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EEG changes following scopolamine administration in healthy subjects. Quantitative analysis during rest and photic stimulation.

This study examined the effects of the anticholinergic drug, scopolamine (0.25 mg) in 16 right-handed healthy volunteers. EEGs were recorded before and 60 min after intramuscular administration, and spectral analysis was performed on EEGs recorded at rest and during photic stimulation. Each subject was also evaluated by the Wechsler Memory Scale (WMS; form 1 or 2) before and 90 min after drug administration. In the resting EEG, the scopolamine administration resulted in a significant increase in the absolute power on the delta band (2.0- 3.8 Hz) and in the relative power on the delta and theta-1 bands (4.0-5.8 Hz) mainly over the central and parieto-occipital regions. In contrast, scopolamine significantly decreased the relative alpha-2 band (9.2-12.8 Hz) power mainly over the frontal regions and the absolute alpha-2 band power at most of the recording sites. The analysis of stimulus data showed that scopolamine significantly decreased fundamental photic driving responses elicited by photic stimulation at 15 Hz, with significant effects confined to the occipital regions. These EEG changes occurred in association with a significant reduction in total WMS scores as well as in scores of logical and visual memory subtests. These findings suggest that, in addition to cognitive impairments, central cholinergic dysfunction can cause EEG changes under both nonstimulus and stimulus conditions.

Adult↗

Effects of scopolamine (0.25-0.75 mg i.m.) on the quantitative EEG and the neuropsychological status of healthy volunteers.

There has been clinical and experimental evidence that cholinergic compounds and precursors of choline are potentially useful in the treatment of dementia. Anticholinergic compounds have also been proposed as a possible acute model for pharmaco-EEG studies focussed on CNS aging. Single doses of scopolamine (0.25-0.75 mg i.m.) and a matching placebo were administered to 8 young healthy volunteers. Quantitative EEG recordings and neuropsychological testing were performed in baseline conditions prior to and 30, 90 and 120 min after drug administration. Scopolamine induced a dose-related increase of relative power in low- and high-frequency components and a decrease in the range 8.0-13.5 Hz and in total signal power. These modifications were found to be limited to the posterior scalp electrode derivations and were observed from the 90-min control onwards. Concomitantly, there was a significant impairment in the subjects' response to neuropsychological testing after the administration of 0.50 and 0.75 mg of scopolamine. At a dose of 0.75 mg, volunteers complained about subjective symptoms which were definitely unpleasant. The effects of this dose on the EEG and the neuropsychological status did not differ significantly from those observed after a dose of 0.50 mg. As regards dose and tolerance, 0.50 mg of scopolamine administered intramuscularly appears to be a suitable dose for pharmaco-EEG studies.

Adult↗

Low doses of scopolamine increase cardiac vagal tone in the acute phase of myocardial infarction.

BACKGROUND: Reduced cardiac vagal tone in patients with myocardial infarction (MI) is associated with a high risk of sudden death. Muscarinic blocking agents in small doses induce a paradoxical increase in cardiac vagal activity in normal subjects. We tested whether low doses of scopolamine delivered transdermally enhance tonic and reflex cardiac vagal activity in patients in the acute phase of MI. METHODS AND RESULTS: Patients were randomized to a scopolamine (n = 17) or a placebo patch (n = 19) in a double-blind fashion 4.20 +/- 0.18 days after acute MI. Cardiac vagal activity was assessed by testing the arterial baroreflex sensitivity (BRS) using the phenylephrine method and by power spectral analysis of the RR interval variability. Twenty-four hours after scopolamine, we found a significant increase in BRS (from 7.05 +/- 1.21 to 13.99 +/- 2.33 ms/mm Hg, P < .05) and in RR variability, expressed as the mean standard deviation of 512 normal consecutive RR intervals (from 18.09 +/- 2.64 to 31.16 +/- 4.16 milliseconds, P < .05). The amplitude of respiratory sinus arrhythmia, measured by the absolute power of the high-frequency spectral component, was also enhanced (from 62.55 +/- 21.49 to 305.33 +/- 95.68 milliseconds squared, P < .05), whereas the power in the low-frequency spectral component of the RR variability, which results from the interaction between cardiac sympathetic and vagal activity, did not change significantly (from 73.12 +/- 24.44 to 126.46 +/- 44.29 milliseconds squared, P = .93). CONCLUSIONS: In patients in the acute phase of MI, low doses of scopolamine cause a sustained increase in cardiac vagal tone and improve the autonomic indices associated with mortality.

Arteries↗

Effects of paeoniflorin derivatives on scopolamine-induced amnesia using a passive avoidance task in mice; structure-activity relationship.

Paeoniflorin (1) and its derivatives having in common a cage-like pinane skeleton with hemiketal-acetal system, were evaluated for their effects on memory impairment induced by scopolamine in mice using a step-down type passive avoidance task. In the test session, 1 and its derivatives were intraperitoneally (i.p.) administered at doses of 0.002, 0.01, 0.02 and 0.2 mmol/kg, and 30 min later (15 min before the experiment), scopolamine (1 mg/kg, i.p.) was given. These compounds showed dose-dependent attenuation in a dose range of 0.002-0.02 mmol/kg and also enhancement of scopolamine-induced decrease in step-down latency. The effects of these compounds, except that of 2',3',4',5'-O-tetraacetyl-3-O-methylpaeoniflorin (8), followed a bell-shaped dose response profile. 8-Debenzoyl-6-deglucosyl-3-O-methylpaeoniflorin (6) showed no significant increase in the step-down latency at all tested doses. Maximum step-down latency was obtained by 3-O-methylpaeoniflorin (3) and 2',3,3',4',5'-penta-O-methylpaeoniflorin (7) (the minimal effective dose was 0.002 mmol/kg). Relative to 3, debenzoylation, as in 8-debenzoyl-3-O-methylpaeoniflorin (4), slightly increased the latency, while deglucosylation, as in 6-deglucosyl-3-O-methylpaeoniflorin (5), significantly reduced the prolongation of latency. Removal of both glucose and benzoyl moieties resulted in the loss of activity as seen in 6. These results revealed that, in addition to the cage-like pinane skeleton, the benzoyl and the glucosyl moieties are important structural elements of the paeoniflorin skeleton as its effects on scopolamine-induced amnesia.

Amnesia↗

Development of tolerance to ambulation-increasing effect of scopolamine dependent on environmental factors in mice.

Effects of repeated administration of scopolamine at 0.5, 2.0 and 8.0 mg/kg s.c. on ambulatory activity in mice were investigated. The drug was administered 5 times at intervals of daily, 3-4 days and weekly. The ambulation-increasing effect of scopolamine progressively decreased when the mice were put into a tilting-type round activity cage of 25 cm in diameter and 13 cm in height during the presence of the acute drug effect. The tolerance, once produced, was maintained even 1 month after the withdrawal. In contrast, development of tolerance to the ambulation-increasing effect of scopolamine could not be found when the mice were put into a glass jar with a 5.5 cm diameter, in which the ambulation was perfectly restricted, after each drug administration. The present results suggest that the tolerance to the ambulation-increasing effect of scopolamine induced by repeated administration may be elicited by an interaction between the experimental situation and the drug effect.

Amphetamine↗

Involvement of alpha 1- but not alpha 2-adrenergic systems in the antagonizing effect of paeoniflorin on scopolamine-induced deficit in radial maze performance in rats.

Paeoniflorin, a major constituent of peony root (1 mg/kg, p.o.), attenuated scopolamine-induced deficit in radial maze performance. Both prazosin (0.5 mg/kg, i.p.) and yohimbine (0.3 mg/kg, i.p.) neither impaired radial maze performance by itself nor augmented the scopolamine-induced performance deficit. Prazosin significantly blocked the antagonizing effect of paeoniflorin on the scopolamine deficit, whereas yohimbine did not affect the paeoniflorin effect. These data suggest that the alpha 1-adrenergic but not alpha 2-adrenergic systems are involved in the antagonizing effect of paeoniflorin on the scopolamine deficit in radial maze performance in rats.

Animals↗

Tetramethylpyrazine improves spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries or scopolamine in rats.

Effects of tetramethylpyrazine (TMP), a major constituent of Ligusticum chuanxiong, on spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries (2VO) and scopolamine were investigated using 8-arm radial maze performance in rats. Permanent 2VO produced a severe learning deficit in non-pretrained rats. Daily administration of TMP (3-10 mg/kg, i.p.) from the 3rd day after permanent 2VO significantly improved the learning deficit. TMP did not influence the impairment of the retention task in the pretrained permanent 2VO rats, but it tended to reduce the number of errors elevated by 3-min delay interposition in these rats. In the scopolamine model, scopolamine (0.3 mg/kg, i.p.) significantly decreased the initial correct response and increased the number of errors. Single administration of TMP (1-3 mg/kg, i.p.) dose-dependently reversed the scopolamine-induced impairment of the maze performance. These results suggest that TMP has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.

Animals↗

Rolipram and its optical isomers, phosphodiesterase 4 inhibitors, attenuated the scopolamine-induced impairments of learning and memory in rats.

We investigated the effects of (+/-)-rolipram, a phosphodiesterase (PDE) 4 inhibitor, and its isomers on scopolamine-induced deficits of learning and memory in rats using an 8-arm radial maze task and a passive avoidance task. 1) In the 8-arm radial maze task, (+/-)-rolipram (0.02-0.2 mg/kg, p.o.), (-)-rolipram (0.01-0.02 and 0.2-0.5 mg/kg, p.o.) and (+)-rolipram (20-50 mg/kg, p.o.) attenuated the scopolamine-induced deficits of spatial cognition. As for the minimum effective dose of each drug, (-)-rolipram was 2 and 2000 times as potent as (+/-)-rolipram and (+)-rolipram, respectively. (-)-Rolipram produced a biphasic dose-response and (+/-)-rolipram produced a broad dose-response. 2) (+/-)-Rolipram and its isomers also attenuated the scopolamine-induced deficits in the passive avoidance response. Also for the minimum effective dose, (-)-rolipram (0.01-0.02 mg/kg) was 2 and 200 times as potent as (+/-)-rolipram (0.02-0.1 mg/kg) and (+)-rolipram (2mg/kg). 3) The behaviorally effective doses of (+/-)-rolipram and its isomers also enhanced the oxotremorine-induced tremors in mice. Comparing these racemic isomers, (-)- and (+/-)-rolipram have more potent effects than (+)-rolipram on scopolamine-induced deficits in the 8-arm radial maze task and passive avoidance task. Especially (+/-)-rolipram has a wide dose range in these behavioral study. These results suggest that the ameliorating effects of rolipram might result from the indirect potentiation of various transmitters including cholinergic and noradrenergic systems by an increase in cAMP with the inhibition of PDE4.

Animals↗

Ameliorative effects of tachykinins on scopolamine-induced impairment of spontaneous alternation performance in mice.

The present study was designed to clarify whether opioid neuronal systems are involved in the beneficial effects of tachykinins such as the neurokinin NK1 receptor agonist, substance P (SP), the neurokinin NK2 receptor agonist, neurokinin A (NKA), and the neurokinin NK3 receptor agonist, senktide, on the scopolamine-induced impairment of spontaneous alternation performance in mice. Intracerebroventricular injections of SP (0.1 microgram), NKA (0.3 microgram) and senktide (3 ng) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing total arm entries, indicating the antiamnesic effects of tachykinins. Furthermore, the inhibitory effects of SP, but not those of NKA or senktide, were almost completely reversed by pretreatment with naloxone (1 mg/kg). However, the effects of SP on the scopolamine-induced impairment of spontaneous alternation performance were not influenced by pretreatment with the mu-opioid receptor antagonist, beta-funaltrexamine (5 micrograms), the delta-opioid receptor antagonist, naltrindole (4 ng), and the kappa-opioid receptor antagonist, nor-binaltorphimine (4 micrograms). These findings suggest that the effects of SP, unlike those of NKA or senktide, on the scopolamine-induced impairment of spontaneous alternation performance associated with spatial working memory are not mediated simply via a single type of opioid receptors, such as mu, delta or kappa.

Animals↗

Scopolamine reduces persistent activity related to long-term encoding in the parahippocampal gyrus during delayed matching in humans.

Recent computational modeling and slice physiology studies have suggested that long-term encoding may depend on sustained spiking during brief memory delays in parahippocampal neurons, and that this persistent spiking activity is modulated by effects of acetylcholine at muscarinic receptors. Our recent functional magnetic resonance imaging (fMRI) study has shown that sustained parahippocampal delay period activity during delayed match-to-sample performance in healthy young individuals predicted subsequent memory of visual stimuli on a recognition memory assessment 20 min later (Schon et al., 2004). The current study combined this fMRI paradigm with a pharmacological manipulation to test whether this long-term encoding-related delay activity is reduced in subjects who receive the muscarinic cholinergic antagonist scopolamine before fMRI scanning. Subsequent memory was predicted by sustained activity during brief memory delays bilaterally in the perirhinal/entorhinal cortex, in the right posterior parahippocampal and mid-fusiform gyri, and in the hippocampal body in healthy young individuals without a scopolamine challenge. This activity was reduced in subjects receiving scopolamine. The results are consistent with computational modeling data and behavioral pharmacological studies, suggesting that long-term encoding-related activity may be reduced if cholinergic receptors are blocked by scopolamine.

Analysis of Variance↗

Transdermally administered scopolamine vs. dimenhydrinate. II. Effect on different types of nystagmus.

The effects of transdermally administered scopolamine (TTS-scopolamine) (release rate 5 micrograms/h, one and two patches) and dimenhydrinate (100 mg) on caloric, angular acceleration induced and optokinetic nystagmus were examined in 16 volunteers in a randomized double-blind study. All drugs induced a statistically significant decrease in maximum velocity of caloric nystagmus, as compared with placebo. In the rotatory test, two TTS-scopolamine and dimenhydrinate reduced the vestibular gain significantly. No changes were observed in time constant. In the optokinetic test, all drugs tended to reduce the responses, but a statistically significant reduction was found only after two TTS-scopolamine. The results indicate that the drugs effective against motion sickness reduce the nystagmic response, which at least partly explains the mode of action of the drugs. The target organ of the drugs is presumably the vestibular nucleus, where vestibular and visual impulses are integrated to ensure optimal gain for vestibular orientation reflexes.

Acceleration↗

Postacquisition scopolamine treatments reveal the time course for the formation of lamb odor recognition memory in parturient ewes.

Institut National de Recherche Agronomique/Centre National de la Recherche Scientifique Within 4 hr after parturition, ewes learn to recognize the odor of their lamb. Whether scopolamine, a muscarinic antagonist, interferes with lamb odor retention was studied. After 4 hr of mother-young contact, ewes were separated from their lambs for 3 hr. During separation, they received intramuscular injections of saline, methylscopolamine (peripheral muscarinic antagonist), or scopolamine. Only scopolamine (100 microg/kg) prevented subsequent lamb recognition. To assess whether this effect depended on the duration of the learning phase, mothers remained with their lambs for 4, 8, or 16 hr before the 3-hr separation period and the scopolamine treatments. Ewes treated after 4 or 8 hr of contact displayed disturbed lamb recognition, whereas those having 16 hr of contact did not. Activation of central muscarinic receptors is therefore important for the formation of lamb odor recognition memory during a critical period of less than 16 hr postpartum.

Animals↗

American ginseng extract reduces scopolamine-induced amnesia in a spatial learning task.

OBJECTIVE: To determine if HT-1001, an extract of American ginseng, affects scopolamine-induced memory and performance deficits in a spatial learning task, alters brain concentrations of aminergic neurotransmitters, and alters choline uptake in synaptosome preparations. DESIGN: Animal study. ANIMALS: 48 Sprague Dawley rats. INTERVENTIONS: Long-term oral administration of a test material or control solution. Intraperitoneal administration of scopolamine (2 mg/kg) 30 minutes before testing. OUTCOME MEASURES: Performance on Morris water maze task, choline uptake, aminergic neurotransmitter analysis, in vitro monoamine oxidase analysis (of compounds). RESULTS: HT-1001 protected against scopolamine-induced amnesia and increased choline uptake in synaptosomal preparations. HT-1001 did not alter brain concentrations of norepinephrine, dopamine, 5-HT (serotonin), 3,4-dihydroxyphenylacetic acid or 5-hydroxyindoleactic acid. HT-1001 had a very weak ability to inhibit monoamine oxidase activity in vitro. CONCLUSIONS: HT-1001 demonstrates a capacity to protect against scopolamine-induced memory deficits.

Animals↗

[EEG study of the anxiolytic effect of scopolamine].

Effect of the central M-cholinolytic scopolamine on spatial organization of the rat brain electrical activity was studied under conditions of high and low emotional-stress responses. The EEG changes were estimated by 840 parameters. A possibility of the EEG discrimination by means of interstrain differences in responses to scopolamine, was shown. A more obvious decrease in spectral power and potentials coherence was revealed in Maudsley Reactive rats (MR) as compared with the Maudsley Nonreactive rats (MNRA), in parieto-temporal and occipital areas of the right hemisphere, and the reverse interrelationship occurred in the anterior parts of the right and posterior parts of the left hemisphere. These findings suggest some specifics in the spatial distribution of the maximum scopolamine action foci depending on the initial emotional level. Changes occurring under the scopolamine effect in different EEG frequency bands are different in the MR and the MNRA rats. The findings are discussed in respect to the EEG indices of anxiolytic component of cholinergic regulation of the brain activity.

Animals↗

Effects of vinconate on scopolamine-induced memory impairment in rhesus monkeys.

Effects of vinconate on specifically impaired short-term memory were studied in rhesus monkeys. Monkeys were trained to perform for orange juice reinforcement under a matching-to-sample response procedure. In the procedure, monkeys had to choose one of two stimuli that had the same color as the sample stimulus. Half of a daily session consisted of simultaneous trials where the sample stimulus was present during the time of choice. The other half of the session consisted of delayed trials where the sample stimulus had been presented but withheld at the time of choice. After the repeated training, the matching-to-sample responses were established with the percentage of correct choice responses (CR%) in both types of trials exceeding 90%. The doses of scopolamine, intervals between administration of this drug and the start of test session, and delay times in delayed trials were adjusted from one monkey to another so that delayed matching-to-sample responses were impaired by scopolamine while simultaneous matching-to-sample responses were less impaired by this drug. Scopolamine (32 or 45 micrograms/kg, s.c.) decreased the CR% for delayed trials more markedly than the CR% for simultaneous trials in four monkeys. Intragastrically administered vinconate at 16 mg/kg attenuated the scopolamine-induced short-term memory impairment. These results suggested that vinconate possesses specific ameliorating action on memory impairment caused by hypofunction of the cholinergic system in the brain.

Acetylcholine↗

[The morphine-scopolamine combination in chloroform anesthesia].

After introduction of surgical anesthesia with general agents such as ether and chloroform, a large number of deaths due to anesthetic toxicity were reported. With the aim to reduce toxicity several types of mixtures were devised. One of the most important was the association of opioids and scopolamine. This technique was compiled in a thesis on the use of morphine and scopolamine during anesthesia with chloroform which was presented by Dr. José Blasco Reta at the University of Madrid the 27th of June of 1907. Claude Bernard was the first to use this technique. He was based on the assumption that a previous injection of 1 cg of morphine acetate will decrease both, the needs and the risk of chloroform since this procedure shortened the excitation period, decreased ether-induced bronchial congestion, and prolonged for several hours the analgesic effect in the postoperative phase. The first who applied this technique in Spain was Dr. Losada, and Dr. Emilio Ruiz observed the rapid action of the mixture. After 1900, Schneiderlein added scopolamine in order to decrease the excitation and to reduce vomiting secondary to the association morphine-chloroform. Scopolamine was administered in 2 or 3 injections. Jun our country Dr. Lozano Monzón and Dr. Recasens used this pharmacologic association and considered it of beneficial effects when applied during labour. In a total number of 4,240 anesthetic procedures using the same technique, Dr. Blasco Reta reported 24 deaths, among them the first that occurred to Mr. Víctor Escribano between 1902 and 1903. Mortality was considered to be 1/1,000 cases.

Anesthesia↗

Ondansetron amelioration of scopolamine induced cognitive deficits in three-panel runway apparatus in rats.

Effect of ondansetron (5-HT3-receptor antagonist) was studied on the working memory deficits induced by scopolamine, a muscarinic receptor antagonist in rats using a three-panel runway apparatus. Varying doses of scopolamine (0.1-0.56mg/kg, ip) were administered alone or in combination with ondansetron (0.01-1.0 mg/kg, ip) and memory errors and latency period of the session were recorded on a three-panel runway apparatus. Treatment with scopolamine (0.56 mg/kg) produced working memory deficits in rats. Treatment with ondansetron (1.0 mg/kg) significantly reduced the scopolamine-induced working memory deficits.

Animals↗

Treatment of motion sickness in parabolic flight with buccal scopolamine.

Treatment of acute motion sickness induced by parabolic flight with a preparation of scopolamine placed in the buccal pouch was investigated. Twenty-one subjects flew aboard a KC-135 aircraft operated by the National Aeronautics and Space Administration (NASA) which performed parabolic maneuvers resulting in periods of 0-g, 1-g, and 1.8-g. Each subject flew once with a tablet containing scopolamine and once with a placebo in a random order, crossover design. Signs and symptoms of motion sickness were systematically recorded during each parabola by an investigator who was blind to the content of the tablet. Compared with flights using placebo, flights with buccal scopolamine resulted in significantly lower scores for nausea (31%-35% reduction) and vomiting (50% reduction in number of parabolas with vomiting). Side effects of the drug during flight were negligible. We conclude that buccal scopolamine is more effective than a placebo in treating ongoing motion sickness.

Administration, Buccal↗