Author Keywords: Temperature acclimation; thermal resistance; ciliary activity; acetylcholine; choline; tetramethylammonium; atropine; physostigmine; denervation supersensitivity; gill tissue; Anodonta anatina anatina; Anodonta cygnea cellensis 相似文献
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1.
A three component pretreatment regimen composed of a carbamate, atropine and mecamylamine offered complete protection against a multiple lethal doses of Soman in rats. In animals, given chemical pretreatment containing physostigmine in the drug regimen, Soman-induced cerebral acetylcholine (ACh) levels were initially elevated but were back down to normal by 30 min post Soman, but in rats given neostigmine in the pretreatment regimen, ACh concentrations were found to be the highest at 30 min after Soman exposure. The data suggest that peripheral acetylcholinesterase (AChE) and nicotinic and muscarinic ACh receptors are critical sites in organophosphorus (OP) anticholinesterase exposure in rats and should be protected to maximize efficacy against OP intoxication. The data also suggest that carbamates which penetrate the blood-brain barrier may be superior to quaternary carbamates in antagonizing OP exposure in that they could be expected to dampen and rapidly abolish OP-induced rises in total brain ACh which in turn should restore normal neural activity in the brain. 相似文献
2.
The effects of hemicholinium-3 (HC-3) or 4-(1-naphthylvinyl)pyridine (4-NVP) alone and together with cholinolytics and/or cholinesterase inhibitors on brain acetylcholine (ACh) levels and survival were studied. Intracerebroventricular (ICVT) injection of 10 μg HC-3 280 min before euthanasia by microwave irradiation reduced rat cerebral ACh levels from 28.4 to 5.4 nmoles ACh/g wet tissue. In rats pretreated with HC-3 alone or with other pretreatment drugs prior to giving up to 2.7 LD50 of soman, iv, cerebral ACh levels increased very little, but in animals not receiving HC-3, brain ACh levels increased to 67.1 nmoles. Treatment of unpoisoned rats with 4-NVP resulted in a significant (26%) reduction in ACh. The inclusion of atropine with 4-NVP resulted in a further reduction in ACh. Pretreatment with 4-NVP caused sign-free doses of physostigmine to produce toxic signs in rabbits and did not enhance the efficacy of carbamate pretreatment against soman. Pretreatment of rabbits with pyridostigmine and atropine methyl nitrate (AMN) failed to provide any protection against soman, but when HC-3, ICVT, was included with those drugs, the protective ratio (PR) against soman was increased from 0.8 to 7.3. These data are consistent with the hypothesis that excess ACh is a primary lesion in organophosphorus anticholinesterase intoxication and that the central nervous system is quite sensitive to excesses of ACh. 相似文献
3.
Abstract: In atropine-pretreated rats, HI-6 (125 mg/kg i.p.) raised the LD50 of Soman (subcutaneous) 5.7 times. Addition of HI-6 (25 μg i.c. v.) failed to enhance this protection further. HI-6 (intraperitoneal) also protected animals from intracerebroventricular Soman. HI-6, administered intracerebroventricularly either alone or in combination with intraperitoneal HI-6, failed to increase protection, nor did it reactivate Soman-inhibited acetylcholinesterase (AChE) in several brain areas. HI-6 (125 or 62.5 mg/kg i.p.) protected rats from Sarin lethality, but only the higher dose significantly altered the brain AChE activity. Furthermore, HI-6 (intraperitoneal) failed to block the Soman-induced increase in acetylcholine (ACh) or choline (Ch) levels in any of the brain areas examined. These data indicate that HI-6 is a very beneficial therapy against Soman, but that no definitive central anticholinergic activity of the compound could be found to explain its protective effects. It is possible that HI-6 acts by noncholinergic central mechanisms, or that it produces its beneficial effects outside the CNS. Furthermore, brain AChE activity does not appear to be indicative of protective effects of this oxime. ACh or Ch levels in this study were not good parameters to predict the outcome of Soman poisoning. 相似文献
4.
The relationship between physostigmine (Phy) concentration, acetylcholine (ACh), choline (Ch) and cholinesterase (ChE) activity was examined in whole rat brain after the administration of [3H]Phy (650 g/kg i.m.). Cholinesterase inhibition was found to be inversely related to Phy levels. Maximal inhibition (80%) was seen at 5 min and by 2 hrs ChE activity had returned to control levels. Acetylcholine levels in whole brain peaked at 30 min at a concentration (80 nmol/g) 2.3 times higher than controls (33 nmol/g). Choline levels were not significantly altered. The regional distribution of Phy concentration and ChE activity was studied in six areas of the brain following i.m. administration of three different dosages of [3H]Phy. Physostigmine concentration and ChE activity showed a dose dependency in each area examined except in SP (medial septum). Striatum (ST) showed the greatest relative increase of ACh up to 30 min, when compared to other areas. Choline levels were not changed in any area with the exception of ST at 5 min where a decrease was seen. There was a relationship between ChE activity, Phy concentration and ACh levels in all areas examined with exception of the medulla oblongata (MO). Our results indicate that even though ChE was inhibited practically uniformly in all brain areas, the percent increase with respect to control animals and the relative increase of ACh varied widely from area to area. This finding has clinical implications in cases in which cholinomimetic therapy is used to elevate ACh levels in specific brain areas which show a cholinergic deficit.Special issue dedicated to Prof. Eduardo De Robertis. 相似文献
5.
J. A. Doebler T. M. A. Bocan R. A. Moore T-M Shih A. Anthony 《Neurochemical research》1983,8(8):997-1011
Effects of various antidotal treatments on neuronal RNA contents and on soman induced RNA and acetylcholinesterase (AChE) depletion were monitored using quantitative cytochemical techniques. In rats treated only with antidotes, atropine depressed whereas pralidoxime (2-PAM) elevated RNA contents of both caudate and cerebrocortical (Layer V) neurons. Soman produced a virtually complete inhibition of AChE activity and a moderate decline in neuronal RNA contents. Atropine pretreatment partially restored neuronal RNA levels. Atropine+2-PAM prophylaxis eventuated in a complete restoration of RNA levels but no reactivation of AChE. Addition of physostigmine to the atropine +2-PAM treatment regimen resulted in appreciable AChE reactivation but reduced RNA levels. The overall data indicate that: (1) soman-induced neuronal RNA depletion can be completely reversed by antidotal pretreatment; (2) no precise relationship exists between the extents of antidote-induced restoration of RNA and AChE levels; and (3) 2-PAM exerts marked effects on the brain neuronal network which are unrelated to AChE reactivation. It is postulated that effects of soman and antidotes on neuronal RNA metabolism may signify alterations in acetylcholine (ACh) sensitivity and that pharmacologic manipulation of ACh responsiveness during organophosphate cholinesterase poisoning may be a mechanism for additional therapeutic intervention. 相似文献
6.
Mice were injected for 1-2 months daily with 10 mg immunoglobulin G (IgG) from four patients with Lambert-Eaton myasthenic syndrome (LEMS); control mice were injected with pooled human IgG from normal donors. Gastrocnemius muscles were homogenised for the assay of acetylcholine (ACh), choline acetyltransferase (ChAT), and cholinesterase (ChE). The ACh, ChAT, and ChE contents of gastrocnemius muscles from "LEMS mice" were about the same as the control values, which were 180 pmol, 40 nmol X h-1 (37 degrees C), and 15 mumol X h-1 (37 degrees C), respectively. Hemidiaphragms were treated with an irreversible ChE inhibitor (Soman) and incubated at 20 degrees C for estimation of ACh release. Resting ACh release from experimental muscles was reduced by about 25% (P2 less than 0.05) and the release evoked by 3 s-1 nervous stimulation by 50% (P2 less than 0.05). On the other hand, 50 mM KCl-induced transmitter release was not abnormal in LEMS mice. The findings indicate that IgG antibody from patients with LEMS may bind to nerve terminal determinants that are involved in quantal and nonquantal ACh release. 相似文献
7.
Rabbits intoxicated with soman were treated with various doses of HS-6 at 3 min following administration of soman to establish whether the antidotal efficacy reported for HS-6 against soman can be attributed in part to reactivation of the inhibited cholinesterase (ChE) enzymes. Within 5 min after treating animals intoxicated with soman with 15 or 30 mg/kg of HS-6 (iv) the whole blood ChE activity increased from 6.0 to 30.5 and 44.2% of control activity, respectively. Because HS-6 apparently is able to reactivate completely the unaged inhibited enzyme, HS-6, 60 mg/kg (iv) was used to measure for the first time the rate of aging of whole blood ChE in soman-intoxicated rabbits. The half time for aging was determined to be 7.6 (5.8 ? 9.4) min, P = 0.05. HS-6 in combination with atropine and pyridostigmine was tested as a pretreatment against soman. When only atropine + pyridostigmine was used in the pretreatment regimen, none of the rabbits survived a 10 LD50 dose of soman (iv). However, when HS-6 (30 mg/kg, iv) was used together with atropine + pyridostigmine in the pretreatment regimen, 87% of the animals survived this high dose of soman. Since HS-6 is a powerful reactivator of unaged, soman-inhibited ChE, the antidotal effectiveness of HS-6 against soman can be attributed in part to the restoration of vital enzyme activity. 相似文献
8.
B. S. Sushko 《Neurophysiology》1998,30(3):135-142
Periodic phasic activity (respiratory discharges) was recorded from the spinal ventral rootsC
4−C
5 in the experiments on isolated medullo-spinal preparations of 1- to 3-day-old rats. Applications of acetylcholine (ACh) in
different concentrations and modifications of pH were tested under normal conditions and after treatment with cholinoblockers,
atropine and benzohexonium, and an acetylcholinesterase blocker, physostigmine. ACh intensified periodic respiratory activity
in a concentration-dependent manner, and the duration of postactivatory depression showed similar dependence. ACh-induced
effects were facilitated after pH of the superfusing solution had been decreased. Atropine decreased the frequency of respiratory
discharges and suppressed responses to ACh applications and pH modification. Contrastingly, benzohexonium and, especially,
physostigmine in concentrations, exerting no significant independent influence on the frequency of respiratory activity, increased
sensitivity of preparations and facilitated responses to ACh applications and pH decrease. Involvement of cholinergic neuronal
mechanisms, localized in the chemosensitive region of the ventral surface of the medulla, in generation of periodic activity
by the medullary respiratory generator is discussed. 相似文献
9.
Fujii T Nakai K Nakajima Y Kawashima K 《Canadian journal of physiology and pharmacology》2000,78(5):392-399
Hippocampal cholinergic neuronal activity is reported to be regulated, at least partly, through serotonin1A (5-HT1A) receptors. Chronic lithium treatment has been shown to alter both behavioral and neurochemical responses mediated by postsynaptic 5-HT1A receptors. We investigated whether long-term lithium treatment affects central cholinergic neurotransmission through 5-HT1A receptor-mediated pathways. Changes in acetylcholine (ACh) release induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, in the rat hippocampus were measured using a microdialysis technique and a radioimmunoassay for ACh. Administration of lithium for 21 days resulted in a serum lithium concentration of 1.03 mM and caused little change in density or affinity of [3H]8-OH-DPAT binding sites in the hippocampus. The local application of 8-OH-DPAT into the hippocampus of lithium treated rats increased the ACh efflux in both the absence and the presence of physostigmine, a cholinesterase (ChE) inhibitor, in the perfusion fluid. The basal ACh efflux of lithium treated rats was not different from that of the control rats under normal conditions, but was significantly higher than that of the controls when ChE was inhibited. These results demonstrate that chronic lithium treatment increases spontaneous ACh release in the hippocampus under conditions of ChE inhibition, but not under normal conditions, and enhances cholinergic neurotransmission through 5-HT1A receptor-mediated pathways, and suggest that activation of 5-HT1A receptor function by lithium is related to the enhancement of hippocampal cholinergic neurotransmission. 相似文献
10.
The effects of subchronic oral administration of metrifonate, a long-acting cholinesterase (ChE) inhibitor, on cholinergic neurotransmission were assessed in young adult male Wistar rats. Animals were treated twice daily with metrifonate. In a pilot study testing a 100 mg/kg dose of metrifonate for up to 14 days, ChE activity was found to steadily decrease to reach maximum inhibition levels of about 55%, 80% and 35% in brain, erythrocytes and plasma. Steady-state inhibition levels were attained by the 10th day of treatment. When metrifonate-treatment was discontinued, ChE activity in plasma returned to control levels within another day, while erythrocyte and brain ChE activity took more than 2 weeks to recover. In subsequent dose-response studies, metrifonate treatment was given for 3 and 4.5 weeks at doses of 0, 12.5, 25, 50, and 100 mg/kg, to different groups of animals, respectively. Correlation analysis indicted that brain ChE inhibition was more accurately reflected by erythrocyte than by plasma ChE inhibition, although all effects were highly correlated. The changes in ChE activity were not paralleled by changes in other parameters of the cholinergic neurotransmission, such as acetylcholine synthesis rate or acetylcholine receptor binding. It is therefore concluded that repeated administration of metrifonate to rats induces a long-lasting inhibition of ChE activity in a dose-related and predictable manner, which is neither subject to desensitization nor paralleled by counterregulatory downregulation of muscarinic or nicotinic receptor binding sites in brain. 相似文献
11.
The effect of heptyl-physostigmine,a new cholinesterase inhibitor,on the central cholinergic system of the rat 总被引:3,自引:0,他引:3
P. De Sarno M. Pomponi E. Giacobini X. C. Tang E. Williams 《Neurochemical research》1989,14(10):971-977
Heptyl-physostigmine (Heptyl-Phy; MF-201) is a new carbamate derivative of physostigmine (Phy) with greater lipophilicity and longer inhibitory action on cholinesterase (ChE) activity than the parent compound. Following single dose administration of 5 mg/kg heptyl-Phy i.m., maximal whole brain acetylcholinesterase (AChE) inhibition (82%) if reached at 60 min. Inhibition of plasma BuChE butyrylcholinesterase (BuChE) remains close to the steady state level (60%) between 120 and 360 min. At 360 min, whole brain AChE activity is still 67% inhibited compared to controls. Inhibition of AChE activity displays brain regional differences which are more significant at 360 min. At this time point, AChe activity in cerebellum is only 40% inhibited while frontal cortex and medial septum are still 80% inhibited. Increases in acetycholine (ACh) levels also show regional differences, however, there is no direct relationship between AChE inhibition and ACh increase. The electrically evoked [3H]ACh release in cortical slices was inhibited only by the highest concentration of heptyl-Phy tested (10–4M). At this concentration ChE activity was 97% inhibited in vitro. In conclusion, our results demonstrate that heptyl-Phy compares favorably to other reversible cholinesterase inhibitors (ChEI), particularly to Phy as far as producing a more long-lasting inhibition of AChE and a more prolonged increase of ACh in brain with less severe side effects. Therefore, it represents an interesting candidate for cholinomimetic therapy of Alzheimer disease (AD).Dept. of Pharmacology, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 20031 China.Special issue dedicated to Dr. Paola S. Timiras 相似文献
12.
ENHANCEMENT OF BRAIN THIAMINE DIPHOSPHATASE ACTIVITY OF RATS BY INJECTION OF CHOLINERGIC DRUGS 总被引:1,自引:1,他引:0
Abstract— The effects of cholinergic drugs on thiamine diphosphatase (TDPase) in rat brain, liver and kidney were studied to clarify the role of the enzyme in the central nervous system.
Brain TDPase activity was markedly increased by intraperitoneal injection of a sub-lethal dose of physostigmine, ambenonium or pentetrazol. These drugs also increased the activity in the kidney, but not liver. Strychnine, atropine, and scopolamine did not affect the activity of brain TDPase, but decreased the enzyme activity of liver and kidney. Physostigmine also increased the activity of brain thiamine monophosphatase.
Brain TDPase activity reacheda maximum 30 minafterphysostigmine injection (1.0mg/kg). However, inhibition of brain acetylcholinesterase activity was greatest 45 min after physostigmine injection. The TDPase and AChE activities had both returned to normal values 60 min after the injection. The durations of these changes of TDPase and AChE activity corresponded to the duration of the tremor induced by physostigmine. The contents of total and phosphorylated thiamines in the brain but not in the liver or kidney were significantly reduced by physostigmine.
The relationship between ACh and activation of TDPase activity by cholinesterase inhibitors is discussed. 相似文献
Brain TDPase activity was markedly increased by intraperitoneal injection of a sub-lethal dose of physostigmine, ambenonium or pentetrazol. These drugs also increased the activity in the kidney, but not liver. Strychnine, atropine, and scopolamine did not affect the activity of brain TDPase, but decreased the enzyme activity of liver and kidney. Physostigmine also increased the activity of brain thiamine monophosphatase.
Brain TDPase activity reacheda maximum 30 minafterphysostigmine injection (1.0mg/kg). However, inhibition of brain acetylcholinesterase activity was greatest 45 min after physostigmine injection. The TDPase and AChE activities had both returned to normal values 60 min after the injection. The durations of these changes of TDPase and AChE activity corresponded to the duration of the tremor induced by physostigmine. The contents of total and phosphorylated thiamines in the brain but not in the liver or kidney were significantly reduced by physostigmine.
The relationship between ACh and activation of TDPase activity by cholinesterase inhibitors is discussed. 相似文献
13.
1. 1.|The thermal resistance of the activity of frontal cilia in the median gills of the fresh water mussel Anodonta anatina was studied.
2. 2.|The resistance acclimation appeared in 2 days in the gills of intact animals, but not in the isolated gills kept at 4, 14 and 24°C, for between 1 to 3 days.
3. 3.|Warm-acclimation increased the ACh sensitivity of the gills of intact mussels.
4. 4.|Isolation of the gills enhanced the thermal resistance.
5. 5.|ACh, choline and tetramethylammonium enhanced the thermal resistance in the isolated gills. whereas atropine and physostigmine diminished it.
6. 6.|It is concluded that in A. anatina the control if the thermal resistance is probably neural.
14.
《Comp. Biochem. Physiol. C, Comp. Pharmacol. Toxicol.》2000,125(1):53-64
Contractions of an echinoderm (sp. Sclerodactyla briareus) smooth muscle, the longitudinal muscle of the body wall (LMBW), were evoked by acetylcholine (ACh) and agonists: epibatidine, muscarine and nicotine (in order of force generation: ACh>muscarine=epibatidine>nicotine). ACh-induced contractions were blocked by atropine by 50%, and methoctramine, by 30%. ACh responses were also blocked by 25% by methyllycaconitine (MLA) but not by d-tubocurarine (dTC). Muscarine initiated large contractions that were completely blocked by atropine. To elucidate possible muscarinic ACh receptor (mAChR) subtypes, muscarinic agonists (oxotremorine, pilocarpine) and antagonists (methoctramine, pirenzepine) were tested. Oxotremorine, pilocarpine, and pirenzepine each enhanced resting tonus and potentiated ACh-induced contractions (order of potency: pilocarpine>oxotremorine=pirenzepine). Muscarine, oxotremorine or pirenzepine generated phasic, rhythmic contractions. Nicotine-induced contractions were almost completely blocked by dTC but were not altered by atropine. Large contractions evoked by epibatidine were potentiated by dTC whereas atropine had no effect on them. MLA blocked spontaneous rhythmicity. Cholinesterase inhibitors, neostigmine or physostigmine, caused marked potentiation of ACh-induced contractions and initiated rhythmic slow wave contractions in previously quiescent muscles. The present pharmacological evidence points to the co-existence of excitatory nicotinic ACh receptor (nAChRs) and mAChRs where nAChRs possibly modulate tone, and the mAChRs initiate and enhance rhythmicity. 相似文献
15.
The presence of 5 or 20 microM choline in the eserinized medium superfusing striatal slices enhanced the spontaneous release of acetylcholine (ACh) at both concentrations and, at 20 microM, the release of transmitter evoked by electrical field stimulation. Neither the electrical stimulation nor the addition of choline altered choline acetyltransferase activity. These results show that ACh release is dependent on the availability of extracellular choline. The rate of choline efflux was 7 times higher than the rate of ACh release, was not affected by stimulation, and was increased by 40% when hemicholinium-3 (HC-3), an inhibition of choline uptake, was present. The muscarinic antagonist atropine (1 microM) increased the evoked release of ACh into both the choline-free medium and that containing 20 microM choline. An adenosine receptor antagonist, 1,3-diethyl-8-phenyl xanthine (10 microM), failed to affect ACh release or the enhancement of release produced by atropine. In medium containing HC-3, stimulation of the slices elicited ACh release for the first 20 min of the 30 min stimulation period (15 Hz); thereafter, although stimulation was continued, the rate of release decreased to that associated with spontaneous release. Tissue ACh contents were not modified by the addition of choline or atropine to the medium, but were depressed by HC-3. Neither atropine nor HC-3 altered tissue choline content. The total amount of ACh + choline released during an experiment was 5-15 times higher than the decrease in tissue levels of these two compounds during the same period of time.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
16.
Koichiro Kawashima Toru Hayakawa Yuko Kashima Takeshi Suzuki Kazuko Fujimoto Hisayo Oohata 《Journal of neurochemistry》1991,57(3):882-887
A vertical-type in vivo microdialysis probe and a sensitive, specific radioimmunoassay (RIA) were used to study the mechanism of acetylcholine (ACh) release in the striatum of anesthetized rats. Without the use of physostigmine, a cholinesterase inhibitor, our RIA could still detect the amount of ACh present in the perfusate (5.6 +/- 0.6 fmol/min, n = 16). Tetrodotoxin (1 microM) produced a significant decrease in the amount of ACh collected in the perfusate, suggesting that basal ACh determined under the present experimental conditions was related to cholinergic neural activity. Atropine (0.1-1 microM) applied topically via the dialysis probe did not affect the amount of ACh recovered in the perfusate in the absence of physostigmine. Addition of physostigmine (10 microM) to the perfusion fluid produced about a 100-fold increase in the amount of ACh collected. In the presence of physostigmine, topical administration of atropine and pirenzepine (0.01-1 microM) through a dialysis probe produced a further three- to fourfold increase in ACh output, whereas a slight increase was produced by AF-DX 116 at the highest concentration (1 microM). These results indicate that presynaptic modulation of ACh release in the striatum does not occur under basal conditions, and that presynaptic M1 muscarinic receptors are involved in the modulation of ACh release when the ACh concentration is raised under certain conditions. 相似文献
17.
The cholinoacetyltransferase activity (CAT) in diaphragm of mice of Bar Harbor strain (129 ReJ dy/dy) with muscular dystrophy was significantly lower than that of phenotypically normal litter mates (129 ReJ dy/+). CAT, tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DβH) activities were found identical in adrenal gland and brain homogenates of normal and dystrophic mice. Subacute injections of atropine (72 μmol/kg i. p., twice daily for 3 days) failed to increase the activity of adrenal CAT in dystrophic mice but increased this enzyme activity in adrenals of normal litter mates. The concentration in brain of dopamine, norepinephrine, serotonin, acetylcholine (ACh), γ-aminobutyric acid (GABA) and some of their precursors were measured. Only the concentration of ACh was significantly lower in the brain of muscular dystrophic mice. The rate of accumulation of brain ACh concentration after the injection of oxotremorine (5μmol/kg i. p.) is slower in muscular dystrophic animals than in normal litter mates. Furthermore, the turnover rate of ACh in total brain was slower in muscular dystrophic mice than in phenotypically normal litter mates. The turnover rate of brain dopamine and norepinephrine in these 2 groups of animals was similar. 相似文献
18.
G G Yarbrough 《Life sciences》1974,15(8):1523-1529
In rats receiving a daily injection of increasing doses of morphine for 25–29 days, the sensitivity of cerebral cortical neurons to acetylcholine (ACh) and the ability of atropine to antagonize ACh effects were examined. While the responses of neurons to ACh were qualitatively and quantitatively similar between morphinized and control animals there was a marked reduction in the efficacy of atropine in blocking ACh effects in the morphine-treated rats. 相似文献
19.
The neurotransmitter acetylcholine (ACh) is present in plants including bryophytes. The first biochemical evidence for ACh hydrolysis by enzyme cholinesterase (ChE) in bryophytes is presented. Thirty-nine species belonging to 16 families of bryophytes were surveyed for ChE activity. Thirty species belonging to 13 families showed ChE activity. Of the bryophytes tested, Anoectangium bicolor showed the highest ChE activity. Widespread distribution of ChE in bryophytes indicates their suitability as a system to study the role of ACh in plants. 相似文献
20.
The effects of five cholinesterase inhibitors on forebrain monoamine and their metabolite levels, and on forebrain and plasma cholinesterase (ChE) activity in rat were studied in acute and chronic conditions. Acute tetrahydroaminoacridine (THA) dosing caused lower brain (68%) and higher plasma (90%) ChE inhibition than the other drugs studied increased levels of brain dihydroxyphenylacetic acid (DOPAC) (236%), homovanillic acid (HVA) (197%) and 5-hydroxyindolaecetic acid (5-HIAA) (130%). Acute physostigmine (PHY) administration caused a 215% increase in brain DOPAC content. Despite high brain ChE inhibition induced by metrifonate (MTF), dichlorvos (DDVP) or naled no changes in brain noradrenaline (NA), dopamine (DA) or serotonin (5-HT) occurred due to treatment with the study drugs in the acute study. In the chronic 10-day study THA or PHY caused no substantial ChE inhibition in brain when measured 18 hours after the last dose, whereas MTF induced 74% ChE inhibition. Long-term treatment with THA or MTF caused no changes in monoamine levels, but PHY treatment resulted in slightly increased 5-HT values. These results suggest that MTF, DDVP and naled seem to act solely by cholinergic mechanisms. However, the central neuropharmacological mechanism of action of THA and PHY may involve changes in cholinergic as well as dopaminergic and serotoninergic systems. 相似文献