The roles of central neurotransmitters in the mechanism of action of psychotropic drugs.

中枢神经递质在精神药物作用机制中的作用。

• 批准号: 60480129
• 负责人: UEKI Showa
• 金额: $ 4.29万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1985
• 资助国家: 日本
• 起止时间: 1985 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-60480129/
• 关键词: Anxiolytics; Antidepressants; Antidementia drug; Conflict behavior; Muricide of the rat; Hypothalamus; Amygdala; 脳内アミン; ニューロペプチドY; ノルアドレナリン; セロトニン

The mechanisms of action of antidepressants, anxiolytics and antidementia drugs were investigated by using relevant models of brain dysfunction in rats.1. Muricide of the rat is selectively suppressed by antidepressants. In olfactory bulbectomized (OB) rats exhibiting muricide, noradrenaline (NA) content increased and NA turnover decreased in the lateral hypothalamus (LH), ventromedial hypothalamus (VMH), mammillary body (MB) and medial amygdala (AME), and serotonin (5-HT) turnover also decreased in LH and MB. In midbrain raphe-lesioned (Raphe) rats, 5-HT and its metabolites markedly decreased, but NA content in LH and VMH significantly increased, in accordance with the development of muricide. In nucleus accumbens-lesiond (Acc) rats exhibiting muricide, NA content significantly increased in LH, VMH and MB, 5-HT content decreased in LH and 5-HT turnover also decreased in MB. All these changes of brain monoamines in muricidal rats were mormalized with muricide suppressed by antidepressants.2. The antimuricide effect of NA microinjected into AME of OB rats was potentiated by neuropeptide Y (NPY). In OB rats exhibiting muricide, NPY content significantly increased in LH, VMH and the amygdala. This increase of NPY was reduced to the normal level with muricide inhibited by antideppressants.3. In the rats exhibiting muricide, the number of 5-HT_2 receptor but not of 5-HT_1 receptor significantly increased in the amygdala in OB rats and in the hypothalamus in Raphe rats. NAergic <alpha>2 receptors decreased in LH and VMH in OB rats.4. The central amygdala (ACE) and MB are the important sites of anticonflict action of benzodiazepines (BDZ), but the mechanism of action of BDZ was different in ACE and MB. The distribution of BDZ receptor subtypes was also different between ACE and MB.5. Relevant dementia models were provided and useful methods to quantitatively measure memory deficits were establishedfor evaluatiang antidementia drugs in rats.

利用大鼠脑功能障碍相关模型，探讨抗抑郁药、抗焦虑药和抗痴呆药物的作用机制。 1．抗抑郁药选择性地抑制大鼠的杀戮。在表现出杀戮的嗅球切除（OB）大鼠中，下丘脑外侧（LH）、下丘脑腹内侧（VMH）、乳头体（MB）和内侧杏仁核（AME）中去甲肾上腺素（NA）含量增加，NA周转减少，LH和MB中血清素（5-HT）周转也减少。在中脑中缝损伤（Raphe）的大鼠中，5-HT及其代谢物显着减少，但LH和VMH中的NA含量显着增加，这与杀伤力的发展一致。在表现出杀戮的伏隔核损伤（Acc）大鼠中，LH、VMH和MB中的NA含量显着增加，LH中的5-HT含量降低，MB中的5-HT周转率也降低。杀鼠大鼠脑单胺的所有这些变化均与抗抑郁药抑制杀鼠行为有关。 2．神经肽 Y (NPY) 增强了 OB 大鼠 AME 中显微注射 NA 的抗杀伤作用。在表现出杀戮的 OB 大鼠中，LH、VMH 和杏仁核中的 NPY 含量显着增加。抗抑郁药抑制杀戮后，NPY的增加可降至正常水平。3．在表现出杀戮行为的大鼠中，OB大鼠杏仁核和Raphe大鼠下丘脑中5-HT_2受体的数量显着增加，但5-HT_1受体的数量没有显着增加。 OB大鼠LH和VMH中NAergic α2受体减少。4．中央杏仁核（ACE）和MB是苯二氮卓类药物（BDZ）抗冲突作用的重要部位，但ACE和MB的BDZ作用机制不同。 ACE和MB.5之间BDZ受体亚型的分布也不同。提供了相关的痴呆模型，并建立了定量测量大鼠记忆缺陷的方法，用于评价抗痴呆药物。

项目成果

Showa Ueki: "Behavioral and electroencephalographic effects of zopiclone, a cyclopyrrolone derivative" Japan. J. Pharmacol.43. 309-326 (1987)

Showa Ueki：“佐匹克隆（一种环吡咯酮衍生物）的行为和脑电图效应”日本。

Tsuneyuki Yamamoto: Pharmacol. Biochem. Behav.26. 111-117 (1987)

山本常之：Pharmacol。

Tadashi Nagatani: European J. Pharmacol.142. 17-22 (1987)

Tadashi Nagatani：欧洲 J. Pharmacol.142。

R. Takahashi Ed.;Showa Ueki: "Psychotropic and Neurotropic drugs and neurotransmitter receptor" Excepta Medica, 11 (1986)

R. Takahashi Ed.；Showa Ueki：“精神药物和神经药物以及神经递质受体”Exceta Medica，11 (1986)

Tsuneyuki Yamamoto: Neuropharmacology. 27. 123-127 (1988)

山本常之：神经药理学。