Pi F, García-Sevilla J A
Departamento de Neurociencias, Universidad del País Vasco, Bizkaia, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 1992 Jun;345(6):653-60. doi: 10.1007/BF00164579.
The physiological importance of brain alpha 2-adrenoceptors in controlling the activity of tyrosine hydroxylase in noradrenergic regions was investigated using the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition as a measure of the rate of tyrosine hydroxylation (and synthesis of noradrenaline) in vivo. In the hypothalamus and cerebral cortex, clonidine (0.025-1 mg/kg, i.p.) decreased (18%-43%) and idazoxan (0.1-80 mg/kg, i.p.) increased (20%-73%) the synthesis of DOPA in a dose-dependent manner. Moreover, pretreatment with idazoxan (0.1 mg/kg) antagonized the effect of clonidine (0.1 mg/kg) in the hypothalamus. After treatment with reserpine (5 mg/kg, s.c., 18 h before decapitation) and depletion of noradrenaline, clonidine (0.5 mg/kg) continued to decrease (50%-55%) but idazoxan (20 mg/kg) failed to increase the synthesis of DOPA, which suggested the involvement of an alpha-auto-receptor mechanism. Acute treatments of rats (not exposed to reserpine) with a wide variety of adrenoceptor agonists such as guanfacine 6, B-HT920, xylazine, bromoxidine (1 mg/kg) and antagonists such as yohimbine, phentolamine, prazosin (10 or 20 mg/kg) resulted in significant decreases (15%-55%) or increases (21%-99%) in the synthesis of DOPA in both brain regions. However, other agonists (oxymetazoline, azepexole, tramazoline, methoxamine) and antagonists (tolazoline, dihydroergotamine, phenoxybenzamine, propranolol) did not modify the synthesis of DOPA. In the hypothalamus and cerebral cortex the effects of the drugs were consistent with the selectivity of alpha-adrenoceptor agonists and antagonists (except prazosin) for an alpha 2-adrenoceptor. The results also suggest that the alpha 2-autoreceptor that modulates the synthesis of noradrenaline in the rat brain appears to belong to the prazosin-sensitive alpha 2B-subtype.
利用脱羧酶抑制后3,4 -二羟基苯丙氨酸（DOPA）的蓄积作为体内酪氨酸羟化速率（和去甲肾上腺素合成）的指标，研究了脑α2 -肾上腺素能受体在控制去甲肾上腺素能区域酪氨酸羟化酶活性中的生理重要性。在下丘脑和大脑皮层，可乐定（0.025 - 1mg/kg，腹腔注射）以剂量依赖性方式降低（18% - 43%）DOPA的合成，咪唑克生（0.1 - 80mg/kg，腹腔注射）则以剂量依赖性方式增加（20% - 73%）DOPA的合成。此外，用咪唑克生（0.1mg/kg）预处理可拮抗可乐定（0.1mg/kg）在下丘脑的作用。在用利血平（5mg/kg，皮下注射，断头前18小时）处理并耗尽去甲肾上腺素后，可乐定（0.5mg/kg）继续降低（50% - 55%）DOPA的合成，但咪唑克生（20mg/kg）未能增加DOPA的合成，这表明存在α - 自身受体机制。用多种肾上腺素能受体激动剂如胍法辛6、B - HT920、赛拉嗪、溴莫尼定（1mg/kg）和拮抗剂如育亨宾、酚妥拉明、哌唑嗪（10或20mg/kg）对未接触利血平的大鼠进行急性处理，导致两个脑区DOPA的合成显著降低（15% - 55%）或增加（21% - 99%）。然而，其他激动剂（羟甲唑啉、阿泽哌唑、曲马唑啉、甲氧明）和拮抗剂（妥拉唑啉、双氢麦角胺、酚苄明、普萘洛尔）并未改变DOPA的合成。在下丘脑和大脑皮层，药物的作用与α - 肾上腺素能受体激动剂和拮抗剂（哌唑嗪除外）对α2 -肾上腺素能受体的选择性一致。结果还表明，调节大鼠脑内去甲肾上腺素合成的α2 -自身受体似乎属于对哌唑嗪敏感的α2B -亚型。
