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PubMed1999

Combining tacrine with milameline reverses a scopolamine-induced impairment of continuous performance in rhesus monkeys.

RATIONALE: Cholinomimetic therapy in Alzheimer's disease (AD) has been hampered by narrow efficacious dose ranges and dose-limiting side effects. These limitations highlight the need for an alternative therapeutic approach for the symptomatic treatment of AD. OBJECTIVES: To determine in rhesus monkeys if combined treatment with the acetylcholinesterase inhibitor tacrine (Cognex) and the muscarinic agonist milameline improve behavioral efficacy in a scopolamine-reversal task without potentiating adverse side effects. METHODS: Behavioral performance of rhesus monkeys was measured using a continuous performance task. The effects of tacrine and milameline, separately or in combination, were determined following administration of an impairing dose of the anticholinergic scopolamine. In addition, tacrine and milameline were given similarly in the absence of scopolamine to determine the presence of adverse side effects. RESULTS: Tacrine and milameline, separately or in combination, reversed the scopolamine-induced decrease in responses on a continuous performance task. Administered in combination, tacrine and milameline significantly improved performance on this task at lower doses and across a broader dose range than when given separately. In the absence of scopolamine, combined treatment did not potentiate the appearance of side effects or produce adverse events significantly different from those observed with either compound alone. CONCLUSIONS: Tacrine and milameline given in combination broadened the range of doses significantly reversing a scopolamine-induced impairment without potentiating adverse side effects.

Animals↗
PubMed2007

Scopolamine in Brugmansia suaveolens (Solanaceae): defense, allocation, costs, and induced response.

Brugmansia suaveolens (Solanaceae) contains tropane alkaloids (TAs), which can act as chemical defenses. Selective pressures might modulate the allocation of alkaloids within the plant, as postulated by optimal-defense theory. By tracing scopolamine, the most abundant TA in this species, we found that scopolamine in an artificial diet, in concentrations similar to those in leaves of B. suaveolens, increased mortality and prolonged developmental time of the larvae of the generalist noctuid moth Spodoptera frugiperda. A diet of undamaged leaves of B. suaveolens also showed a large negative effect on the growth of larvae of S. frugiperda compared to a diet of leaves of Ricinus communis, a species that did not have negative effects on this moth; more valuable plant parts, such as young leaves, flowers, and unripe fruits with seeds, have higher scopolamine concentrations than other tissues; leaves of B. suaveolens increase their content of scopolamine after artificial damage. The highest induction was found 24 hr after the damage, and after that, scopolamine content decreased to constitutive levels. This increase represented a cost, because in another experiment, a treatment with methyl jasmonate, an elicitor hormone, increased scopolamine production 9.5-fold and decreased leaf growth 2.3-fold; a diet of artificially damaged leaves of B. suaveolens showed a negative effect on the growth of larvae of S. furgiperda compared to undamaged leaves, suggesting that damage by herbivores induces resistance. Our data are in line with the optimal-defense theory, but experiments in the field with herbivores that share an evolutionary history with B. suaveolens must be undertaken to understand the dynamics of TA allocation in response to herbivory.

Acetates↗
PubMed1997

Minimal effects of dextroamphetamine on scopolamine-induced cognitive impairments in humans.

The central anticholinergic drug scopolamine has been used to model aspects of the memory impairment that occurs in Alzheimer's disease and in aging. To determine whether nonspecific stimulant effects can attenuate the cognitive impairment induced by scopolamine, we studied the effects of scopolamine and the stimulant dextroamphetamine in 17 young normal volunteers. After a baseline day of cognitive testing, subjects participated in two study days, in which they received dextroamphetamine (d-AMP) (0.25 mg/kg p.o.) + scopolamine (0.5 mg i.v.) and placebo + scopolamine, in randomized order under double-blind conditions. There were no statistically significant differences in cognitive test performance between the two drug conditions with the exception of one of the category retrieval tasks. Stimulant effects were documented to occur by other measures. We conclude that d-AMP at the dose used does not attenuate the memory impairment induced by scopolamine.

Adult↗
PubMed1987

Reversal of scopolamine-induced amnesia and alterations in energy metabolism by the nootropic piracetam: implications regarding identification of brain structures involved in consolidation of memory traces.

Pretreatment with scopolamine, 3 mg/kg, prevented the acquisition of a passive avoidance task in rats. These amnesic effects of scopolamine could largely be overcome by treatment with 100 mg/kg of the nootropic drug piracetam. In order to identify the brain structures involved, the effects of these drugs on regional energy metabolism were measured throughout the brain, utilizing Sokoloff's 2-deoxyglucose autoradiographic procedures. Scopolamine, 3 mg/kg, reduced glucose utilization in several areas of the cerebral cortex. These effects were largest in the parietal and temporal cortices. Other areas affected included the sensorimotor and cingulate cortices, the ventral and lateral thalamus, and the dendritic neuropil of the CA1, CA2, and CA3 regions of the hippocampus. The regional depressions in glucose metabolism observed following scopolamine treatment in the rat had some resemblance to depressions in glucose metabolism reported for Alzheimer's disease patients in positron emission tomography studies. Piracetam, 100 mg/kg, did not alter the energy metabolism of any of the 41 brain regions examined. However, this dose of piracetam completely reversed the scopolamine-induced depressions in the hippocampus. Piracetam partially but significantly reversed the scopolamine effects in the cingulate cortex. It is concluded that the data provide support for the hippocampal-cholinergic theory of memory as originally formulated by Meyers and Domino in 1964 and give insight into the mechanisms by which nootropics work.

Amnesia↗
PubMed1987

Selectivity of pirenzepine in the central nervous system. II. Differential effects of pirenzepine and scopolamine on performance of a representational memory task.

The behavioral effects of the two muscarinic antagonists scopolamine and pirenzepine were examined using a representational memory task for rats in a T-maze. Rats were pretrained to a criterion of 100% correct responses for daily sessions of 10 paired-run trials. The training procedures eliminated all neophobic or wary responses, and response times were invariably short (less than 3 s). Following the initial training sessions, guide cannulae were surgically implanted bilaterally over the hippocampus of each animal. Following recovery from surgery, animals were injected with saline (0.5 microliter to each hippocampus), scopolamine hydrobromide (0.5 microliter of a 60 mg/ml solution (30 micrograms) to each side), or pirenzepine (0.5 microliter of a 69.1 mg/ml solution (34.6 micrograms) to each side) according to a fixed schedule. Saline injections aimed between the blades of the dorsal dentate gyrus failed to produce any change in the performance of the memory task. Initial doses of scopolamine, applied to the same area, produced a decrease in the percentage of correct responses as did the initial dose of pirenzepine. In contrast to pirenzepine, scopolamine also produced increases in response times even to the point of defaulted trials (response times greater than 90 s) in some animals following drug injections. Saline injections failed to produce significant impairments on the days following scopolamine injections, although animals receiving pirenzepine injections were still impaired on the two days immediately following the initial pirenzepine injection. Subsequent doses of pirenzepine were ineffective in producing an impairment of performance while scopolamine injections were less effective than the initial dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Substance P markedly ameliorates scopolamine-induced impairment of spontaneous alternation performance in the mouse.

We investigated the effects of intracerebroventricular injection of substance P (SP) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance in the mouse. SP (0.001-3 micrograms) alone did not influence either spontaneous alternation performance or total arm entries. Scopolamine (1 mg/kg) impaired spontaneous alternation performance accompanied by an increment in total arm entries. In contrast, SP (0.01-1 micrograms) significantly improved the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing the scopolamine (1 mg/kg)-induced increase in total arm entries. The effects of SP (0.1 micrograms) on the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance were almost completely reversed by pretreatment with WIN 62577 (1 mg/kg), a tachykinin NK-1 receptor antagonist. These results suggest that SP improves the scopolamine-induced impairment of spontaneous alternation performance through the mediation of tachykinin NK-1 receptors.

Androstenes↗
PubMed1995

Glucose enhancement of scopolamine-induced increase of hippocampal high-affinity choline uptake in mice: relation to plasma glucose levels.

The administration of glucose has been shown to improve memory for various learning tasks in rodents. In humans, glucose also increases declarative memory performance in elderly people and in some patients with mild Alzheimer's disease. One of the possible physiological bases for the effect of glucose on memory processes is a facilitation of cholinergic function through increased synthesis. In support of this hypothesis, glucose was shown to attenuate the amnesia induced by scopolamine and, in similar conditions, glucose increased extracellular levels of acetylcholine following a scopolamine injection. To further examine the interaction between glucose and cholinergic function, the present experiment measured the effects of combined injections of glucose and scopolamine on hippocampal sodium-dependent high-affinity choline uptake, an indirect index of cholinergic activity. Results showed that the injection of 3 g/kg glucose enhanced the increase in high affinity choline uptake in hippocampal synaptosomes produced by scopolamine. A regression analysis revealed the existence of a positive correlation between plasma blood glucose level and hippocampal choline uptake particularly in the animals receiving a combined injection of scopolamine and glucose. These data further support the hypothesis that glucose administration can facilitate acetylcholine synthesis under certain conditions and that this action could explain how glucose attenuates scopolamine-induced amnesia.

Analysis of Variance↗
PubMed1992

Effects of cortical ablation on apomorphine- and scopolamine-induced changes in dopamine turnover and ascorbic acid catabolism in the rat striatum.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid and dehydroascorbic acid (DHAA) were measured by HPLC in the striatum of rats whose fronto-parietal cortex had been unilaterally ablated after a single injection of apomorphine (1 mg/kg s.c.), scopolamine (0.6 mg/kg s.c.) or L-glutamate (500 mg/kg i.p.). Unilateral cortical ablation decreased striatal levels of glutamate in both striata ipsilateral (35%) and contralateral (17-25%) to the lesion. Apomorphine and scopolamine significantly increased (+94 and +122%, respectively) the DHAA/ascorbic acid ratio in the striata ipsilateral to the lesion in unoperated and sham-operated rats (+72 and +34%, respectively), but both drugs failed to increase it in ablated rats. L-Glutamate significantly increased the DHAA/ascorbic acid ratio in unoperated (+53%) and ablated rats (+37%). The increase in sham-operated rats (+34%) did not reach statistical significance. Apomorphine and scopolamine significantly decreased the DOPAC/DA ratio in the striata ipsilateral to the lesion of unoperated, sham-operated and ablated rats. The decrease in the DOPAC/DA ratio induced by apomorphine and scopolamine was greater in ablated rats than in sham-operated rats. L-Glutamate induced only minor changes in striatal DA and DOPAC levels. We conclude that the apomorphine- and scopolamine-induced increase in ascorbic acid oxidation in the striatum requires intact cortico-striatal glutamatergic pathways. Cortical ablation potentiates the apomorphine- and scopolamine-induced inhibition of striatal DA turnover.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Effects of scopolamine on performance of rats in a delayed-response radial maze task.

The effects of the cholinergic blocker scopolamine on performance of rats in an 8-arm radial maze were studied. In Experiment 1, rats received injections of scopolamine-HBr (0.2 mg/kg, IP) or saline, 20 min before a trial. The drug impaired performance only when midtrial delays were introduced (10 sec, 5, 20, 60 or 120 min), during which the animals were removed from the apparatus, and to a similar extent at all delays. Injection of scopolamine directly after choice 4 in a 20 min delayed trial affected performance at a dose of 0.4 mg/kg, but not at 0.2 mg/kg. In Experiment 2, the rats were kept in the apparatus during the delay. There was a significant effect of scopolamine at 0.1 and at 0.2 mg/kg, initially irrespective of the length of the delay (10 sec, 2.5 or 5 min). After considerable training, administration of scopolamine (0.2 mg/kg) had no significant effect at the 10 sec delay but did impair performance after longer (5 or 10 min) midtrial intervals. These results suggest that scopolamine has differential effects, depending on dose and degree of training, and that an effect on memory storage may be one of them.

Animals↗
PubMed1994

Effects of hormonal treatment and history on scopolamine inhibition of lordosis.

The muscarinic receptor blocker, scopolamine, inhibits the display of lordosis behavior in female rats but its effectiveness depends on hormonal conditions. In these experiments, systemic administration of scopolamine (0.031-4 mg/kg) inhibited lordosis in ovariectomized rats brought into receptivity by treatment with a low dose of estradiol benzoate (EB, 0.25 micrograms for 3 days) with progesterone (P, 500 micrograms for 1 day), or a high dose of EB (25 micrograms for 3 days) with and without P. However, the effectiveness of scopolamine was reduced at the high dose of EB and with the addition of P. Furthermore, scopolamine failed to inhibit lordosis in females treated on a second week with the high dose of EB with or without P, unless an interval of at least 3 weeks separated the two sets of steroid treatments. The reduced effectiveness of scopolamine cannot be explained by peripheral mechanisms because its inhibitory effect on lordosis also was reduced following repeated hormonal exposure even when scopolamine was infused directly into the lateral ventricles.

Acetylcholine↗
PubMed1976

Short-term memory in the rhesus monkey: disruption from the anti-cholinergic scopolamine.

Two separate experiments were conducted to evaluate the effects of the anti-cholinergic scopolamine on primate visual discrimination and short-term memory (STM). In the first experiment it was shown that relatively mild doses of scopolamine severly impaired visual discrimination performance, even though the test procedure provided strong stimulus control. This deficit in visual discrimination suggested that previous research which used the delayed matching to sample procedure (DMS) to evaluate the role of cholinergics in primate STM may have confounded an accurate measure of specific STM effects because the DMS is inherently dependent on accurate visual discrimination. Therefore, the second experiment evaluated the effects of scopolamine on STM, using an automated apparatus and test procedure designed to minimize the discrimination component and other confounding variables present in the earlier research. In this second experiment, an indirect delayed response (DR) procedure was used, measuring the monkeys' ability to recall simple stimulus events over retention intervals of 0, 2.5, 5, and 10 sec. The monkeys were tested under 2 doses of the anti-cholinergic scopolamine and their performance was compared to that obtained on several nondrug control days. Contrary to earlier reports using the DMS, a clear interaction of drug and retention interval occurred in this situation. Under scopolamine, greatest impairments occurred on the longest delays, with little or no effect with zero second retention. Furthermore, the impairments observed on the longer delays were even greater with the highest dose of scopolamine. These data, therefore,support the notion that cholinergic mechanisms play an important role in the expression of STM in primates.

Acetylcholine↗
PubMed1981

Time dependent changes in anterograde scopolamine-induced amnesia in rats.

These experiments studied the effect of scopolamine on memory formation and subsequent memory recall. Different groups of rats were trained on a Y-maze brightness discrimination task 20 min after IP injection of 2 mg/kg scopolamine HBr, an anticholinergic. Retention tests were then conducted 1 day or 2, 4, or 6 weeks after training. Deficits in retention performance were observed at 1 day and 2 weeks after training but not at the longer intervals. In addition, other rats were trained in the same manner and after the same dose of scopolamine but were then retention tested 20 min after 0.5 mg/kg physostigmine salicylate, a cholinesterase inhibitor. These subjects also showed deficits at 1 day and 2 weeks but were not different from controls at the longer intervals. Amnesia was not, however, produced after treatment with scopolamine methyl nitrate or by injections of scopolamine HBr administered immediately after training. These results suggest that scopolamine, present in the central nervous system during training or within the first few moments thereafter, modifies the formation of the memory trace in such a way that memory is not available for recall for a period of weeks.

Animals↗
PubMed1987

Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine.

The effect of cognition-enhancing agents oxiracetam and aniracetam on scopolamine-induced amnesia and brain acetylcholine decrease was investigated in the rat. Acetylcholine levels were measured by means of a gas-chromatographic method. Scopolamine (0.63 mg/kg IP 60 min before training) prevented the acquisition of a passive avoidance conditioned response ("step through": retest 30 min after training) and brought about a 64, 56 and 42% decrease in acetylcholine level in the cortex, hippocampus and striatum respectively. Oxiracetam (50 and 100 mg/kg IP) administered 30 min before scopolamine reduced the scopolamine-induced amnesic effect and decrease in acetylcholine level in the cortex and hippocampus, but not in the striatum. Lower and higher doses of oxiracetam were ineffective. Aniracetam (100 mg/kg PO) also prevented scopolamine-induced amnesia but attenuated acetylcholine decrease in the hippocampus only. Aniracetam (300 mg PO) reduced acetylcholine decrease in the hippocampus but did not prevent scopolamine-amnesia. In conclusion, oxiracetam and aniracetam exert a stimulatory effect on specific central cholinergic pathways. However, a direct relationship between cognition-enhancing properties and cholinergic activation needs further confirmation.

Acetylcholine↗
PubMed1993

Peony and its major constituent, paeoniflorin, improve radial maze performance impaired by scopolamine in rats.

A traditional Chinese medicine, Shimotsu-to has been shown to improve spatial working memory in rats. Shimotsu-to consists of four herbs, Japanese angelica root, cnidium rhizome, peony root, and rehmannia root. In the present study, the effects of aqueous extracts of each component herb on scopolamine (0.3 mg/kg)-induced spatial working memory disruption were examined using an eight-arm radical maze task in rats. Among the four component herbs, peony root extract (0.25 and 1 g dried herb/kg, PO) exhibited the most potent antagonizing effect on the scopolamine disruption of the choice accuracy. Japanese angelica root extract (1 g dried herb/kg, PO) also significantly attenuated the scopolamine disruption, whereas neither cnidium rhizome nor rehmannia root affected it. Paeoniflorin (0.01-1 mg/kg, PO), a major constituent of peony root, dose-dependently attenuated the scopolamine-induced impairment in the choice accuracy. Scopolamine (0.3 mg/kg, IP) significantly decreased the acetylcholine contents in the hippocampus, cortex, and striatum. Although paeoniflorin alone did not affect the acetylcholine contents, pretreatment with paeoniflorin significantly prevented the scopolamine-induced decrease in the acetylcholine content in the striatum, but not in the hippocampus or cortex. These data suggest that peony root mainly contributes to the cognitive enhancing effect of Shimotsu-to and that paeoniflorin may be one of the active constituents of peony root.

Acetylcholine↗
PubMed1991

Comparison of the effects of scopolamine administered before and after acquisition in a test of visual recognition memory in monkeys.

The effect of scopolamine on visual recognition memory in rhesus monkeys was assessed with a delayed nonmatching-to-sample task employing trial-unique stimuli. During the acquisition phase, 40 sample stimuli were presented sequentially. During the test phase, these same stimuli were presented in the reverse order, each paired with a novel stimulus. The animal was rewarded for choosing the novel stimulus in each pair. Two versions of this design were used. In Task 1, scopolamine (10.0 or 17.8 micrograms/kg) was administered 20 min prior to acquisition, which was followed immediately by the test phase. In Task 2, the drug was administered immediately after acquisition, which was followed 20 min later by the test phase. Performance was impaired in a dose-related manner in Task 1, but not at all in Task 2, indicating that the effects of scopolamine on performance cannot be attributed to an impairment either in the retrieval of stored information or in the attentive or perceptual discriminative processes needed for such retrieval, or, by implication, for storage. In addition, the forgetting curves for scopolamine in Task 1 were parallel to those of the control sessions; i.e., the curves did not diverge with increasing delay intervals, indicating that scopolamine did not increase the rate of forgetting. Taken together, the results suggest that scopolamine interferes selectively with the initial storage of the information to be remembered.

Animals↗
PubMed1993

Effects of low dose transdermal scopolamine on heart rate variability in acute myocardial infarction.

OBJECTIVES: We hypothesized that by enhancing parasympathetic activity, low dose transdermal scopolamine would increase heart rate variability after myocardial infarction. BACKGROUND: Low heart rate variability is associated with increased mortality after acute myocardial infarction. METHODS: Conventional time domain heart rate variability was measured from 24-h Holter recordings of 61 consecutive male patients (mean age 58 +/- 10 years, left ventricular ejection fraction 44.7 +/- 15.5%) 6 days (median) after acute myocardial infarction. Patients were then randomly assigned to wear one patch of transdermal scopolamine or a matching placebo patch for 24 h, during which their 24-h heart rate variability was remeasured. RESULTS: Compared with placebo, transdermal scopolamine caused a significant increase in time domain measures of 24-h heart rate variability by 26% to 35% above baseline. Transdermal scopolamine was well tolerated. CONCLUSIONS: Low dose transdermal scopolamine safely increases cardiac parasympathetic activity and short-term heart rate variability after acute myocardial infarction. Whether the effect of transdermal scopolamine on heart rate variability is a reasonable surrogate for improvement of long-term morbidity and mortality requires an appropriate designed investigation.

Administration, Cutaneous↗
PubMedDate not supplied

Effects of scopolamine on spontaneous alternation and shuttle avoidance in rats exposed to alcohol in utero.

The behavioral effects of the anticholinergic scopolamine were examined in rats exposed to alcohol prenatally. Pregnant Long-Evans rats received isocaloric liquid diets containing either 35% or 0% ethanol-derived calories on Days 6-20 of gestation. A pair-feeding procedure was used, and a lab chow control group was also included. In Experiment 1, adult offspring were tested on a spontaneous alternation task following 1 mg/kg scopolamine or saline. Independent of prenatal treatment, scopolamine caused an increase in the number of trials to alternate. In Experiment 2, offspring were tested on a two-way shuttle avoidance learning task following a 1 mg/kg injection of scopolamine or methylscopolamine. Alcohol-exposed animals injected with methylscopolamine made fewer avoidances than controls on the second day of testing while treatment with scopolamine enhanced avoidance performance to control levels. These data suggest that prenatal exposure to alcohol does not interfere with scopolamine-induced changes in the behavior of adult rats.

Animals↗
PubMed2006

Effect of scopolamine on the hippocampal theta rhythm during an eight-arm radial maze task in rats.

The changes in the hippocampal theta rhythm during an impairment of reference and working memory of radial maze task induced by scopolamine administration were studied. Intraperitoneal injection of scopolamine at doses of 0.5 and 1.0 mg/kg caused a significant increase in the number of total, reference memory and working memory errors. On the other hand, scopolamine significantly increased the hippocampal theta power (5-12 Hz) at doses (0.5 and 1.0 mg/kg) that caused an impairment of reference and working memory. A significant increase in the peak frequency of the hippocampal theta rhythm was also observed with scopolamine, even at a dose of 0.2 mg/kg. At doses of 0.2, 0.5 and 1.0 mg/kg, scopolamine caused a decrease in the locomotor activity during the radial maze task. From these results, it may be concluded that an increase in amplitude of the hippocampal theta rhythm induced by scopolamine is closely associated with memory/learning function of the eight-arm radial maze.

Animals↗