Rophe neurons: effect of tricyclic antidepressant drugs.
Rophe neurons: effect of tricyclic antidepressant drugs.
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Rophe神经元：三环类抗抑郁药物的作用。
DOI：
10.1016/0006-8993(72)90432-5
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发表时间：
1972
期刊：
影响因子：
2.9
通讯作者：
G. Aghajanian
中科院分区：
文献类型：
--
作者：
M. Sheard;A. Zolovick;G. Aghajanian
生化研究表明，三环类抗抑郁药物丙咪嗪（IMI）、阿米替林（AMI）和氯丙咪嗪（CMI）可阻断神经末梢对5-羟色胺（5-HT）的再摄取。IMI、CMI和AMI对5-HT神经元膜泵的阻断作用优于去甲肾上腺素（NA）神经元，而去地帕胺（DMI）和proprotyline （PTI）等次级胺对NA神经元膜泵的阻断作用更有效6。我们以前已经发现，不同化学结构的单胺氧化酶（MAO）抑制剂能显著抑制中脑中缝单元放电1。中脑中叶区是含有5 -羟色胺的神经元的位置。这一发现表明MAO抑制剂可以改变大脑中含有单胺的神经元单位的生理活性。解释这些发现的一种可能的机制是，内源性胺的积累继发于MAO抑制，通过负反馈导致中脑单元放电下降。5-羟色胺在再摄取过程中的累积可能会导致叔胺作用的燃烧速度减慢，而同等剂量的仲胺则会产生小得多的影响或根本没有影响。我们现在报道，叔胺CMI， IMI， AMI抑制中速神经元的放电速率，而次胺DMI和PTI在同等剂量下具有很小或没有抑制作用。用水合氯醛麻醉雄性大鼠（Charles River, 250-275 g），置于立体定向装置中。通过机械微驱动器将微电极（钨电极或玻璃电极填充2 M饱和亚甲基蓝氯化钠，尖端直径1-2# M）放入中脑中缝区。信号通过负电容放大器显示在示波器屏幕上。单个单元的放电速率由一个电子计数器跟踪，其模拟输出以电位计记录。用远端体温计监测大鼠体温，用灯保持大鼠体温在35.5 ~ 36.5℃之间。在这些条件下，raphe单元显示出大约1-2个尖峰/秒的规律节奏。收集基线率约10 min，然后静脉或腹腔注射CMI、IMI、AMI、DMI和PTI药物。静脉注射剂量为0.5至2.5 mg/kg，腹腔注射剂量为1至15 mg/kg。每次实验后，用钨电极制作一个小的阳极损伤。用小电流从电极上挤出一个亚甲基蓝斑点来标记玻璃微电极尖端。电极尖端的精确位置随后通过组织学检查确定。从腹腔注射后约3-5分钟和静脉注射IMI、AMI或CMI后约30秒开始，中脑背侧或正中中脑中缝单位的放电速率逐渐下降，直到随后的放电速率非常缓慢。大剂量静脉注射会导致更快的减慢，然后，更罕见的是，根据剂量的不同，暂时停止放电（图1）。相比之下，相同剂量范围的DMI和PTI仅产生轻微或没有减缓
Biochemical studies~-7, 11 suggest that the tricyclic antidepressant drugs, imipramine (IMI), amitriptyline (AMI), and chlorimipramine (CMI) block the reuptake of 5-hydroxytryptamine (5-HT) by nerve endings. IMI, CMI, and AMI were more efficient in blocking the membrane pump of 5-HT neurons than norepinephrine (NA) neurons, whereas secondary amines such as desipramine (DMI) and protriptyline (PTI) were more efficient in blocking the membrane pump of NA neurons 6. We have found previously that monoamine oxidase (MAO) inhibitors of various chemical structures produce a marked depression of midbrain raphe unit firing 1. The midbrain raphe region is the site of serotonin-containing neurons s. This finding demonstrates that MAO inhibitors can modify the physiological activity of monoamine containing neuronal units in the brain. One possible mechanism to explain these findings is that accumulation of endogenous amine secondary to MAO inhibition results in depressed raphe unit firing through negative feedback. An accumulation of 5-HT from a block in reuptake might therefore be anticipated to result in a slowing of firing rate from the action of the tertiary amines while the secondary amines in equivalent doses would produce a much smaller effect or none at all. We now report that the tertiary amines CMI, IMI, AMI depress the firing rate of raphe neurons whereas secondary amines DMI and PTI have either minimal or no depressant effects in equivalent doses. Male rats (Charles River, 250-275 g) were anesthetized with chloral hydrate and placed in a stereotaxic apparatus. Microelectrodes (tungsten or glass filled with 2 M sodium chloride saturated with methylene blue, with tip diameters 1-2# m) were lowered into the midbrain raphe region with a mechanical microdrive. The signals were led through a negative capacitance amplifier and displayed on an oscilloscope screen. The firing rate of individual units was followed with an electronic counter whose analogue output was recorded potentiometrically. Rat temperature was monitored by tele-thermometer and maintained between 35.5 and 36.5 C by means of a lamp. Under these conditions raphe units display a regular rhythm of approximately 1-2 spikes/sec 2.A baseline rate was collected for about 10 min and then the drugs CMI, IMI, AMI, DMI and PTI were given either by intravenous or intraperitoneal injection. Intravenous doses ranged from 0.5 to 2.5 mg/kg and intraperitoneal doses ranged from l to 15 mg/kg. Following each experiment a small anodal lesion was made with tungsten electrodes. Glass microelectrode tips were marked by a spot of methylene blue extruded from the electrode with a small current. Precise location of electrode tips was then later determined by histological examination. Commencing about 3-5 min after intraperitoneal injection and about 30 sec after intravenous injection of IMI, AMI, or CMI, the rate of firing of dorsal or median midbrain raphe units decreased gradually until a very slow rate of firing ensued. Larger doses intravenously would cause more rapid slowing and then, more rarely, temporary cessation of firing for varying periods depending on the dose (Fig. 1). In contrast, the same dose range of DMI and PTI produced only slight or no slowing