢α2 - 肾上腺素能受体敏感性、大鼠皮质、海马和下丘脑的酪氨酸羟化酶活性以及钾离子诱发的大鼠皮质和海马突触体中[3H]去甲肾上腺素释放的影响。短期（4天）而非急性给予毛果芸香碱，会使α2 - 肾上腺素能受体激动剂可乐定对蓝斑神经元放电率的抑制作用出现小幅但具有统计学意义的增加，半数有效剂量（ED50）降低290%（P<0.001）。然而，较长时间（11天）给予毛果芸香碱后，未观察到可乐定对蓝斑的作用有变化。在大鼠大脑皮质而非海马或下丘脑，长期（19天）给予毛果芸香碱会使可乐定对酪氨酸羟化酶活性的抑制作用降低（55%，P<0.05），但不会改变α2 - 肾上腺素能受体拮抗剂咪唑克生的刺激作用。此外，给予毛果芸香碱进行治疗（4天、11天和19天）不会改变可乐定[10(-8)-10(-5) M]对钾离子诱发的大鼠皮质和海马突触体中[3H]去甲肾上腺素释放的抑制作用。这些结果表明，给予毛果芸香碱会轻微增强部分而非全部由脑突触前α2 - 肾上腺素能受体介导的功能反应。总之，这些结果不支持毛果芸香碱长期治疗会导致α2 - 肾上腺素能受体超敏合适模型的假说。
