Giralt M T, García-Sevilla J A
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Spain.
Eur J Pharmacol. 1989 May 30;164(3):455-66. doi: 10.1016/0014-2999(89)90253-7.
The specific binding of [3H]clonidine (KD and Bmax) to rat brain membranes was used as a biochemical index to directly evaluate alpha 2-adrenoceptor changes after manipulation of synaptic noradrenaline (NA) pools or stimulation or blockade of the receptor. Acute (2 h) and prolonged (7 days) inhibition of NA synthesis with alpha-methyl-p-tyrosine (150 mg/kg) or acute (2 h) and chronic (14 days) treatment with reserpine (0.1-0.5 mg/kg) reduced the NA content by 15-90%, which also resulted in marked reductions (35-55%) of the KD values for [3H]clonidine in all brain regions studied. In contrast to alpha-methyl-p-tyrosine, chronic reserpine treatment did not alter the Bmax values for [3H]clonidine or [3H]UK 14304 in any brain region. In the hypothalamus and cerebral cortex, acute (2 h) and chronic (7-14 days) treatment with the monoamine oxidase (MAO) inhibitors clorgyline (1 mg/kg) or tranylcypromine (5 mg/kg) increased the content of NA by 6-100%, which led to marked reductions (20-50%) of Bmax without altering the KD values for [3H]clonidine. Similarly, prolonged (21 days) inhibition of NA neuronal uptake with cocaine or protriptyline (10 mg/kg) also resulted in decreases in Bmax (20-25%) with no alterations in KD in the hypothalamus. In various brain regions, chronic (14 days) but not short-term (1 day) treatment with clonidine (0.1 mg/kg) or yohimbine (10 mg/kg) resulted in decreases (30-40%) and increases (15-20%), respectively, in Bmax without altering the KD values for [3H]clonidine. The results indicate that drugs which deplete endogenous NA up-regulate alpha 2-adrenoceptors (increased affinity of [3H]clonidine binding sites) while drugs which increase the intraneuronal and/or synaptic NA pools down-regulate the receptors (decreased number of [3H]clonidine binding sites). These adaptive receptor changes appear to be dependent on NA availability.
以[3H]可乐定（KD和Bmax）与大鼠脑膜的特异性结合作为生化指标，直接评估操纵突触去甲肾上腺素（NA）库或刺激或阻断该受体后α2 -肾上腺素能受体的变化。用α-甲基-对-酪氨酸（150 mg/kg）急性（2小时）和长期（7天）抑制NA合成，或用利血平（0.1 - 0.5 mg/kg）急性（2小时）和慢性（14天）治疗，使NA含量降低了15 - 90%，这也导致在所研究的所有脑区中，[3H]可乐定的KD值显著降低（35 - 55%）。与α-甲基-对-酪氨酸不同，慢性利血平治疗在任何脑区均未改变[3H]可乐定或[3H]UK 14304的Bmax值。在下丘脑和大脑皮层，用单胺氧化酶（MAO）抑制剂氯吉兰（1 mg/kg）或反苯环丙胺（5 mg/kg）急性（2小时）和慢性（7 - 14天）治疗，使NA含量增加了6 - 100%，这导致Bmax显著降低（20 - 50%），而未改变[3H]可乐定的KD值。同样，用可卡因或普罗替林（10 mg/kg）长期（21天）抑制NA神经元摄取，也导致下丘脑Bmax降低（20 - 25%），而KD无变化。在各个脑区，用可乐定（0.1 mg/kg）或育亨宾（10 mg/kg）慢性（14天）而非短期（1天）治疗，分别导致Bmax降低（30 - 40%）和升高（15 - 20%），而未改变[3H]可乐定的KD值。结果表明，消耗内源性NA的药物上调α2 -肾上腺素能受体（[3H]可乐定结合位点亲和力增加），而增加神经元内和/或突触NA库的药物下调该受体（[3H]可乐定结合位点数量减少）。这些适应性受体变化似乎取决于NA的可用性。
