Neurochemical study on pharmachological action of antimanic drugs using by microdialysis method

为了研究抗躁狂药物的作用机制，进行了两项动物实验和一项人体实验，其中一项人体实验测定了健康受试者对去甲丙咪嗪（DEMETHYMIMPRAMINE，DEMETHYMIMPRAMINE）和可乐定的生长激素（GH）反应。6名受试者在6个月的时间间隔内测试了三次，其中五名始终显示出稳定的生长激素反应，而只有一名显示出相当不稳定的GH反应。在1例受试者中观察到GH对地塞米松和可乐定的反应减弱。结果提示，多巴胺和可乐定刺激GH分泌试验可作为中枢突触后α 2肾上腺素能功能易损性的标志。在动物研究中，在Fischer 344大鼠中，在单次施用苯乙醇胺-N-甲基转移酶（PNMT）抑制剂DCMB后，测定自发活动计数。该药物抑制PNMT以及az肾上腺素受体。然后，育亨宾，纯az肾上腺素受体抑制剂，被用作阳性对照。在Fischer 344大鼠中，α 2肾上腺素能受体 ...更多信息 与布法罗大鼠相比，下丘脑和下脑干的TOR亚敏感性和较高的PNMT活性。这些药物在Fischer 344大鼠中引起大量活动，但DCMB引起的活动明显高于育亨宾引起的活动。提示肾上腺素能神经元可能调节中枢α_2肾上腺素能受体的敏感性。用脑透析法测定育亨宾对Wistar系大鼠下丘脑细胞外液中3-甲氧基-4-羟基苯乙二醇（MHPG）含量的影响。通过高效液相色谱法测量MHPG水平。单次腹腔注射育亨宾后，MHPG水平升高。这一结果提示育亨宾可能对下丘脑α_2肾上腺素能受体产生突触前抑制作用，MHPG可能是下丘脑α_2肾上腺素能受体突触前敏感性的生物学标志。这些结果在第五届国际生物精神病学大会、第二十届日本精神药理学大会和第十二届日本生物精神病学大会上报告。少

Two animal experiments and one human study were performed for investigating the mode of action of antimanic drugs.In a human study, growth hormone(GH)response to desmethylimipramine(DMI)and clonidine was measured in healthy subjects. Of six subjects tested three times at 6-month intervals, five always showed a stable growth hormone response, whereas only one had a rather instable GH response. The blunted GH response to DMI and clonidine was seen in a subject. These results suggested that DMI and clonidine stimulated GH secretion test may be vulnerability markers for central postsynaptic a2 adrenergic function. Those were published in "Seishinigaku".In animal studies, locomotor activity counts were determined in Fischer 344 rats after a single administration of a phenylethanolamine-N-methyltransferase(PNMT)inhibitor, DCMB. This drug inhibits PNMT as well as az adrenoceptor. Then, yohimbine, pure az adrenoceptor inhibitor, was used as a positive control. In Fischer 344 rats, a2 adrenocep … More tor subsensitivity and higher PNMT activity were found in the hypothalamus and lower brainstem compared with Buffalo rats. These drugs profused hyperactivity in Fischer 344 rats, but DCMB induced hyperactivity was significantly higher than that induced by yohimbine. This result suggested that adrenergic neuron may regulate central alpha_2 adrenoceptor sensitivity. The effect of yohimbine on 3 methoxy 4 hydroxyphenylethylenglycol(MHPG)in extra cellular fluid of hypothalamus was determined by brain dialysis method in Wistar strain rats. MHPG levels were measured by high performance liquid chromatography. MHPG levels were increased after a single intraperitoneal injection of yohimbine. This result suggested that yohimbine may produce presynaptic alpha_2 adrenoceptor inhibition and that MHPG may a biological marker of presynaptic alpha_2 adrenoceptor sensitivity in hypothalamus. These results were reported at the 5th international Congress of Biological Psychiatry, the 20th Congress of Japanese Psychopharmacology and the 12th Congress of Japanese Biological Psychiatry. Less