EFFECTS OF HISTAMINE-H-3-RECEPTOR LIGANDS ON VARIOUS BIOCHEMICAL INDEXES OF HISTAMINERGIC NEURON ACTIVITY IN RAT-BRAIN
EFFECTS OF HISTAMINE-H-3-RECEPTOR LIGANDS ON VARIOUS BIOCHEMICAL INDEXES OF HISTAMINERGIC NEURON ACTIVITY IN RAT-BRAIN
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DOI：
10.1016/0014-2999(89)90225-2
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发表时间：
1989-05-02
影响因子：
5
通讯作者：
SCHWARTZ, JC
中科院分区：
文献类型：
--
作者：
GARBARG, M;TUONG, MDT;SCHWARTZ, JC
本文研究了组胺H3受体激动剂(R)-α-甲基组胺和拮抗剂硫代巴比妥胺与三类脑组织胺受体的相互作用。组胺刺激豚鼠脑片3‘’，5‘-环磷酸腺苷蓄积不受硫代巴比妥钠(0.1 mM)和(R)的影响，α-甲基组胺仅在毫摩尔浓度时刺激环腺苷酸蓄积。因此，在大脑中，(R)α-甲基组胺和硫代巴比妥胺在H3受体上的效力至少是在H1或H2受体上的10万倍。在体内，由α-氟甲基组氨酸在突触体组分引起的组胺耗竭测定的大鼠大脑皮层组胺的转化率不被甲吡胺和唑替丁所改变，但在低剂量(ED50=2 mg/kg)时被硫代巴比妥钠显著增强。硫代巴比妥钠还引起突触体组胺的长期减少和可放射免疫分析的N-tau-甲基组胺的增加。相反，(R)α-甲基组胺显著减少大脑皮层[~3H]组胺合成(ED50=5 mg/kg)。这种持久的作用伴随着突触体组胺的增加和N-tau-甲基组胺水平的下降。将这些变化与血药浓度进行比较。因此，这两种H3受体配体似乎以一种持久和相反的方式显着地改变了大脑组胺神经元的活性。
The interaction of the potent histamine H3-receptor ligands i.e. (R).alpha.-methylhistamine, an agonist, and thioperamide, an antagonist, with the three classes of cerebral histamine receptors was studied in vitro and in vivo. The histamine-induced stimulation of 3'',5''-cyclic AMP accumulation in slices of guinea-pig hippocampus was not modified by thioperamide (up to 0.1 mM) and (R).alpha.-methylhistamine stimulated cyclic AMP accumulation only at millimolar concentrations. Hence, both (R).alpha.-methylhistamine and thioperamide were at least 100 000-fold more potent at H3- than at H1-or H2-receptors in brain. In vivo, the turnover of histamine in rat cerebral cortex, as determined from its depletion elicited by .alpha.-fluoromethylhistidine in a synaptosomal fraction was not modified by mepyramine and zolantidine but was markedly enhanced by thioperamide at a low dose (ED50 = 2 mg/kg). Thioperamide also elicited a long-lasting decrease in synaptosomal histamine and increase in radioimmunoassayable N.tau.-methylhistamine. In contrast, (R).alpha.-methylhistamine markedly reduced cortical [3H]histamine synthesis (ED50 = 5 mg/kg). This long-lasting action was accompanied by an increase in synaptosomal histamine an a decrease in N.tau.-methylhistamine levels. These changes were compared with those in plasma drug levels. Hence the two H3-receptor ligands appear to modify the activity of cerebral histamine neurons markedly and in a long-lasting and opposite manner.