Effects of acute and chronic administration of antidepressant drugs on the central cholinergic nervous system: Comparison with anticholinergic drugs

The purpose of this investigation was to study the effects of antidepressant drugs on the central cholinergic system of the rat after acute and chronic administration. Drugs (antidepressants and non-antidepressants) were first divided into highly potent, moderately potent or weak anticholinergic categories based upon the ability of each compound to displace [³H]-QNB ([³H]quinuclidinyl benzilate from synaptosomal membranes. One antidepressant drug and one non-antidepressant drug, with similar anticholinergic properties, were chosen as representative agents of each category of anticholinergic potency. Acute administration of amitriptyline or atropine (highly potent anticholinergics) increased the level of high affinity uptake of choline in the hippocampus and striatum. Imipramine and thioridazine (moderately potent anticholinergics) increased the uptake of choline only in the striatum. After acute administration, the effects of nomifensine and d-amphetamine (weak anticholinergics) differed on striatal uptake of choline. Following 30 days pretreatment with any drug, an acute challenge dose of that drug no longer altered the uptake of choline in either region. After chronic administration, amitriptyline increased the density of muscarinic receptors in the cortex whereas atropine increased the density of receptors in the cortex, hippocampus and striatum. The other agents did not alter receptor parameters in the regions examined. Since the central cholinergic actions of the antidepressants were similar to the central actions of the non-antidepressants, it is concluded that the effects of the antidepressants on the central cholinergic nervous system are more closely related to the side effects of these agents than to their therapeutic mechanism of action.     

中枢神经系统的药代动力学参数及其意义

血脑屏障可阻碍药物进入中枢神经系统。本文系统介绍了中枢神经系统的药代动力学研究常用的几个参数:PS积、内清除率(Kin,CLin,)、外清除率(Kout,CLout)、T1/2eq,in、摄取百分比(%ID/g)、脑/血分配系数(Kp,Kp,u和Kp,uu),游离药物表观分布容积(Vu,brain)和脑内药物半衰期(T1/2,brain)。其中,PS积用来评价药物通过血脑屏障的能力、内清除率(Kin,CLin,)、外清除率(Kout,CLout)、T1/2eq,in、T1/2,brain用来描述药物进出中枢神经系统内的速度;%ID/g、Kp,uu用来评价药物进入大脑的程度;Vu,brain评价药物在脑内的分布特点。     

Biochemical evidence of adrenergic interaction with cholinergic function in the central nervous system of the rat

The effect of centrally administered norepinephrine (NE) into the lateral ventricle on choline acetylase activity (ChAc), endogenous levels of NE, dopamine (DA) and serotonin (5HT) was studied in different regions of the rat brain. In normal rats, the highest activity of choline acetylase was found in the cerebral cortex, followed by the brain stem, the diencephalon, the hypothalamus and least in the cerebellum. Chronic administration of NE significantly increased the choline acetylase activity in all regions studied, whereas both the acute and the in vitro studies showed no significant change except in the brain stem. Serotonin level was increased in the cerebellum, but decreased in the diencephalon and the brain stem. There was no significant alteration in the level of NE in all areas studied except in the hypothalamus where there was an increase in the mean concentration. Tissue level of DA showed a significant increase in the cerebral cortex and the hypothalamus. Behaviourally, there was a significant increase in food intake on the first day of treatment with no significant change in water intake. The data suggests that NE may be involved in the regulation of acetylcholine synthesis. The significance of interaction between different monoamines and acetylcholine may be important in the study of drug tolerance phenomena.This work was supported by USPHS grant MH-12383; Dr. Ho is a recipient of a PMA Foundation grant award in morphology-pharmacology.     

The effect of chronic atropine administration on mouse motility and on ACh levels in the central nervous system

Changes in mouse motility and CNS cortical and subcortical ACh levels were studied after chronic (20 days) administration of 30, 40 and 60 mg/kg/day atropine. An increase in motility similar to that induced by acute atropine administration was observed, whereas the ACh levels reduction caused by acute administration was not repeated. These results suggest that changes in mouse motility caused by atropine are not correlated to its modification of ACh levels in the CNS.     

牛黄千金散对中枢的抑制作用

目的探讨牛黄千金散对中枢的抑制作用。方法给小白鼠灌胃牛黄千金散 ,分别采用苯甲酸钠咖啡因和电刺激引起惊厥 ,观察牛黄千金散的对抗作用 ;加用戊巴比妥钠给小白鼠灌胃 ,药后15min内观察翻正反射消失作为催眠指标 ;加用可待因给小白鼠灌胃 ,用扭体法观察小白鼠的镇痛作用 ;牛黄千金散小白鼠灌胃 ,用抖笼法观察对小白鼠自发活动的影响。结果牛黄千金散对药物和电刺激引起的惊厥均有对抗作用 ,并能加强戊巴比妥钠的催眠作用 ;加强可待因的镇痛作用 ;对小白鼠自发活动也有一定的抑制作用 ,与生理盐水对照组比较有非常显著的差异(P<0.01)。结论牛黄千金散有明显的中枢抑制作用。     

On the interaction of drugs with the cholinergic nervous system

Tolerance to physostigmine salicylate was induced in mice using various schedules of s.c. injections. The rate and degree of tolerance development were assessed by comparing the ED₅₀ values (equipotent doses) and by comparing the peak effects induced by a constant dose. These were measured on four systemic responses induced by the drug — hypothermia, tremor, salivation, and the effects measured in the rotarod test. The degree of tolerance development was found to be dose-dependent with a maximal achievable tolerance for every dose. The tolerance development to the four systemic effects differed in time course: tolerance to the hypothermia was induced even with daily injections, while tolerance to the salivation and rotarod effects could be detected only when the drug was given every 4 h. No tolerance developed to the tremor with any of the schedules and doses used. The maximal achievable tolerance degree and the pattern of changes of the duration were different for each systemic effect. The tolerance was found to be reversible, with different rates of recovery, for the different effects. The tolerance state could not be correlated with changes in the pattern of brain acetylcholinesterase (AcChE) inhibition by physostigmine in vivo or with changes in the rate of the enzyme's spontaneous reactivation.Scopolamine. HBr given 10 min before physostigmine prevented tolerance development. In addition, cross-tolerance to various muscarinic agonists and cholinesterase inhibitors was found in the physostigmine-tolerant mice. The correlation between these results and our previous findings concerning possible biochemical adaptations is presented and discussed.     

On the interaction of drugs with the cholinergic nervous system

A symmetrical cross-tolerance was found between two phencyclidine derivatives-phencyclidine and cyclohexamine-and also between two cholinergic drugs-physostigmine and oxotremorine. On the other hand, mice rendered tolerant to the phencyclidine derivatives showed cross-tolerance to these cholinergic drugs, but no cross-tolerance was observed in the opposite direction.The applicability of such experiments to the elucidation of neurochemical interactions of centrally acting drugs is discussed.     

On the interaction of drugs with the cholinergic nervous system

Phencyclidine [1(1-phenylcylohexyl) piperidine] and cyclohexamine [1(1-phenylcyclohexyl) ethylamine) were used as model psychotropic drugs to study the phenomenon of tolerance in mice. The behavioral effects of these drugs were measured by forced motor activity using the rotarod test. Tolerance develops progressively with chronic treatment at a rate and to a degree that are dose-dependent. The optimal conditions for tolerance induction are s.c. administration with 4-h intervals. The process of tolerance development is expressed in concomitant changes in five indices chosen for its quantification: ED50 values, duration, duration-dose dependency, critical falling time, and body weight. All these changes were found to be totally reversible, with no carry-over between two consecutive tolerance cycles. It was established that cyclohexamine is a better tolerance-inducer than phencylidine, although the nature of the tolerance developed for both drugs is qualitatively similar.     

Morphological studies of the endomorphinergic neurons in the central nervous system

Endomorphins (EMs) are newly found endogenous opioid peptides. Both endomorphin-1 (EM-1) and -2 (EM-2) are composed of four amino acids. Their high affinity and specificity for mu-opioid receptors have been confirmed by many physiological and pharmacological studies. In the present minireview, we discuss the distribution and localization of these peptides. While EM-2 is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. We also discuss the possible coexistence of EM with other neurotransmitters. Finally, we introduce some new results regarding the ultrastructure and synaptic relationships of EM-2 obtained by the immunoelectron microscopic method.     

胆囊收缩素对中枢阿片系统的调节作用

胆囊收缩素(cholecystokinin,CCK)是 1928年由 Ivy 和 Oldberg 在狗的胃肠道中发现的一种多肽激素,其不但具有胃肠道激素的功能,还以神经递质和神经调质的形式发挥着重要的生理作用,是一种典型的脑肠肽[1].有研究发现,阿片肽、胆囊收缩素及其受体在中枢神经系统重叠分布,并且八肽胆囊收缩素(cholecystokinin octapeptide,CCK-8)是目前已知作用最强的内源性抗阿片肽[2],在抗伤害性反应(antinociceptive effects)、镇痛耐受及成瘾过程中具有重要的拮抗作用.因此,两种神经肽之间的相互作用关系已成为当今的研究热点,本文将对CCK在中枢阿片系统的相关调节作用及其机制方面的研究进展进行简要综述.     

系统性红斑狼疮合并中枢神经系统病变28例临床研究

目的 对系统性红斑狼疮(SEE)合并中枢神经系统(CNS)病变的临床特点、诊治经验进行研究。方法 对我院28例有CNS病变的SLE住院及专科门诊的病人进行回顾性分析。结果 在SLE发病2年内起病者占75％：活动期病人24例：焦虑、抑郁等为主要表现者占31．2％。其次为癫痫占21．4％;60％病人脑脊液检查异常：影像学主要表现为梗塞、出血、脑萎缩等。治疗后18例病情好转,死亡6例。结论 SLE合并CNS病变临床表现多样,其诊断主要依靠临床表现、脑脊液及影像学检查：治疗应强调个体化原则。     

钩藤生物碱对中枢神经系统的药理作用研究进展

钩藤是我国一种常用药材,对心血管系统、中枢神经系统和血液系统等均具有比较广泛的药理活性,临床上主要用于治疗高血压、焦虑等疾病。现代中药药理研究表明,钩藤对中枢神经系统的药理作用主要表现为镇静、抗癫痫、抗惊厥和对神经元的保护等,其中对神经元的保护作用与多种神经递质相关,具有多种作用机制,已被国内外越来越多的医药工作者所重视,综述钩藤生物碱对中枢神经系统的药理作用研究进展。