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PubMed1995

Scopolamine impairs acquisition and facilitates consolidation of fear conditioning: differential effects for tone vs context conditioning.

Cholinergic antagonism impacts selected learning tasks. To understand where scopolamine exerts its action, learning tasks differentially sensitive to hippocampus and amygdala lesions were used. Hippocampal lesions prevent context fear conditioning without effect on tone conditioning. These lesions also produce a time-dependent retrograde deficit in context conditioning. The amygdala is necessary for both tone and context conditioning. To examine the possibility that cholinergic antagonism mimics hippocampal damage or amygdala damage, rats were given scopolamine (1 mg/kg) either before or after fear conditioning. In the fear conditioning procedure, rats received tone-footshock or context-footshock pairings. Evidence of conditioning to the tone and the context was provided by observation of freezing. When given prior to training, scopolamine blocked fear conditioning to the tone in a dose-dependent fashion but had no effect on context conditioning. The impairment of tone conditioning did not occur with methylscopolamine, indicating the central action of the drug. Rats given scopolamine immediately following fear conditioning, tested later in a drug-free state, froze more to the tone than rats given a control injection. The effect of scopolamine on freezing to the context was not reliable. The present results suggest that scopolamine's impact on fear conditioning is mediated by some mechanism other than impaired hippocampal or amygdala functioning.

Acoustic Stimulation↗
PubMed1989

Scopolamine treatment and fimbria-fornix lesions: mimetic effects on radial maze performance.

Long-Evans female rats were "trained" in an 8-arm radial maze and subsequently tested under systemic treatment with physostigmine (0.05 mg/kg, IP), scopolamine methylbromide (MBr) and scopolamine hydrobromide (HBr; 0.5 mg/kg, IP), whose effects were compared to those of aspirative lesions of the fimbria-fornix pathways. During the predrug trials, rats with lesions showed impaired performances compared to those of intact rats. Whereas physostigmine had no significant effect in either group, scopolamine HBr impaired performances of intact rats in a manner closely parallel to all measured behavioral effects of the lesions (errors, "correct arms" and strategies). The scopolamine HBr-induced deficits were not correlated with the percentage of "spatial" strategies. Under scopolamine HBr treatment the performances of rats showing preferences for "spatial" strategies did not differ significantly from those of rats showing preferences for "orientation" strategies. These results provide further support for the involvement of cholinergic processes in working memory and suggest that scopolamine-induced central cholinergic disruption may mimic the effects of fimbria-fornix lesions in an 8-arm radial maze. They also somewhat qualify previous reports on 1) the poor sensitivity of an uninterrupted radial maze testing procedure to pharmacological treatment and 2) the abilities of rats to resist muscarinic blockade depending on the strategies they use in the maze.

Animals↗
PubMed1993

Comparison of the effects of scopolamine and methylscopolamine on the performance of a fixed-ratio discrimination in squirrel monkeys.

In the presence of a stimulus behind the center key, squirrel monkeys were required to complete one of two fixed ratios (FRs) on the center key (FR 30 or FR 25). Completion of the ratio turned off the center-key stimulus and produced a stimulus behind each of the two side keys. If the completed ratio was high (e.g., FR 30), a response on the left key produced a food pellet. If the ratio was low (e.g., FR 25) a response on the right key produced food. Errors produced a brief timeout. Dose-effect curves for scopolamine (0.001-0.18 mg/kg) and methscopolamine (0.0032-5.6 mg/kg) were determined under a FR 30 vs. FR 25 discrimination, which controlled both moderate levels of accuracy and high rates of responding. Scopolamine produced a dose-related decrease in overall response rates and increase in percent errors. Methscopolamine decreased response rates and increased percent errors in a dose-related manner much like scopolamine. However, scopolamine was found to be about 10 times more potent on a mg/kg basis than methscopolamine. Scopolamine is in general considered to be centrally acting due in part to its lipid solubility. The results from these studies suggest that methscopolamine, in general considered to be peripherally acting, may also cross the squirrel monkey blood-brain barrier at high doses and produce behavioral effects comparable to those of scopolamine.

Animals↗
PubMed1992

Scopolamine deficits in negative patterning discrimination: evidence for a role of the central cholinergic system in retention but not acquisition of non-spatial configural association learning.

The effects of scopolamine (0.1 mg/kg s.c. and 0.6 mg/kg s.c.) were assessed on the acquisition and retention of a negative patterning discrimination task in rats. At 0.1 mg/kg scopolamine did not affect either acquisition or retention of the task. At 0.6 mg/kg scopolamine did not affect acquisition but did impair retention of the task. This impairment is likely to be centrally mediated as N-methyl scopolamine (0.6 mg/kg s.c.) did not affect retention. Lack of effect of scopolamine on acquisition of the task indicates that the central cholinergic system is not a necessary substrate of the acquisition of non-spatial configural associations. The scopolamine-induced deficit in retention of the task, suggests that there may, however, be a central cholinergic involvement in the retention/retrieval of this type of learning.

Amphetamine↗
PubMed1998

Scopolamine-induced cognitive impairment as a predictor of cognitive decline in healthy elderly volunteers: a 6-year follow-up.

OBJECTIVE: To determine if scopolamine-induced cognitive impairment in healthy elderly people predicts cognitive decline 6 years later. DESIGN: Prospective cohort study. SETTING: Elderly care research unit. PARTICIPANTS: Healthy elderly people who were part of a volunteer panel of research subjects. INTERVENTIONS: Scopolamine 0.2 mg administered subcutaneously at baseline. MAIN OUTCOME MEASURES: Cognitive drug research computerized cognitive testing battery pre- and post-scopolamine, with repeat testing over 6 years later. MAIN RESULTS: 16/24 subjects were retested. Although marked decrements in cognitive functioning were seen with scopolamine, there was little change in performance over 6 years, and no significant association was seen between scopolamine-induced decrement and change over time. CONCLUSIONS: The scopolamine challenge test is not likely to play a role in the preclinical diagnosis of Alzheimer's disease.

Aged↗
PubMed1975

Effects of repeated doses of scopolamine on the electroencephalographic stages of sleep in normal volunteers.

Single doses of scopolamine markedly alter sleep patterns in man. This study intended to evaluate the persistence of these changes during continued administration. The design consisted of a sequence of habituation, no-medication, saline (control), scopolamine (0.006 mg/kg intramuscularly 3 consecutive nights), and saline. The first dose of scopolamine markedly retarded the onset of stage rapid eye movement (REM) sleep (p less than 0.005) and diminished the total amount of REM sleep during the night (p less than 0.025). A decrease in total number of eye movements (p less than 0.05) and an increase in body movements (p less than 0.025) were also observed. Changes after the second dose of scopolamine were less marked but still significant. The third dose of scopolamine produced less marked changes than the preceding two. When compared with the first scopolamine night, the onset of stage REM was retarded to a lesser extent (p less than 0.05) and the total amount of REM sleep was increased (p less than 0.05). An increase in the duration of the first REM period was also observed. Rebound effects on the appearance of the first REM period (p less than 0.01), number of eye movements (p less than 0.001), total amount of REM sleep (p less than 0.01), and body movements were observed in the last saline night.

Adult↗
PubMed1988

Interaction of alcohol and transdermally administered scopolamine.

In a placebo-controlled, randomized, double-blind cross-over study in 12 healthy volunteers the effect of acute alcohol intake during treatment with transdermally administered scopolamine (TTS-scopolamine) was investigated. One group of six subjects reached maximal blood alcohol concentrations (BAC) of 80 mg/dL and another group of six subjects a BAC of 130 mg/dL. There was no significant potentiation of alcohol effects on critical flicker fusion frequency by TTS-scopolamine. Sensorimotor function (choice reaction task) was also not significantly more influence by the combination. There was no effect of scopolamine on the elimination of alcohol. The urinary excretion of scopolamine was not influenced by oral intake of alcohol. TTS-scopolamine caused only minor side effects in a few volunteers, such as dry mouth (2 of 12) and blurred vision (1 of 12).

Administration, Cutaneous↗
PubMed2000

Effects of glucose on scopolamine-induced learning deficits in rats performing the Morris water maze task.

In order to assess the effects of glucose on drug-induced spatial learning deficits, three experiments were conducted using the Morris water maze. Scopolamine and glucose were injected ip at various stages of training. Rats of Wistar strain served as subjects. In Experiment 1, scopolamine (0.4 mg/kg) and 10, 100, or 500 mg/kg of glucose were administered every day from the start of training, and the effect on acquisition was evaluated. In Experiment 2, scopolamine and 100 or 500 mg/kg of glucose were administered after 6 days of training, and the effect on performance was assessed. In Experiment 3, scopolamine and 500 mg/kg of glucose were injected after 2 days of training, and the effect on the following trial was tested. In all experiments, scopolamine impaired acquisition/performance of the task. Glucose at 500 mg/kg showed a significant enhancing effect on acquisition regardless of scopolamine injection only when injected daily from the start of training (Experiment 1). Glucose injected after the performance has reached asymptote (Experiment 2) did not affect performance, and glucose in the middle of training showed a slight but insignificant enhancing effect (Experiment 3). These results may suggest that the effect of glucose changes as a function of the degree of learning of the spatial learning task. The possibility of task specificity of the glucose effect was also discussed in relation to the cholinergic systems and local cerebral glucose utilization.

Animals↗
PubMed1988

Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines.

Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.

Animals↗
PubMed1988

Scopolamine produces environment-specific conditioned activity that is not blocked by pimozide in rats.

A classical conditioning paradigm was employed to determine if the stimulant effects of the anticholinergic scopolamine could show conditioning. In experiment 1 rats had 12 60-min pairings of scopolamine (1.0 or 8.0 mg/kg, IP) with a distinctive environment that monitored horizontal and vertical activity. Experimental (paired) groups received the drug 30 min prior to each session, whereas control (unpaired) groups received saline. Following each session the Paired groups were injected with saline, and the Unpaired groups received the same doses of scopolamine. After every fourth pairing a test session assessed conditioning by comparing activity of paired und unpaired groups in response to saline. Scopolamine enhanced horizontal activity, although conditioning was seen only with 8.0 mg/kg. The low dose increased vertical activity, whereas an initial decrease was observed with 8.0 mg/kg. However, conditioned vertical activity was seen with both doses. Experiment 2 assessed the possible role of dopamine in conditioning with 8.0 mg/kg scopolamine. Rats treated as in experiment 1 were additionally given 0.4 mg/kg pimozide 4 h prior to each pairing session. Pimozide did not block scopolamine's stimulant effect. Conditioned horizontal and vertical activity were also observed, suggesting that this effect may be mediated by direct changes within cholinergic systems.

Animals↗
PubMed1994

Different effects of scopolamine on extracellular acetylcholine levels in neostriatum and nucleus accumbens measured in vivo: possible interaction with aversive stimulation.

The in vivo microdialysis technique was used to measure extracellular concentrations of acetylcholine (ACh) in the neostriatum (NS) and nucleus accumbens (NAc) of freely moving rats after intraperitoneal administration of the muscarinic receptor antagonist scopolamine (0.5 mg/kg) or vehicle. Simultaneously, behavior was monitored. The administration of scopolamine induced an increase in extracellular ACh levels in the NS, which reached a maximum of about 185% within one hour after injection and returned to baseline values about three hours after injection. In the NAc, an increase of similar time-course was observed; however, this increase reached a maximum of 250%, which was significantly higher than the one observed in NS. These changes in ACh levels were accompanied by enhanced locomotion, rearing and grooming; however, the behavioral changes were of shorter time-course than those of extracellular ACh. The injection of vehicle did not affect ACh levels in NS, but induced a significant increase (60%) in the NAc. The levels of behavioral activity after vehicle injection did not differ from pre-injection levels. These results suggest, that the cholinergic systems in the NAc and NS are differently affected by peripheral administration of both scopolamine and vehicle. The differential effects of scopolamine in NS and NAc could reflect pharmacodynamic differences between these two striatal brain areas, perhaps due to a higher density of cholinergic interneurons or muscarinic autoreceptors in the NAc in comparison to the NS. However, the increase of extracellular ACh observed after vehicle injection suggests that factors such as aversive stimulation through the injection procedure can increase ACh release in the NAc and that such a mechanism can interact within the action of scopolamine. Thus, the stronger action of scopolamine on extracellular ACh in the NAc might be an additive effect of the drug with that of the injection procedure.

Acetylcholine↗
PubMed1993

Effects of acute doses of oxiracetam in the scopolamine model of human amnesia.

The scopolamine model of amnesia has been used to test the pharmacodynamic efficacy of oxiracetam in 12 healthy volunteers. The subjects were divided into four experimental groups, according to a double-blind cross over incomplete randomized block design. After a baseline neuropsychological examination, each subject received in two separate sessions one of the following treatments, as acute oral doses: oxiracetam 800, 1600, 2400 mg or placebo. One hour after treatment scopolamine hydrobromide (0.5 mg) was given subcutaneously. The cognitive performance was tested before and 1, 2, 3 and 25 h after scopolamine administration. Scopolamine caused a deterioration of performance of verbal episodic memory, semantic memory and attention tests. In comparison to placebo, oxiracetam improved the overall test performance, with a statistically significant difference at the dose of 1600 mg on delayed recall of word lists, and showed dose-related antagonism of scopolamine-induced effects also on semantic memory and attention. The efficacy of an acute dose of oxiracetam in reducing scopolamine-induced cognitive impairment supports the potential usefulness of this pharmacological model of amnesia for studying the effects of cognition enhancers in humans.

Adult↗
PubMed1992

Hypersensitivity to scopolamine in the elderly.

Scopolamine hydrobromide, 0.43 mg/70 kg, was administered by subcutaneous injection to ten young and ten elderly subjects. A comprehensive neuropsychological test battery was used to assess the effects of scopolamine, as compared to placebo, on cognitive function. As previously reported for this group of young subjects, scopolamine significantly impaired performance on tests of recent memory and visuospatial praxis. The same effects were observed in the elderly subjects, but the magnitude of the effects was much larger. The scopolamine injections produced significant psychomotor slowing in the elderly, whereas higher doses of the drug are required to produce this effect in young subjects. In both young and old subjects scopolamine failed to affect immediate memory, language function, object sorting, and the frequency of intrusion errors (although trends toward an effect were more apparent in the elderly). Remote memory, tested in the elderly only, was also unaffected. The results suggest that scopolamine's cognitive effects are quantitatively more pronounced in elderly subjects than young subjects, but that they are qualitatively similar and do not constitute a valid model for the cognitive dysfunction associated with Alzheimer's disease.

Adolescent↗
PubMed1995

Caffeine attenuates scopolamine-induced memory impairment in humans.

Caffeine consumption can be beneficial for cognitive functioning. Although caffeine is widely recognized as a mild CNS stimulant drug, the most important consequence of its adenosine antagonism is cholinergic stimulation, which might lead to improvement of higher cognitive functions, particularly memory. In this study, the scopolamine model of amnesia was used to test the cholinergic effects of caffeine, administered as three cups of coffee. Subjects were 16 healthy volunteers who received 250 mg caffeine and 2 mg nicotine separately, in a placebo-controlled double-blind cross-over design. Compared to placebo, nicotine attenuated the scopolamine-induced impairment of storage in short-term memory and attenuated the scopolamine-induced slowing of speed of short-term memory scanning. Nicotine also attenuated the scopolamine-induced slowing of reaction time in a response competition task. Caffeine attenuated the scopolamine-induced impairment of free recall from short- and long-term memory, quality and speed of retrieval from long-term memory in a word learning task, and other cognitive and non-cognitive measures, such as perceptual sensitivity in visual search, reading speed, and rate of finger-tapping. On the basis of these results it was concluded that caffeine possesses cholinergic cognition enhancing properties. Caffeine could be used as a control drug in studies using the scopolamine paradigm and possibly also in other experimental studies of cognitive enhancers, as the effects of a newly developed cognition enhancing drug should at least be superior to the effects of three cups of coffee.

Adult↗
PubMed1995

The effects of scopolamine, lorazepam, and glycopyrrolate on classical conditioning of the human eyeblink response.

Human eyeblink conditioning, a relatively simple form of learning and memory, has previously been shown to be impaired by the central and peripheral anticholinergic scopolamine. The present study compared the behavioral effects of scopolamine with the benzodiazepine lorazepam and a peripherally active anticholinergic, glycopyrrolate. Thirty-six healthy normal volunteers (mean age: 23.7 years) were studied with 12 assigned double-blind to each of three drug conditions (0.5 mg scopolamine IV, 2 mg lorazepam PO, or 0.2 mg glycopyrrolate IV). Subjects underwent classical conditioning of the eyeblink response in which the conditioned stimulus was an 80 dB binaural tone, and the unconditioned stimulus was a 2 psi airpuff to the right eye. Ten trials of unpaired stimulus presentations were followed by 60 paired trials and finally by an extinction period of five tone-alone presentations. An eyeblink response that occurred during the tone but before the airpuff was scored as a conditioned response (CR). Subjects treated with lorazepam (43% mean CRs) and scopolamine (51% mean CRs) exhibited a significantly lower asymptotic level of conditioning than those treated with glycopyrrolate (85% mean CRs; P < 0.01). However, during extinction, lorazepam-treated subjects (35% CRs) showed a lower overall level of responding to the tone than either scopolamine (60% CRs) or glycopyrrolate (62% CRs) treated subjects (P < 0.05). It seems unlikely that these differences could be accounted for by drug-induced alterations in motor responses because there were no significant differences between the three drug conditions in the frequency, latency, or amplitude of unconditioned responses to the airpuff. Overall, our data indicate that scopolamine and lorazepam impair eyeblink conditioning and suggest that some of the effects of benzodiazepines and anticholinergics on learning and memory can be differentiated using this paradigm.

Adult↗
PubMedDate not supplied

The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure.

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.

Aging↗
PubMed2003

Separate and combined effects of scopolamine and nicotine on retrieval-induced forgetting.

RATIONALE: Proficiency of information processing is likely to derive from a combination of effective processing of relevant information and efficient inhibition of unwanted or irrelevant material. Compromised inhibitory processes have been associated with the memory deficits in dementia and the elderly. These deficits in inhibition could be directly related to the reduced cholinergic function evident in dementia of the Alzheimer type (DAT). Scopolamine, a cholinergic antagonist, has been associated with disinhibition. Nicotine, a cholinergic agonist, has been associated with enhanced focus and reduced intrusions in both healthy adults and people with dementia. OBJECTIVE: This study examines the separate and combined effects of nicotine and scopolamine on inhibitory processes using retrieval induced forgetting (RIF). METHODS: In two studies, minimally deprived smokers received either nicotine or no nicotine, in the second study combined with placebo, 0.3 or 0.5 mg SC scopolamine. All volunteers completed the RIF procedure providing within-subject measures of inhibition in an episodic recall paradigm. RESULTS: Nicotine did not modulate recall of practised exemplars but it did increase inhibition of unpractised exemplars. Consistent with an effect on encoding, scopolamine reduced recall for all exemplars. Scopolamine did not differentially affect practised or unpractised exemplars, relative to the control words. CONCLUSION: Independent of its potential to influence memory at encoding, nicotine can affect task performance by inhibiting unpractised (and by implication, irrelevant) material, thereby reducing interference and benefiting the task in hand. The absence of effects of scopolamine on inhibition in the RIF paradigm argues for a more complex subdivision of "inhibitory" processes, which may be differentially influenced by cholinergic blockade.

Adult↗
PubMed2004

Dose-specific effects of scopolamine on canine cognition: impairment of visuospatial memory, but not visuospatial discrimination.

RATIONALE: The cholinergic system is linked extensively to memory, but its exact role remains controversial. In particular, scopolamine-induced impairment in rodents is not task specific, which may be due to difficulty in developing rodent protocols to assess deficits in recent memory, in which the remembered event is brief and distinct, and/or to non-specific behavioral impairment. OBJECTIVES: The present study sought to determine whether scopolamine-induced deficits in recent memory, using a working memory task, could be dose-specifically dissociated from deficits in associative memory in dogs. METHODS: A Latin-square design was used to determine the effect of scopolamine (5, 10 and 15 microg/kg; SC) on a variable delayed-non-matching-to-position (DNMP) task, which assesses visuospatial working memory. Subsequently, the minimal effective dose (15 microg/kg; SC) was administered prior to testing on a landmark discrimination task, which provides a measure of allocentric spatial ability, a black-white discrimination task, an oddity discrimination task and tests of exploratory behavior. We also investigated the effects of a 30 microg/kg dose (SC) on tests of oddity discrimination and behavioral activity. RESULTS: A 15 microg/kg dose produced significant impairment on the DNMP task, but did not affect performance of any discrimination task and did not alter behavior on tests of open field or curiosity. A 30 microg/kg dose caused disruption on discrimination performance and on open field measures. CONCLUSIONS: Working memory performance is most sensitive to scopolamine-induced impairment and can be dissociated from scopolamine-induced deficits in discrimination performance and non-cognitive behaviors. The present results indicate that scopolamine-induced impairments of working memory in the dog can serve as a model of age-related cholinergic dysfunction.

Aging↗