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PubMed1993

Attenuation of scopolamine-induced spatial memory deficits in the rat by cholinomimetic and non-cholinomimetic drugs using a novel task in the 12-arm radial maze.

The effects of cholinomimetic and non-cholinomimetic agents on spatial memory using a novel task in the 12-arm radial maze were investigated. The task was designed to reduce the tendency to use non-spatial strategies. Animals were repeatedly trained to retrieve food rewards from three arms, until a criterion level of performance was reached. Scopolamine (0.03 and 0.1 mg/kg SC), but not N-methylscopolamine (0.1 mg/kg SC) disrupted performance of this task. Physostigmine (0.3 mg/kg SC) and pilocarpine (30 mg/kg SC) completely reversed the deficit of performance produced by scopolamine. Furthermore, the ACE inhibitor Hoe 288 (10 nmol ICV) and the angiotensin AT1 receptor antagonist losartan (10 mg/kg SC) also significantly attenuated the scopolamine-induced deficit. These results show that this novel task in the radial maze is sensitive to the disruptive effects of scopolamine and can identify cognitive enhancing effects of both cholinomimetic and non-cholinomimetic drugs. Thus, this maze task provides a useful model for the evaluation of novel cognitive enhancing agents.

Angiotensin Receptor Antagonists↗
PubMed1988

Modelling dementia: effects of scopolamine on memory and attention.

Scopolamine, a muscarinic cholinergic antagonist, is capable of inducing transient memory impairment in normal subjects. Against the background of the cholinergic hypothesis of Alzheimer's disease (AD) the present study was designed to investigate the effects of low oral doses of scopolamine on a range of cognitive functions known or hypothesized to be affected in AD. Twenty healthy volunteers (18-48 yr) performed a battery of automated cognitive tasks under each of five treatments: oral scopolamine 0.3 mg, 0.6 mg, 1.2 mg; oral methylscopolamine 0.6 mg; placebo. Alongside analogous tests of verbal and non-verbal memory, the battery enabled assessments of a range of attentional functions: alerting, sustained attention, selective attention, and covert orientation. A profile of effects was observed within and beyond the realm of memory. While some functions were unaffected by the drug (e.g. alerting) and others were impaired at the highest dose (e.g. verbal learning) still others were affected in a linear dose-dependent manner (sustained attention; visual contrast sensitivity). These observations are discussed in the context of the "scopolamine model" of AD.

Adolescent↗
PubMed1986

Motor activity changes and conditioned taste aversions induced by administration of scopolamine in rats: role of the area postrema.

Three experiments examined the effects of centrally and peripherally acting scopolamine (scopolamine hydrochloride-SHC) or only peripherally acting scopolamine (scopolamine methyl nitrate-SMN), on motor activity levels and the ability of these agents to induce taste aversions. In Experiment 1 rats were injected with isotonic saline, 1 mg/kg SHC, or 1 mg/kg SMN. SHC produced significant increases in stabilimeter activity (p less than 0.025) and in rearing response frequency (p less than 0.01), whereas SMN resulted in significantly less activity (p less than 0.025). Both agents induced strong conditioned taste aversions to saccharin (p less than 0.01). Experiment 2 examined the role of the area postrema in mediating these drug induced behavioral changes. Sham lesioned and area postrema lesioned rats were given saline, SHC or SMN (1 mg/kg for both drugs) and examined for changes in activity, rearing response frequency and induction of taste aversions to saccharin. SHC again produced significant increases in activity (p less than 0.01), whereas SMN produced decrements in activity (p less than 0.05). However, the brain lesion did not consistently alter the effects of these drugs on activity but it did reduce the amount of the decrement observed in rearing responses in SMN treated rats. The brain lesion also altered the ability of the drugs to induce taste aversions. Both SMN and SHC produced strong taste aversions in the sham lesioned rats (p less than 0.01) but no significant aversions were observed in the area postrema lesioned rats. Experiment 3 examined the ability of the brain lesion to alter the effects of SMN by using a within groups design. Area postrema lesions were found to attenuate but not abolish, the inhibitory effects of SMN on both activity levels and rearing responses (p less than 0.03). The results of these experiments suggest that in the absence of the chemically-sensitive area postrema both SMN and SHC fail to induce taste aversions and the inhibitory effect of SMN on spontaneous activity is attenuated.

Animals↗
PubMed1990

Effects of scopolamine on antipredator defense reactions in wild and laboratory rats.

Two experiments were designed to investigate the effects of scopolamine hydrobromide (0.25-1.0 mg/kg), and its methyl derivative, on the defensive reactions of rats to nonpainful threat stimuli. In the first experiment, over the dose range studied neither compound significantly altered avoidance, freezing, defensive threat or attack in wild Rattus rattus confronted by the experimenter and other predator-related stimuli. Scopolamine hydrobromide did, however, produce a dose-dependent increase in flight distance; this effect was not seen with the methyl compound, confirming central cholinergic mediation. In the second experiment, no dose of either compound significantly altered the behaviour of Long-Evans rats prior to cat exposure. During cat exposure, however, scopolamine hydrobromide (but not methyl scopolamine) increased the amount of time spent in the vicinity of the cat, increased scanning and rearing, and reduced grooming behaviour. Although reliable, the latter effects were not pronounced. Together, these data do not support a major involvement of central muscarinic receptor mechanisms in the regulation of defensive patterns in wild or laboratory rats.

Aggression↗
PubMed1990

Scopolamine differentially disrupts the behavior of male and female Wistar rats in a delayed nonmatching to position procedure.

Evidence is available that pharmacological interference with the cholinergic system may disrupt behavior in experimental procedures designed to investigate learning and memory processes. Recently it has been suggested that the cholinergic system may be sexually dimorphic. The present experiment was designed to investigate whether or not manipulation of the cholinergic system differentially affected memory processes in both sexes. Male and female Wistar rats were exposed to a delayed nonmatching to position procedure and were challenged with increasing doses of scopolamine hydrobromide (a central and peripheral muscarinic receptor blocker) and scopolamine methyl bromide (which does not pass the blood-brain barrier). Response accuracy decreased in both sexes as the delay interval duration increased. Behavioral differences between saline-treated males and females were not observed. Response accuracy decreased dose-dependently after subjects were injected with scopolamine hydrobromide. Response accuracy also decreased after treatment with scopolamine methyl bromide, but to a smaller extent. Males showed less accurate responding after treatment with either drug than females. These results provide behavioral evidence for the hypothesis that cholinergic functioning may differ between the sexes.

Animals↗
PubMed1985

Antagonism of physostigmine induced lethality by a combination of scopolamine and methscopolamine.

The antagonistic effects of scopolamine, methscopolamine, and a combination of methscopolamine and scopolamine were evaluated in preventing physostigmine induced lethality in Swiss Webster mice. Low dose scopolamine was found to be highly effective in reversing high dose (3 X the LD100) physostigmine induced lethality, in contrast to methscopolamine, which was ineffective except in very high doses. A combination of scopolamine and methscopolamine was more effective than either drug alone.

Animals↗
PubMed1983

Effects of scopolamine on stimulus sensitivity and response bias in a visual vigilance task.

Signal detection analysis was used to examine the effects of scopolamine on a visual vigilance task. A group of non-smokers performed the 60-min task on three separate occasions, receiving a different dose of scopolamine each time. Scopolamine significantly lowered stimulus sensitivity and prevented the rise in response bias which occurred over time in the placebo condition. In a second study methscopolamine was found to have no effect on either stimulus sensitivity or response bias, showing that peripheral cholinergic blockade was not involved in the effects of scopolamine on these measures. It is concluded (1) that in this study central cholinergic blockade disrupted vigilance performance by lowering stimulus sensitivity, and (2) that this finding provides further evidence that central cholinergic pathways are involved in the control of human information processing.

Adolescent↗
PubMed1989

A simple but highly sensitive radioreceptor assay for the determination of scopolamine and biperiden in human plasma.

Simple and sensitive methods are described for the determination of scopolamine and biperiden in human plasma. Each method consists of two steps. After extraction of scopolamine and biperiden with chloroform or n-hexane respectively and evaporation of the organic solvent, both drugs are determined by their ability to inhibit the specific binding of tritiated N-methyl-scopolamine to mouse brain homogenates. The lower limits of detection are plasma levels of about 50 pg/ml scopolamine and about 200 pg/ml biperiden.

Animals↗
PubMed1993

Effects of scopolamine on autonomic profiles underlying motion sickness susceptibility.

The purpose of this study was to examine the effects of scopolamine on the physiological patterns occurring prior to and during motion sickness stimulation. In addition, the use of physiological profiles in the prediction of motion sickness was evaluated. Sixty subjects ingested either 0.6 mg scopolamine, 2.5 mg methscopolamine, or a placebo. Heart rate (HR), respiratory sinus arrhythmia (an index of vagal tone), and electrogastrograms were measured prior to and during the exposure to a rotating optokinetic drum. Compared to the other groups, the scopolamine group reported fewer motion sickness symptoms, and displayed lower HR, higher vagal tone, enhanced normal gastric myoelectric activity, and depressed gastric dysrhythmias before and during motion sickness induction. Distinct physiological profiles prior to drum rotation could reliably differentiate individuals who would develop gastric discomfort from those who would not. Symptom-free subjects were characterized by high levels of vagal tone and low HR across conditions, and by maintaining normal (3 cpm) electrogastrographic activity during drum rotation. It was concluded that scopolamine offered motion sickness protection by initiating a pattern of increased vagal tone and gastric myoelectric stability.

Adult↗
PubMed1986

Alleviation of induced vertigo. Therapy with transdermal scopolamine and oral meclizine.

Twelve healthy subjects received seven-day treatments on a randomized, double-blind, crossover basis, of a transdermal scopolamine system, oral meclizine, and placebo, separated by one-week intervals. Just prior to each treatment, and on days 1 and 7 of each treatment, subjects received two warm (44 degrees C) caloric irrigations of each external auditory canal. Following each irrigation, subjects rated their vertigo symptoms. Subjects reported on their side effects daily throughout each treatment period. Vertigo symptoms on day 1 of treatment were significantly less with transdermal scopolamine than oral meclizine or placebo and on day 7 were significantly less with both scopolamine and meclizine than the placebo. On day 1, meclizine did not reduce vertigo symptoms significantly when compared with the placebo. Drowsiness was greater with use of oral meclizine than transdermal scopolamine.

Dehydration↗
PubMed1998

Pharmacokinetics and pharmacodynamics of scopolamine after subcutaneous administration.

The effects of subcutaneously administered scopolamine on quantitative electroencephalogram (qEEG) and cognitive performance were evaluated and correlated with pharmacokinetic parameters in a randomized, double-blind placebo-controlled crossover study of 10 healthy male volunteers. Changes in qEEG and cognition were determined for 8 hours after drug administration. Scopolamine produced dose- and time-dependent impairments of attention and memory and a time-dependent increase in delta power (1.25-4.50 Hz) and a decrease in fast alpha power (9.75-12.50 Hz) on qEEG compared with placebo. Maximum serum concentrations of scopolamine occurred 10 to 30 minutes after drug administration. Mean peak serum concentrations (free base) were 3.27, 8.99, and 18.81 ng/mL after administration of 0.4, 0.6 mg, and 0.8 mg scopolamine, respectively. Elimination half-life was approximately 220 minutes. The findings indicate temporary changes in qEEG and psychometric tests, and support the possible use of such a testing model for impaired cognitive functions such as age-related memory disturbances.

Adult↗
PubMed2001

Prophylaxis against organophosphate poisoning by sustained release of scopolamine and physostigmine.

Protection efficacy of continuous prophylactic administration of physostigmine and scopolamine against sarin-induced toxicity was evaluated previously in guinea pigs. The present study in large animals used Beagle dogs, that serve as an animal model with cholinergic sensitivity similar to that of humans. Pretreatment with physostigmine salicylate and scopolamine hydrochloride at dose rates of 2.5 and 1 microg x kg(-1) x h(-1), respectively, was administered via Alzet mini-osmotic pumps. At the time of exposure, the physostigmine salicylate concentration in plasma was 0.7 ng x ml(-1) and the scopolamine hydrochloride concentration was ca. 0.2 ng x ml(-1), both of which are levels known to be well tolerated in humans. Whole-blood cholinesterase inhibition was 15-20%. This regimen conferred full protection against 2.5 x LD50 i.v. of sarin. Albeit the high-dose exposure, cholinergic toxicity symptoms were mild with no convulsions. About 11-14 min following poisoning the treated animals started to walk and 15-20 min following exposure full recovery was observed and the dogs behaved normally. With higher dose rates of physostigmine salicylate and scopolamine hydrochloride, at plasma concentrations of 2.1 and 0.6 ng x ml(-1), respectively, treated dogs regained normal posture 6-10 min after exposure.

Animals↗
PubMed1996

Scopolamine- and morphine-induced deficits in water maze alternation: failure to attenuate with glucose.

Glucose has previously been shown to improve performance on memory tasks and to ameliorate performance deficits induced by scopolamine or morphine. To test the generality of these observations, Sprague-Dawley rats were trained to alternate choices to reach an escape platform in a two-choice circular water maze. The rats attained a high level of alternation, alternating on a mean of 9 of 10 daily trials. Daily glucose injections (100 and 250 mg/ kg) failed to facilitate acquisition of the alternation. Single injections of scopolamine (0.5, 1.0, and 2.0 mg/kg), but not methylscopolamine (0.5 mg/kg), and daily injections of scopolamine (0.5 mg/kg) or morphine (5.0 mg/kg) impaired alternation performance. The scopolamine- and morphine-induced deficits in alternation behavior were not ameliorated by pretrial glucose injections at doses which have previously been found to be effective (100 and 250 mg/kg). The mechanism of glucose facilitation of memory is currently unknown. The present results show that glucose given at previously established effective doses does not activate the mechanism or produces too weak an effect to be observed in water maze alternation.

Animals↗
PubMed1996

Apparent vs real effects of scopolamine on the learning of an active avoidance task.

The effects of scopolamine hydrobromide (0.5 and 2 mg/ kg) administered intraperitoneally to Balb/c male mice before or after training in active avoidance were explored in four training sessions and in a subsequent test session, free of drug. Animals given scopolamine prior to training performed better than controls, an effect that was reversed in the session free of drug. However, a deeper analysis of the data permits us to interpret this increment in the number of avoidance responses as a consequence of the increase in activity produced by the drug and not as learning. In the animals injected with scopolamine after sessions no effects were observed. In conclusion, the results of the present experiment confirm that scopolamine produces an impairment in the acquisition of an active avoidance task, but also show that this impairment can be easily masked by the facilitating effects of the drug on activity.

Animals↗
PubMed1987

Presynaptic effects of scopolamine, oxotremorine, noradrenaline and morphine on [3H]acetylcholine release from the myenteric plexus at different stimulation frequencies and calcium concentrations.

The inhibition by three modulators (oxotremorine, noradrenaline, morphine) of acetylcholine release from the myenteric plexus preincubated with [3H]choline was investigated at different stimulation frequencies and calcium concentrations. Moreover, [3H]acetylcholine release evoked by a low (0.1 Hz) or a high (10 Hz) stimulation rate was investigated at different calcium concentrations either in the absence or presence of scopolamine. A reduced calcium concentration (0.6 mmol/l) inhibited acetylcholine release more at 0.1 Hz (74% +/- 3%) than at 10 Hz (44% +/- 8%). Scopolamine enhanced the stimulated acetylcholine release at a calcium concentration of 1.8 mmol/l. At calcium concentrations higher than 1.8 mmol/l scopolamine failed to enhance transmitter release markedly. A reduction of the calcium concentration (less than 1.8 mmol/l) significantly enhanced the effect of scopolamine, when acetylcholine release was evoked at 0.1 Hz. Oxotremorine (10 mumol/l) completely suppressed acetylcholine release at 1 Hz (120 pulses). When 120 pulses were applied at 10 Hz the maximal effect was only a 64% inhibition and the concentration-response curve was significantly shifted to the right. However, after a reduction of both the train length or the calcium concentration oxotremorine produced a complete inhibition of acetylcholine release evoked at 10 Hz. In contrast to the effect of oxotremorine, the concentration-response curves for morphine and noradrenaline were similar at 1 Hz and 10 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Effects of nootropic drugs in a scopolamine-induced amnesia model in mice.

Scopolamine (3 mg/kg IP) given before an acquisition trial, reduced the retention of a one-trial passive avoidance "step through" response in mice. A single administration of cholinergic agonists such as oxotremorine, BM-5, or arecoline, antagonized this amnesic effect of scopolamine. A significant anti-amnesic effect was also found with nootropic drugs such as piracetam and ucb L059, whereas ucb L060 (the enantiomer of ucb L059), oxiracetam and rolziracetam were shown to be ineffective. Moreover, ucb L059, administered twice daily for 3 days, counteracted the amnesic effects of scopolamine completely, whereas ucb L060 was again inactive. The results demonstrate that: (a) this model of impaired cognition by scopolamine is able to discriminate between closely related chemical substances and even stereoisomers; and (b) nootropic drugs, such as ucb L059, are more effective after repeated rather than after acute administration.

Amnesia↗
PubMed1986

Relation between behaviorally augmented tolerance and upregulation of muscarinic receptors in the CNS: effects of chronic administration of chronic administration of scopolamine.

The present experiment was planned to provide information about relations between behaviorally augmented tolerance and accompanying upregulation of muscarinic receptors (mAChR) (physiological tolerance) in the CNS during chronic administration of the cholinergic antagonist scopolamine. Analyses of the data on mAChR binding established significant upregulation (Bmax) had occurred in the cortex, hippocampus, and striatum of animals treated with scopolamine, but not of those in the saline or methylscopolamine groups. There were no treatment effects in affinity (KD). The effect of scopolamine administered before a behavioral test session was to cause an acute decrease in FR5 responding to water reinforcement, and hence in resulting water consumption. Animals immediately compensated for this decrement by higher response rates during a free drinking (FDR) period which followed. When scopolamine was injected between the FR5 and FDR periods, FR5 responding increased to compensate for the drug's effect on the FDR. There was evidence that physiological tolerance also occurred as indicated by a more slowly developing trend toward recovery of levels of behavioral responding related to mAChR upregulation, although full recovery to pretreatment baselines did not occur within the 25 days of chronic treatments. The results as a whole are consistent with a multifactorial model of tolerance development, to which both behavioral and neurochemical processes contribute.

Animals↗
PubMed1977

Scopolamine induced learning failures in man.

Two experiments were performed to determine the locus of the amnestic effects of scopolamine in man. The first experiment involved 24 volunteers receiving one of three doses of scopolamine (5, 8 or 10 microng/kg) or a placebo, intravenously. The subjects were tested for retention of material learned prior to administration of the drug, acquisition of new information, and retention of material learned while under the influence of the drug. Results indicated that scopolamine has its primary effect on the acquisition of new material and less of an effect on the retrieval of information already learned. The second experiment was designed to refine and expand upon the results of the first and involved 18 volunteers receiving eith 5 or 10 microng/kg of scopolamine or a placebo, intravenously. The subjects were given four trials to learn a list of verbal materials, and their recall for that material was measured at various intervals up to 24 h. These results confirmed those of the first experiment in that the predominant influence of the drug was to impair the acquisition of new information. Implications of these results for memory mechanisms are discussed.

Adult↗