医学神经生物学：第八章 单胺类神经递质

第八章 单胺类神经递质2016-3儿茶酚胺 (catecholamine,CA)去甲肾上腺素 noradrenaline , NE或NA 多巴胺 dopamine, DA 肾上腺素 adrenaline, E或A吲哚胺 (indolamine)5-羟色胺（ serotonine, 5-HT)单胺类递质 monoamines儿茶酚胺 catecholamine 吲哚胺 indolamine Arvid Carlsson (1958): high level in striatum, 70% of the total content in brainHornykiewicz (1960): critical loss of DA neurons in PD patients Dahlstrom (1964): prescribe DA pathways in CNS by fluorescent- histochemisty 1971: 6-OHDA is toxic for DA function1976: antipsychotic activity correlated with DA receptor binding activity1978: detect DA concentration with voltammetry1979: classification of DA receptors 1982: detect DA release by microdialysis1983: MPTP neurotoxicity 1988: D2 receptor cloned 1991: DA transporter cloned 1996: knock out DA transporter mice 2000: Nobel Prize （神经系统信号传导（神经系统信号传导慢突触传递慢突触传递新药研发）新药研发）Milestones in the research history of DA 单胺类神经元在脑内的分布及神经纤维投射 中枢单胺类递质的生物转换 中枢单胺类递质的受体及受体介导的信号通路 单胺类递质在神经精神疾病中的作用Outline一、脑内分布及投射1，NE神经元胞体分布及纤维投射2，DA神经元胞体分布及纤维投射3，5-HT神经元胞体分布及纤维投射Falck-Hillarp technique -to detect monoamines distribution in CNSFormaldehyde vapour / glyoxylic acid（水合乙醛酸）（水合乙醛酸）isoquinoline（异喹啉）（异喹啉）condensation productsbright-green flurorescence (DA, NA) yellow flurorescence (5-HT)monoamine (DA, CA, 5-HT)1962年，Falck-Hillarp发现甲醛可诱发单胺类物质生成荧光物质Dahlstrom和Fuxe在1964年通过甲醛诱发荧光方法检测到大鼠脑内单胺类神经元的分布及投射蓝斑核的NE黑质的DA中缝核群的5-HTMajor Noradrenergic (blue), Dopaminergic (red) and Serotonergic (green) Pathways in the CNS1.1 NE神经元胞体在脑内的分布聚集成簇，A1 A7主要集中在脑干的蓝斑核及外侧被盖核 locus coeruleus complex 蓝斑 -A4, A6 lateral tegmental nuclei 外侧被盖核 -A1, A3, A5, A7, A2 LC1.2 NE神经纤维在脑内广泛投射Norepinephrine pathways in rat brain被盖背侧束-脑桥腹侧/内侧前脑束丘脑前核,腹侧核,外侧核及内外侧膝状体 缰核脚间束杏仁核,海马和新皮层缰内侧核小脑脚-小脑中央核群及小脑皮质下丘脑蓝斑蓝斑Norepinephrine pathways in rat brainLateral tegmental nuclei通过小脑上脚腹侧进入中脑上行腹侧束系统上行腹侧束系统小脑第三脑室背侧周围中脑网状系统及下丘脑Norepinephrine pathways in rat brain去甲肾上腺素能下行束,或脊髓系2.1 DA神经元胞体在脑内的分布聚集成簇，A8 A17主要集中在中脑（ A8 A10 ）和间脑（ A11 A17 ）A9 （substantia nigra, SN 黑质） A10 （ventral tegmentum，VTA， 腹侧被盖区 )A9A10A10A92.2 DA能神经纤维在脑内广泛投射黑质 纹状体： A8、 A9 纹状体中脑 边缘皮质通路： A10 伏隔核、嗅结节 A10 前额叶皮层、嗅皮层 A9、A10 前扣带皮层结节漏斗通路（DA能短投射）： A12、A14 漏斗、垂体前叶下行通路： A11等 脑干、脊髓 projection pathways of DA neurons纹状体： 10 g/g伏隔核： 5 g/g嗅结节： 6 g/g皮 质： D2RDADA减少，D1R激活不足，产生阴性症状VTA、伏隔核：D1R D2RDA增多，D2R亢进，产生阳性症状5-HT、NE也与精神分裂症有密切关联PFC的NE调控皮质边缘通路的DA信号PFC的5-HT2A受体调节VTA的DA释放六、中枢单胺类递质与抑郁症抑郁症（depression）病因复杂，发病机制不明确表现为明显而持久的心境低落伴有相应的思维、行为、认知改变Depression Catecholamine Hypothesis1.Fifteen percent of individuals prescribed reserpine for hypertension developed depression.2.MAOIs being prescribed for tuberculosis were found to elevate mood.3.Cocaine and amphetamine, which increase catacholamines, elevate mood.4.NE is found in abundance in the limbic systems and is thought to regulate mood.5.Depressed individuals show low levels of MHPG, a metabolite of NE.6.Tricyclic antidepressant drugs were found to inhibit the reuptake of NE.Problems with the Catacholamine Hypothesis1.Tryicyclic antidepressant drugs required several days or weeks to alleviate the symptoms of depression.2.Healthy individuals did not show elevated mood with tricyclic antidepressants.3.Cocaine and amphetamine are not good antidepressants.4.Non-tricylcic antidepressants that specifically affected 5-HT were found to be clinically affective in alleviating the symptoms of depression.Depression - Serotonin Hypothesis1.The most clinically effective antidepressants are those that are most selective for reuptake of 5-HT (SSRIs).2.The data that previously were taken in support of the catacholamine hypothesis could also support the role of 5-HT because reserpine, MAOIs and tricyclics also affect 5-HT. 3.But the effects of SSRIs also take days or weeks even though the biochemical action on 5-HT reuptake is immediate. Depression - Support for the Serotonin HypothesisDepressed individuals have:1.Lower levels of plasma tryptophan.2.Lower CSF levels of 5HIAA.3.Decreased platelet 5-HT uptake suggesting lower levels of 5-HT release.4.Blunted responsiveness to serotonin agonist challenge suggesting decreased 5-HT responsiveness.YOU SHOULD BE ABLE TO1，了解并掌握单胺类神经元在脑内核团分布；2，了解并掌握单胺类递质的生物转换过程，包括合成、储存、释放、重摄取、酶解等环节中的关键蛋白，以及影响因素3，了解并掌握单胺类递质在细胞膜上及囊泡膜上的两类转运体的异同4，了解转运体的摄取对于单胺类递质活动的意义5，了解并掌握单胺类递质受体的分类及特性6，了解并掌握治疗神经精神疾病的药物可能在哪些环节影响单胺类递质的功能7，了解单胺类递质参与的生理功能8，了解单胺类递质在神经精神疾病中的作用