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Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model.

18 older normal volunteers (mean age = 66.5 +/- 7.9 years) and 46 younger volunteers (mean age = 27.0 +/- 6.1 years) were administered the anticholinergic drug scopolamine (0.5 mg i.v.) followed by a battery of cognitive tests evaluating attention, learning and memory. The older subjects were significantly more impaired than the younger by scopolamine on some tests of learning and memory. This increased sensitivity of the older group to scopolamine is consistent with studies in animals and humans showing decreased cholinergic system function with age. The findings also indicate that age is an important variable to consider in using the scopolamine model of memory impairment. The cognitive impairment caused by scopolamine in younger subjects in this and prior studies is similar to some, but not all aspects of the impairment which occurs in normal aging. Scopolamine also caused impairments on digit span and word fluency tasks, which are not consistent with normal aging changes. In the older group of subjects, scopolamine produced aspects of the cognitive impairment which occurs in AD on tests of episodic memory and learning, vigilance-attention, category retrieval, digit span, and number of intrusions. Other areas of cognition that are of relevance to aging and AD such as psychomotor speed, praxis, concept formation and remote memory were not evaluated in this study. Some of these are being evaluated in ongoing studies, along with additional and more specific tests of retrieval from knowledge memory, implicit memory and attention. The scopolamine model has provided a fruitful pharmacologic starting point for the study of a number of cognitive operations. The idea of dissecting apart aspects of memory systems pharmacologically depends on the availability of neurochemically specific drugs and on the specificity and sensitivity of neuropsychological tests for distinct cognitive operations or domains. Further studies using such tools will aid not only in the understanding of the impairments which occur in aging and in AD, but also of the conceptualization of memory and other cognitive operations and ultimately the physiological mechanisms involved in memory and learning.

Acetylcholine↗
PubMed1992

Blockade of conditioned taste aversion by scopolamine and N-methyl scopolamine: associative conditioning, not amnesia.

The anticholinergic, scopolamine, consistently disrupts one-trial passive avoidance conditioning but the effects of such drugs on one-trial conditioned taste aversion (CTA) are variable and contradictory. In the present study, treatment of rats with scopolamine impaired the suppression of sucrose intake by post-ingestion administration of lithium chloride (LiCl) in a two-bottle choice test. A similar effect was obtained by using N-methyl scopolamine which penetrates the brain only to a limited degree on acute administration. The blockade of CTA could be prevented in three ways: (i) by exposing the rats to sucrose only on the training day, (ii) by pre-exposing the rats to both sucrose and scopolamine, and (iii) by using a less palatable sucrose/ascorbate mixture. The results demonstrate that the effect of scopolamine on taste aversion is not mediated by the central nervous system, and can be modified by altering the novelty and relative salience of the taste conditioned stimulus. These experiments suggest that conditioned associations between taste and LiCl, and scopolamine and LiCl may underlie the blockade of CTA by scopolamine.

Amnesia↗
PubMed1989

Scopolamine and methylscopolamine differentially affect fixed-consecutive-number performance of male and female Wistar rats.

Male and female Wistar rats were trained on a fixed-consecutive-number schedule in which a response on a food lever was followed by the presentation of reinforcement when at least three, but not more than seven responses had been completed on a work lever. Subjects were treated with different doses of the centrally acting cholinergic antagonist scopolamine hydrobromide or the more peripherally active cholinergic antagonist scopolamine methylbromide (0.08, 0.16 or 0.32 mg/ml/kg) once behavior had stabilized. Scopolamine hydrobromide and scopolamine methylbromide dose-dependently decreased response rates in males and females. Scopolamine methylbromide decreased response rates more than equivalent doses of scopolamine hydrobromide and the rate-suppressant effects of both drugs were more marked in males than in females. Scopolamine hydrobromide dose-dependently decreased response accuracy, but differences between males and females were not observed. Response accuracy also decreased after scopolamine methylbromide, but did not vary as a function of the dose of the drug. The decrease in response accuracy induced by both drugs was attributable to an increase in the percentage of trials with a premature switch from the work lever to the food lever. Both scopolamine hydrobromide and scopolamine methylbromide dose-dependently increased the number of premature switches. Differences between males and females were not observed. Administration of scopolamine hydrobromide and scopolamine methylbromide also decreased the number of obtained reinforcers in a dose-dependent manner. Females obtained significantly fewer reinforcers than males, while scopolamine methylbromide affected the number of obtained reinforcers to a larger extent than scopolamine hydrobromide.

Animals↗
PubMed1992

The effect of estrogen treatment on scopolamine inhibition of lordosis.

Previous evidence indicates that the cholinergic muscarinic antagonist, scopolamine, inhibits lordosis in female rats. In the experiments reported here, the effects of various doses and repeated administrations of estrogen on the scopolamine inhibition of lordosis were examined. In the first experiment, intraperitoneal injections of scopolamine (1 mg/rat) completely inhibited lordosis in ovariectomized rats primed with low doses of estradiol benzoate (0.25 or 0.5 micrograms for 3 days) and progesterone (500 micrograms). However, scopolamine was significantly less effective in inhibiting lordosis in females primed with a higher dose of estradiol benzoate (25 micrograms for 3 days) and progesterone (500 micrograms). When hormone priming was repeated on subsequent weeks, scopolamine continued to inhibit lordosis in females that received 0.25 micrograms estradiol benzoate but was less effective in females primed with 0.5 micrograms. Scopolamine failed to inhibit lordosis in females treated with 25 micrograms estradiol benzoate on these later tests. In the second experiment, various doses of scopolamine (1, 2, or 4 mg/rat) were administered intraperitoneally to females primed with the highest dose of estradiol benzoate (25 micrograms) and progesterone (500 micrograms). Lordosis was inhibited equally by all scopolamine doses during the first week. As in the first experiment, scopolamine failed to inhibit lordosis at all doses on subsequent weeks of testing. These results indicate that the ability of scopolamine to inhibit lordosis is reduced by increasing the dose or the number of estrogen exposures. Because higher doses of scopolamine failed to restore its inhibitory effect on lordosis an upregulation of muscarinic receptors by estrogen cannot account for the reduced effectiveness of scopolamine.

Animals↗
PubMed1991

Nausea prophylaxis using transdermal scopolamine in the setting of patient-controlled analgesia.

We evaluated the effectiveness of transdermal scopolamine in patients receiving morphine via patient-controlled intravenous analgesia following intra-abdominal gynecologic surgery. Soon after arrival in the post-anesthesia recovery unit (time 0), patients were randomized either to receive or not receive a postauricular transdermal scopolamine patch. Nausea and vomiting were scored on a 0-3 scale at this time and at 2, 4, 6, and 24 hours. Patients were treated with droperidol as deemed necessary by the primary care nurse. Within 2-4 hours, transdermal scopolamine patients evidenced less nausea and vomiting and required less droperidol than their counterparts who did not receive transdermal scopolamine. A significant decline in the severity of nausea was noted in the transdermal scopolamine group between 2-24 hours; significant inter-group differences were noted for changes in nausea severity during the 0-6-hour and 0-24-hour intervals. Transdermal scopolamine patients evidenced a significant (P less than .05) decrease in the severity of vomiting during the first 2 hours, significantly different from the increase in the non-transdermal scopolamine patients. After the 4-hour assessment, no transdermal scopolamine patients required droperidol; nine doses were administered to the patients who were not given transdermal scopolamine (P less than .05). Thus, transdermal scopolamine therapy appears to be an effective means of treating the nausea and vomiting that are encountered after gynecologic surgery.

Administration, Cutaneous↗
PubMed1991

Determination of the enantiomeric purity of scopolamine isolated from plant extract using achiral/chiral coupled column chromatography.

The optical purity of scopolamine derived from Datura sanguinea was determined using coupled column chromatography. A C18 column was used to separate scopolamine from the additional alkaloids and other biological material present in the vegetal extract. The C18 column was coupled through a six-port switching valve to two beta-cyclodextrin columns in series which were used to resolve the scopolamine enantiomers. A single acetylated beta-cyclodextrin column gives equivalent results to the native cyclodextrin columns because of slightly higher enantioselectivity for scopolamine. A multistep extraction procedure is used to isolate scopolamine from the vegetal material. 4-6% of the scopolamine in the final extract was found to be the d enantiomer. Sample extracts as well as commercial scopolamine hydrobromide were treated under various conditions commonly encountered during typical commercial extraction procedures and analyzed in order to determine if the d enantiomer was present in the original material or if it was produced during the extraction process and, if so, determine which step and conditions contribute to racemization. Both the salt and the extract were found to be susceptible to racemization under basic conditions (greater than or equal to pH 9) although the extract appeared to be more susceptible than the salt. Tropic acid formed from the hydrolysis of scopolamine seemed to be completely racemized even though the remaining scopolamine was only partially racemized. Within experimental error, no d enantiomer was found in the original fresh plant material.

Acetylation↗
PubMed2025

The effect of scopolamine on memory and attention: a systematic review and meta-analysis.

BACKGROUND: Scopolamine is a muscarinic receptor antagonist and is widely utilized as a "memory-loss model." However, its impact across different memory and attention tasks and using different modes of administration has yet to be clearly evaluated. This systematic review and meta-analysis investigates the effect of scopolamine, across all routes of administration and across different dosages, on memory and attention performance in healthy humans (PROSPERO ID: CRD42024531634). METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched (on 20 April 2024) for studies that utilized scopolamine and assessed memory and/or attention. Random-effects meta-analyses were conducted across a range of memory and attention tasks using "Comprehensive Meta-Analysis," Version 3, to evaluate differential pharmacological effects on cognitive tasks between the scopolamine and placebo groups. RESULTS: Forty-six studies fulfilled the inclusion and exclusion criteria. Scopolamine negatively impaired performance on all memory tasks (immediate memory, delayed recall, digit span, Buschke selective reminding task, and recognition memory) and led to slower reaction times for three of the five attention tasks examined (choice reaction time, simple reaction time, and rapid visual information processing) compared to placebo. Scopolamine's negative effect on memory and attention was greater with injectable (e.g., intramuscular, intravenous, and subcutaneous) compared to non-injectable routes of administration (e.g., intranasal, oral, and transdermal). CONCLUSION: This study supports the use of scopolamine as a "memory-loss model," particularly when given by an injectable route of administration. Future clinical trials should evaluate the bioavailability of scopolamine across different routes of administration to ensure therapeutic benefits outweigh any potential adverse cognitive effects.

Humans↗
PubMed1976

Effects of scopolamine and methscopolamine on acquisition and retention of rat one-way shuttle box behavior and total brain acetylcholine.

The effects of scopolamine HBr (0.032 to 10.0 mg/kg), methscopolamine Br (1.0 and 10.0 mg/kg) and 0.36 mg/kg NaBr on acquisition and retention of one-way avoidance behavior and total brain acetylcholine (ACh) were studied in male albino rats. Compared to equimolar NaBr, scopolamine caused a dose-related impairment in acquisition of avoidance responding while methscopolamine did not. Retention of avoidance behavior in trained rats was also disrupted, but the detrimental effect was smaller and occurred only following large doses of scopolamine. The per cent escape behavior was not decreased by any of the treatments. It increased as avoidance was decreased. Scopolamine caused a dose-related increase in latency and avoidance and escape responding compared to equimolar NaBr. However, scopolamine increased the latency of avoidance at lower doses and to a greater degree than it increased the latency of escape. Escape latencies were significantly increased only at the largest dose (10 mg/kg). These dose-related effects of scopolamine were greater during acquisition than during retention. Small doses (0.032 mg/kg) shortened latency of avoidance during retention. Methscopolamine increased avoidance and escape latencies only at the largest dose (10 mg/kg). Scopolamine produced a dose-related decrease in brain ACh which correlated well with the per cent avoidance in acquisition (r = 0.95) and retention (r = 0.88) trials. It is concluded that a muscarinic cholinergic antagonist with central actions like scopolamine affects selective aspects of avoidance behavior in low doses, and that these changes are highly correlated with brain ACh levels.

Acetylcholine↗
PubMed1991

Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine.

Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.

Animals↗
PubMed1976

Scopolamine: effects on fear or defense responses in the rat.

In previous research scopolamine reduced fear or defense responses of rats to a cat, and removal of the rats' olfactory bulbs had the same effect. This suggested that scopolamine might have affected defense responses by blocking olfactory perception of the stimulus cat. The present experiments studied this possibility and explored further the effects of scopolamine on defense responses of the hooded rat. In Experiment 1 rats treated with scopolamine were found to be responsive to olfactory cues from a cat. When cat smell, but not a cat, was present in the apparatus, scopolamine-treated rats showed a large and significant suppression of food consumption. In Experiment 2 the effects of scopolamine on defense responses were shown to be generalizable to an inanimate stimulus, mechanical robot. Scopolamine caused significantly less freezing and avoidance and significantly shorter latencies to drink in the presence of the robot. One of the primary findings of the present research is that scopolamine has now been shown to reduce the defensive response of freezing in a variety of stimulus situations. This finding was thought to have important implications for the literature relating anticholinergic drugs and avoidance behavior.

Animals↗
PubMed1992

Cholinergic blockade with scopolamine in adult cats. Effects on the behaviors evoked by apomorphine and amphetamine.

1. The aim of this work is to analyse the role that the cholinergic system could play in the production of the behaviors evoked by apomorphine and amphetamine in adult cats. These two drugs were injected s.c. in separate sessions, before and after a s.c. administration of scopolamine which blocked the muscarinic receptors. The pre and post-scopolamine results of the behaviors produced by the two catecholaminergic drugs were compared using the non-parametric Wilcoxon signed rank test. 2. In a previous step a dose-response study of the behavioral effects of scopolamine, in doses of 0.05, 0.1, 0.4 and 0.8 mg/kg was carried out in ten cats. The Kruskal-Wallis and the non-parametric multiple comparison tests were employed. A dose-dependent decrease in motility (locomotion) and a dose-dependent increase in inappetence and pupillary dilation were found. 3. In thirteen cats which were injected with 2 mg/kg of apomorphine and 2.5 mg/kg of amphetamine the findings were: 1--apomorphine after scopolamine produced a decrease in the hypermotility, compared with the results observed with the former drug previous to scopolamine; 2--with amphetamine an increase in immobility and a decrease in indifference were observed. 4. The authors conclude that the decrease in motility recorded with apomorphine and amphetamine after scopolamine, could be attributed to the proper effect of scopolamine. No explanation could be found for the decrease in indifference found by injecting amphetamine after scopolamine. 5. Considering the antagonistic effect between the dopaminergic and the cholinergic systems and that the latter one has an arousal effect, we postulate that the behavioral indifference produced by apomorphine and amphetamine could be the result of a kind of blockade of the cholinergic system when the catecholaminergic system is activated through the administration of the two cited drugs.

Amphetamine↗
PubMed1990

Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy.

The authors evaluated the effect of transdermal scopolamine on the incidence of postoperative nausea, retching, and vomiting after outpatient laparoscopy in a double-blind, placebo-controlled study. A Band-Aid-like patch containing either scopolamine or placebo was placed behind the ear the night before surgery. Anesthesia was induced with fentanyl (0.5-2 micrograms/kg iv), thiopental (3-5 mg/kg iv), and succinylcholine (1-1.5 mg/kg iv) and maintained with isoflurane (0.2-2%) and nitrous oxide (60%) in oxygen. Scopolamine-treated patients had less nausea, retching, and vomiting compared with placebo-treated patients (P = 0.0029). Severe nausea and/or vomiting was present in 62% of the placebo group but only 37% of those getting the scopolamine patch. Repeated episodes of retching and vomiting were also less frequent in the scopolamine group compared with the placebo group (23% vs. 41%; P = 0.0213) as was the need for additional antiemetic therapy (13% vs. 32%; P = 0.0013). Patients in the scopolamine group were also discharged from the hospital sooner (4 +/- 1.3 vs. 4.5 +/- 1.5 h; P = 0.0487). Side effects were more frequent among those patients treated with the scopolamine patch (91% vs. 45%; P less than 0.05) but were not troublesome. The authors conclude that transdermal scopolamine is a safe and effective antiemetic for outpatients undergoing laparoscopy.

Administration, Cutaneous↗
PubMed1978

The involvement of catecholamine in scopolamine-induced locomotor activation and rotational behaviour in mice.

Scopolamine-induced locomotor activation was studied in comparison with the responses to apomorphine and methamphetamine in mice. The responses to scopolamine and methamphetamine were markedly depressed by the pretreatment with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, while the activation response to apomorphine was not affected. p-Chlorophenylalanine did not affect the response to scopolamine. Phenoxybenzamine reduced the responses to scopolamine and methamphetamine, but did not affect the apomorphine response. Propranolol did not affect the responses to the three agonists, scopolamine, apomorphine and methamphetamine. Antipsychotic drugs haloperidol and pimozide reduced the responses to the three agonists. Haloperidol was especially effective in this regard. These results suggest the involvement of catecholamine in the locomotor activation produced by scopolamine. In the rotational behaviour model which is sensitive to dopamine receptor stimulating agents, effects of the three agonists were studied. Scopolamine produced the ipsilateral rotation in mice with unilateral striatal 6-hydroxydopamine-induced lesions. Methamphetamine induced the ipsilateral rotation, while apomorphine produced the contralateral rotation. The rotations induced by three agaonists were suppressed by pimozide. The results indicate the participation of dopamine in the scopolamine-induced rotational behaviour in mice.

Animals↗
PubMed1991

Hyperbaric oxygen and scopolamine.

Scopolamine (Hyoscine), an anticholinergic compound is widely used for the prophylaxis and treatment of motion sickness and might be used with oxygen diving and hyperbaric oxygen therapy. We therefore decided to test the interaction of scopolamine with oxygen at high pressure. Thirty-six rats implanted with cortical EEG electrodes were injected subcutaneously with two doses of scopolamine (0.02 or 0.2 mg.kg-1), or the vehicle (saline), 30 min before exposure to 5 atm abs (0.5 MPa) oxygen. Electroencephalogram and heart rate were monitored continuously. Spectral analysis of the EEG was carried out, and the duration of the latent period before convulsions was determined. No significant difference was found in the duration of the latent period between the control rats receiving vehicle (saline) and rats injected with scopolamine (n = 12 for each group). Changes in background EEG activity and maximal dilation of the pupil were detected at both scopolamine doses. Heart rate significantly decreased at 0.02 mg.kg-1 and increased at the dose of 0.2 mg.kg-1 scopolamine. Our findings indicate that the duration of the latent period preceding hyperoxic seizures is not altered by scopolamine in rats; however, other side effects of the drug regarding visual and cardiovascular symptoms should be considered when scopolamine is used in combination with hyperbaric oxygen.

Animals↗
PubMed1990

A comparison of the effects of cholinergic and dopaminergic agents on scopolamine-induced hyperactivity in mice.

The effects of cholinesterase inhibitors, cholinergic agonists, dopaminergic agonists and dopaminergic antagonists on the hyperactivity produced by the muscarinic cholinergic antagonist scopolamine were evaluated in mice. Scopolamine (0.3-10 mg/kg) produced a dose-related increase in locomotor activity, with a peak effect at 3.0 mg/kg. The cholinesterase inhibitor physostigmine (0.03-0.175 mg/kg) was without effect on locomotor activity when administered alone, whereas the cholinesterase inhibitor tetrahydroaminoacridine hydrate (0.3-10 mg/kg) decreased locomotor activity. Both physostigmine and tetrahydroaminoacridine hydrate attenuated the effects of scopolamine. Administered alone, the cholinergic agonists oxotremorine (0.01-0.3 mg/kg) and RS86 (0.1-3.0 mg/kg) produced dose-related decreases in locomotor activity, whereas pilocarpine (0.3-10 mg/kg) had no effect on locomotor activity. None of these three muscarinic agonists significantly attenuated the hyperactivity produced by scopolamine. Administered alone, the dopaminergic agonists quinpirole (0.003-0.1 mg/kg), S-(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (0.3-10 mg/kg) and SKF 38393 (8-64 mg/kg) had no significant effect on activity, whereas apomorphine (0.3-10 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) increased activity. Quinpirole, apomorphine and S-(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine produced dose-related reversals of the increases in locomotor activity produced by scopolamine. The hyperactivity effects of d-amphetamine were approximately additive with scopolamine, whereas SKF 38393 did not significantly affect scopolamine. The mixed D1/D2 dopaminergic antagonist haloperidol (0.003-3.0 mg/kg) and the selective D1 antagonist SCH 23390 (0.01-0.3 mg/kg) produced dose-related decreases in locomotor activity when administered alone, and also produced dose-related reversals of the hyperactivity produced by scopolamine.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Oxiracetam antagonizes the disruptive effects of scopolamine on memory in the radial maze.

The effects exerted by oxiracetam on the disruption of performance induced by scopolamine in the radial arm maze were investigated in overtrained rats. Scopolamine induced a dose-related decrease in the efficiency of responding and an increase of running time. The effect of the SC injection of 0.2 mg/kg scopolamine on the efficiency of responding was antagonized by the IP administration of 30 mg/kg oxiracetam, while the effect on running time induced by the same dose of scopolamine was not. Physostigmine (0.3 mg/kg SC) antagonized both effects of 0.2 mg/kg scopolamine. Methylscopolamine, at the dose of 0.2 mg/kg SC, was devoid of any effect on both parameters. Increasing the dose of methylscopolamine to 0.63 mg/kg did cause serious peripheral effects which eventually prevented some animals from completing the task. Similar peripheral effects were observed after administration of 0.63 mg/kg scopolamine. The effects of this dose of scopolamine on efficiency and running time were not antagonized by pretreatment with 100 mg/kg oxiracetam. Oxiracetam alone (30 or 100 mg/kg IP) did not modify the performance of previously trained rats. The present results suggest that oxiracetam selectively restores cholinergic mechanisms which are involved in learning and memory.

Animals↗