Heal D J, Prow M R, Buckett W R
Research Department, Boots Company, Nottingham, U.K.
Eur J Pharmacol. 1989 Oct 24;170(1-2):19-28. doi: 10.1016/0014-2999(89)90128-3.
Since brain alpha 2-adrenoceptors occur both pre- and postsynaptically, experiments were carried out to determine the synaptic locations of those receptors mediating clonidine-induced hypoactivity and mydriasis. Intraperitoneal (i.p.) injection of clonidine (1-3000 micrograms/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED50 values were: 120 micrograms/kg for hypoactivity (95% confidence limits 103-140 micrograms/kg), 54 micrograms/kg for mydriasis (95% confidence limits 40-74 micrograms/kg) and 18 micrograms/kg for MHPG reduction (95% confidence limits 8-36 micrograms/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose dependently produce mydriasis, but not hypoactivity, after peripheral (0.1-5 mg/kg i.p.) or central (0.5-10 micrograms i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 micrograms idazoxan or yohimbine, but not 2.5 micrograms prazosin or pindolol, showing this effect was mediated by central alpha 2-adrenoceptors. Methamphetamine (1-10 micrograms i.c.v.) potentiated the mydriasis induced by clonidine (50 micrograms/kg i.p.) suggesting this was a postsynaptic alpha 2-adrenoceptor response. By contrast, methamphetamine (1-10 micrograms i.c.v.) dose dependently reversed clonidine (100 micrograms/kg i.p.) hypoactivity indicating this response was mediated by presynaptic alpha 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. x 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 micrograms/kg i.p.) and markedly attenuated clonidine (100 micrograms/kg i.p.) hypoactivity.
由于脑内α2-肾上腺素能受体存在于突触前和突触后，因此开展了实验以确定介导可乐定引起的活动减退和瞳孔散大的那些受体的突触位置。给小鼠腹腔注射可乐定（1 - 3000微克/千克），剂量依赖性地诱发了这两种反应，并且还降低了脑内3 - 甲氧基 - 4 - 羟基苯乙二醇（MHPG）的浓度。半数有效剂量（ED50）值分别为：活动减退为120微克/千克（95%置信限为103 - 140微克/千克），瞳孔散大为54微克/千克（95%置信限为40 - 74微克/千克），MHPG降低为18微克/千克（95%置信限为8 - 36微克/千克），这表明这些反应可能均由突触前介导。然而，发现增加去甲肾上腺素周转的甲基苯丙胺在外周（腹腔注射0.1 - 5毫克/千克）或中枢（脑室内注射0.5 - 10微克）注射后，剂量依赖性地产生瞳孔散大，但不产生活动减退。甲基苯丙胺（腹腔注射0.5毫克/千克）引起的瞳孔散大，可通过脑室内注射1微克咪唑克生或育亨宾而消除，但不能通过注射2.5微克哌唑嗪或吲哚洛尔消除，表明这种作用是由中枢α2-肾上腺素能受体介导的。甲基苯丙胺（脑室内注射1 - 10微克）增强了可乐定（腹腔注射50微克/千克）诱发的瞳孔散大，提示这是一种突触后α2-肾上腺素能受体反应。相比之下，甲基苯丙胺（脑室内注射1 - 10微克）剂量依赖性地逆转了可乐定（腹腔注射100微克/千克）引起的活动减退，表明这种反应是由突触前α2-肾上腺素能受体介导的。使用DSP - 4（腹腔注射100毫克/千克，共2次）破坏去甲肾上腺素能神经元证实了这些假设。这种处理可防止对甲基苯丙胺（腹腔注射0.5毫克/千克）的瞳孔散大反应，但不能防止对可乐定（腹腔注射100微克/千克）的反应，并显著减弱可乐定（腹腔注射100微克/千克）引起的活动减退。
