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PubMed1995

Scopolamine prevents augmentation of stereotypy induced by chronic methamphetamine treatment.

Cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. We have previously shown that blockade of muscarinic cholinergic receptors prevents the development of locomotor sensitization to methamphetamine. The present study was conducted to examine whether scopolamine, a muscarinic cholinergic antagonist, would also block augmentation of stereotypy induced by chronic methamphetamine (MA) treatment. Rats treated with MA (2.5 mg/kg, SC) for 10 days indicated significantly enhanced stereotyped behavior when tested with MA (2.5 mg/kg) after a 7- to 8- day withdrawal. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the augmentation of stereotypy. Rats treated with scopolamine alone showed no difference in MA-induced stereotypy compared to those treated with saline. Scopolamine methylbromide, a derivative of scopolamine that does not easily cross the blood-brain barrier, had no effect on the augmentation of stereotypy. These results suggest that stimulation of central muscarinic cholinergic receptors plays a role in the development of sensitization to the stereotypy stimulating effect of methamphetamine.

Animals↗
PubMed1995

Mianserin as a discriminative stimulus in rats: asymmetrical cross-generalization with scopolamine.

The present study was conducted to determine if the tetracyclic antidepressant mianserin could be established as a discriminative stimulus in rats. One group of rats was trained to discriminate mianserin (4.0 mg/kg, IP) from saline in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (0.25 mg/kg, IP) from saline. Generalization testing with the training drugs yielded an ED50 of 0.502 mg/kg for the mianserin-trained rats and an ED50 of 0.048 mg/kg for the scopolamine-trained rats. Asymmetrical cross-generalization between mianserin and scopolamine was observed, because scopolamine produced mianserin-appropriate responding, but mianserin did not produce scopolamine-appropriate responding. This study is the first demonstration that rats can be trained to discriminate mianserin from saline and that antagonism of muscarinic cholinergic receptors is sufficient to produce mianserin-appropriate responding.

Animals↗
PubMed1995

Scopolamine and lorazepam exert different patterns of effects in a test battery assessing stages of information processing.

The effects of a single dose of scopolamine (0.5 mg) SC and of lorazepam (2.5 mg) PO were tested in two independent studies for their effects on performance in a psychometric battery which measured functions related to different stages of information processing. Attention and vigilance were measured by a continuous attention task and a vigilance task, respectively. Working memory and reasoning were evaluated by the rapid information processing and logical reasoning task; memory acquisition and storage were measured by pre- and post-drug immediate and delayed recall using visual material. The following pattern of effects was revealed; both scopolamine and lorazepam impaired performance in attentional and vigilance tasks as well as in the rapid information processing task significantly (P < 0.05) when compared with their own placebo; in the logical reasoning task lorazepam significantly prolonged the time required to solve a problem; scopolamine did not have any effect on this task. Scopolamine impaired performance in the immediate recall but left delayed recall unaffected; lorazepam impaired only delayed recall, immediate recall remaining unaffected. These data suggest that scopolamine at this dose impaired mostly attention and early stages of information processes; lorazepam at the dose tested impaired also the later acquisition and encoding aspects of memory.

Adult↗
PubMed1996

Age-related decline in central cholinergic function demonstrated with scopolamine.

Scopolamine hydrobromide was administered intravenously to 23 normal subjects (40-89 years) in doses of 0.1 mg, 0.25 mg, and 0.5 mg, in a double-blind. Placebo-controlled, random-order fashion. The effects of scopolamine, as compared to placebo, were assessed using a comprehensive cognitive test battery, as well as behavioral and physiological measures. Scopolamine produced the expected dose-dependent impairments in most of the cognitive functions assessed. Behavioral and physiological measures were also affected, but only minimally. More importantly, there was a significant overall correlation between age and scopolamine-impaired performances on psychomotor speed, short-term recall, visual tracking speed, visuo-motor coordination, and sequencing ability. There was, however, some inter-individual variability in this phenomenon. The results provide further evidence that cholinergically mediated cognitive functions show an increased sensitivity to scopolamine with age, albeit with heterogeneity that bears further investigation.

Adult↗
PubMed1992

Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats.

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P less than 0.10) to reduce the amnesia.

Amnesia↗
PubMed1995

The effects of d-cycloserine, a partial agonist at the glycine binding site, on spatial learning and working memory in scopolamine-treated rats.

The present study investigated the effect of d-cycloserine, a partial agonist at the glycine binding site on NMDA receptor complex, on the performance of scopolamine-treated adult rats in a water maze task assessing spatial learning and in a delayed non-matching to position task assessing working memory in a spatial context. In the spatial learning task, scopolamine (0.4 mg/kg, i.p.) impaired acquisition (increased escape latency and distance) and increased swimming speed of rats. D-cycloserine (1.0 mg/kg, i.p.) reversed the deficits in acquisition performance but not the increases in behavioral activity. In the working memory task, scopolamine (0.2 mg/kg, i.p.) produced deficits on nonmnemonic rather than on mnemonic performance factors; scopolamine delay-independently decreased the percent correct responses and reduced behavioral activity of rats. D-cycloserine (1.0, 3.0 and 10 mg/kg, i.p.) did not reverse these performance deficits. When administered alone, the moderate to higher doses of d-cycloserine had no effects on working memory but the lower dose produced slight deficits in mnemonic performance factors; the 1.0 mg/kg dose delay-dependently decreased the percent correct responses without affecting behavioral activity of rats. In the water maze task, d-cycloserine had no effects on acquisition performance or behavioral activity of rats. These results suggest that acute, systemic administration of d-cycloserine does not improve spatial learning or working memory. However, at appropriate doses this agent may be efficacious in disease states of central cholinergic hypofunction since 1.0 mg/kg d-cycloserine was able to reverse the scopolamine-induced deficits in acquisition.

Animals↗
PubMed1986

Contrasting baseline-dependent effects of amphetamine, chlorpromazine and scopolamine on response switching in the pigeon.

Both amphetamine and scopolamine increase low rates and reduce high rates of responding. It has been suggested that the dependence of the effects of these drugs on control rate may be due to their non-specific disruptive cue properties rather than to specific pharmacological actions. To examine whether this possible non-specific disruption also applied to response-choice, pigeons were trained under a schedule in which 30 key-peck responses were required. This fixed-ratio could be completed by responding in any order on either or both of two keys, and then the first switch between the two keys was reinforced by the presentation of food. Under control conditions, the probability of the birds switching between the keys increased as the ratio progressed, resulting in performance which could be analysed in a manner analogous to rate-dependent analyses of responding under fixed-interval (FI) schedules. The birds were then treated with amphetamine (0.4-3.2 mg/kg), chlorpromazine (1.0-30 mg/kg) and scopolamine (0.01-0.10 mg/kg). Amphetamine increased switching at all baselines, to probabilities greater than chance (i.e. P. switch greater than 0.5). Scopolamine resulted in response choice converging towards chance, whereas chlorpromazine reduced switching when the baseline probabilities were high. Thus: amphetamine increases switching in pigeons as it has previously been shown to do in rats, and this effect is not due to regression towards random choice, the opposite effect of a reduction in switching can occur after chlorpromazine treatment, and whereas the effects of amphetamine and scopolamine on response rate may be similar, the effects of the two drugs on response choice are dissociable, with only scopolamine resulting in a randomisation of performance.

Animals↗
PubMed2003

Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats.

RATIONALE: Cholinergic receptor blockade produces memory deficits in animal models. These deficits can be prevented by 5-HT3 receptor antagonists, such as ondansetron, which increases acetylcholine release. We investigated the effects on cognitive performance of combined treatments of ondansetron with either flumazenil, a GABA(A) receptor benzodiazepine site antagonist, or tacrine, a cholinesterase inhibitor, which are also able to prevent scopolamine-induced cognitive impairment. METHODS: Spatial learning and memory was assessed by studying the effects of single and combined treatments on acquisition and retention of the Morris water maze task in rats. RESULTS: Scopolamine (0.6 mg/kg) induced significant learning and retention deficits. Both ondansetron (0.1 microg/kg) and tacrine (3 mg/kg) partially prevented the scopolamine-induced learning deficit. A full reversal was only found after the combined treatment of ondansetron with flumazenil (10 mg/kg) and also after tacrine in combination with ondansetron. Likewise, scopolamine-induced retention deficit was fully counteracted by the combined treatment of ondansetron with either flumazenil or tacrine, and only partially by any of the single treatments tested. CONCLUSIONS: The scopolamine-induced impairment of learning and retention in the water maze is fully prevented by ondansetron when given in combination with either flumazenil or tacrine, suggesting that both combined treatments result in a potentiated cholinergic function and may constitute the basis of a new therapy for cognitive disorders.

Animals↗
PubMed2006

Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping.

RATIONALE: Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. OBJECTIVES: The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. MATERIALS AND METHODS: The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. RESULTS: Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance). CONCLUSIONS: These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.

Animals↗
PubMed2000

Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats.

RATIONALE: Rolipram, a selective inhibitor of cyclic AMP-specific phosphodiesterase (PDE4), has been shown to enhance scopolamine-induced impairment of working memory. However, its effect on reference memory, which appears to be related to the level of cyclic AMP (cAMP), has not been investigated yet; in addition, the mechanism involved in its effects on memory remains to be elucidated. OBJECTIVES: To investigate the effects of rolipram on working and reference memories impaired by scopolamine and the involvement of cAMP. METHODS: By administration (IP) of rolipram and forskolin, an activator of adenylyl cyclase (AC), the effects of both drugs on the number of correct choices and errors in experiment 1 and, the frequency of both working memory errors and reference memory errors in experiment 2 were observed in two eight-arm radial maze tasks in rats. RESULTS: In experiment 1, rolipram (0.01-1.0 mg/kg) attenuated the scopolamine-induced (0.5 mg/kg) increase in the total number of errors in dose- and time-dependent manners. The minimum effective dose of rolipram was 0.05 mg/kg and the effects lasted nearly 60 min. By contrast, forskolin (1.0-10.0 mg/kg) failed significantly to affect any of the above indices altered by scopolamine. In experiment 2, rolipram (0.05 and 0.1 mg/kg) decreased the frequencies of both working and reference memory errors that were elevated by scopolamine. Forskolin did not alter either type of error at a dose that increased the exploration time. CONCLUSION: Rolipram may exert its effects of reversing both working and reference memory impairments via increased cyclic AMP concentrations in certain signal transduction pathways, rather than by a generalized increase in cAMP.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Acute dose-effects of scopolamine on false recognition.

RATIONALE: Recently, there has been increased research interest in the phenomenon of false recognition, in which participants claim to recognize words that had not been presented during an initial study phase but that are associatively related to presented words. Acute administration of the benzodiazepine hypnotic triazolam has been shown to decrease false recognition rates. However, no false recognition studies have examined the effects of scopolamine, an anticholinergic drug that might produce a different profile of memory-impairing effects than the benzodiazepines due to its distinct neurochemical profile. OBJECTIVE: This study was designed to examine the acute dose-effects of scopolamine on false recognition. METHODS: The effects of subcutaneously administered scopolamine (0.3 and 0.6 mg/70 kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated-measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: Scopolamine produced dose-related reductions in both true and false recognition rates, and induced a more conservative response bias relative to placebo for recollection-based ("remember") responses to studied words. CONCLUSIONS: While scopolamine's effects on false recognition are similar to those observed previously with triazolam, its effects on response bias may differ from those of triazolam.

Adult↗
PubMed1997

Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia.

Two experiments examined dose-related effects of 200, 400 and 600 micrograms scopolamine (n = 24, s.c.) and 5 and 10 mg diazepam (n = 6, PO) on parallel tests of visual memory and learning taken from the CANTAB battery. Scopolamine significantly impaired accuracy of performance on a delayed matching to sample test of visual recognition memory in a dose- and delay-dependent manner, but had only marginal decremental effects on a test of visuospatial paired associates learning. Scopolamine significantly lengthened decision times in a visual search matching to sample task at the 400 and 600 micrograms doses, without significantly affecting accuracy. The drug also impaired performance on tests of spatial (on accuracy and response time measures) and pattern (on response time only) memory. Most of the deleterious effects on scopolamine were removed by covariance analyses with indices of subjective sedation, but the effects of delayed matching accuracy and latency remained. By contrast, diazepam significantly impaired paired associates learning but affected delayed matching to sample in a delay-independent manner. These results suggest that scopolamine can produce selective deficits in tests of short-term visual recognition memory which do not depend on overall impairments in arousal and which contrast with deficits in visual associative learning produced by diazepam. They have implications for the pharmacological modelling of dementia and memory disorders in man and for the neurochemical substrates of the short-term recognition memory and associative learning for visual stimuli.

Adult↗
PubMed1993

Influence of transdermal scopolamine on cardiac sympathovagal interaction after acute myocardial infarction.

In 41 survivors of acute myocardial infarction (AMI) a prospective study was performed in 2 sequential phases. In phase 1, the role of baroreflex sensitivity and heart rate variability as predictors of inducible and spontaneous sustained ventricular tachyarrhythmias was evaluated. In phase 2, the effects of transdermal scopolamine on baroreflex sensitivity, spectral and nonspectral measures of heart rate variability were investigated. At a mean follow-up of 10 +/- 3 months after AMI, 5 of 41 patients (12%) developed a late arrhythmic event. Of these, all (100%) had inducibility of sustained monomorphic ventricular tachycardia at programmed stimulation compared with 3 of 36 patients (8%) without events (p < 0.0001). At multivariate analysis, baroreflex sensitivity had the strongest relation to both inducibility of sustained monomorphic ventricular tachycardia (p < 0.0001) and occurrence of arrhythmic events (p < 0.0001). Of 41 patients, 28 (68%) consented to undergo phase 2 of the investigation. Baroreflex sensitivity significantly (p < 0.00001) increased after transdermal scopolamine as well as heart rate variability indexes. Of these, the mean of SDs of normal RR intervals for 5-minute segments (p < 0.0001) and the total power (p < 0.0001) had the most significant improvement after scopolamine. The present investigation confirms that assessment of autonomic function is an essential part of arrhythmic risk evaluation after AMI. Transdermal scopolamine, administered to survivors of a recent AMI, reverses the autonomic indexes that independently predict arrhythmic event occurrence. On the basis of these data, transdermal scopolamine could be a potential useful tool in the prophylaxis of life-threatening ventricular arrhythmias after AMI.

Administration, Cutaneous↗
PubMed1988

Effects of scopolamine treatment on long-term behavioral deficits following concussive brain injury to the rat.

Scopolamine (0.1, 1.0, or 10.0 mg/kg) or saline was systemically (i.p.) administered to rats 15 min prior to concussive fluid percussion brain injury. Animals pretreated with the 1.0 mg/kg dose exhibited significantly (P less than 0.05) less motor deficits and less body weight loss and recovered to baseline performance sooner than saline-treated rats. Mortality and associated convulsions were significantly lower in rats pretreated with the 1.0 mg/kg dose of scopolamine. A 1.0 mg/kg dose of scopolamine administered (i.p.) 30 s after injury also significantly reduced behavioral deficits. No differences were observed between saline- and scopolamine-treated animals in either the incidence or duration of transient apnea following injury. A 1.0 mg/kg dose of scopolamine administered (i.p.) 15 min prior to epidural clip compression of the spinal cord had no effect on the severity of motor function deficits assessed by an inclined plane test. The data from these experiments suggest muscarinic cholinergic involvement in at least some of the long-term behavioral deficits following mild and moderate levels of brain injury. These results suggest that muscarinic cholinergic antagonists may prove beneficial in the treatment of human head injury.

Animals↗
PubMed1992

Postinjury scopolamine administration in experimental traumatic brain injury.

A single bolus dose of scopolamine (1.0 mg/kg) or saline (equal volume) was injected (i.p.) at 15, 30 or 60 min after fluid percussion traumatic brain injury in the rat. Scopolamine administered at 15 min postinjury significantly reduced beam walking deficits and body weight loss assessed for 5 days after injury. Scopolamine treatment at 30 or 60 min postinjury had no effect on behavioral outcome assessed for 5 days after injury. Plasma concentrations of scopolamine were measured with a radioreceptor assay. The plasma half-life for scopolamine was 21.6 min in injured rats and 17.3 min in normal rats (P less than 0.05). These results, along with evidence from previous studies, suggest that a brief period of excessive neuronal excitation can produce relatively long-lasting behavioral deficits. The temporal effectiveness of receptor antagonist intervention in this process appears to be brief.

Animals↗
PubMed1994

Scopolamine abolishes cerebral blood flow response to somatosensory stimulation in anesthetized cats: PET study.

The effect of the cholinergic blocker, scopolamine on the cerebral blood flow (CBF) response to vibrotactile stimulation of a fore paw was studied using high-resolution positron emission tomography and H2 15O in 5 pentobarbital-anesthetized cats. Before scopolamine injection, the CBF response to the stimulation was found in the contralateral somatosensory cortex (mean ratio (contralateral/ipsilateral) control: stimulated 1.02 +/- 0.02: 1.17 +/- 0.05; P < 0.01). After intravenous injection of scopolamine (0.35 mg/kg), the CBF response was abolished. However, the cerebral metabolic rate of glucose (CMRGlu) response to the same stimulation was unchanged after scopolamine injection in the same cats. We concluded that scopolamine abolishes the CBF response but not neuronal response to stimulation. We suggest that cholinergic mechanisms may play an important role for mediating CBF coupling to neuronal activity during physiological stimulation.

Anesthesia↗
PubMed1994

Effects of a single intravenous dose of scopolamine on the quantitative EEG in Alzheimer's disease patients and age-matched controls.

Quantitative EEG (qEEG) was evaluated in Alzheimer's disease (AD) patients and age-matched controls following the administration of a single acute intravenous dose of scopolamine. Eleven AD patients and 8 cognitively intact age-matched controls underwent qEEG in baseline conditions, following double-blind intravenous administration of 0.5 mg scopolamine or placebo. At baseline, AD patients had significantly decreased absolute and relative alpha and increased relative theta amplitudes. In both groups, scopolamine administration was followed by a decrease in absolute and relative alpha amplitude, and increase in the absolute and relative delta activity. The increase in the absolute and relative delta amplitude by scopolamine was significantly more prominent in the controls; the decrease of alpha activity, while larger in controls, was not statistically different from AD. We conclude that scopolamine affects the change in delta amplitude differently in AD patients and controls, probably reflecting the reduced cholinergic tone in AD.

Aged↗
PubMed1984

Social play in juvenile rats during scopolamine withdrawal.

Scopolamine induced blockade of play fighting in juvenile rats and the rapid induction of behavioral tolerance to an initially effective dosage suggested a rebound in social play following chronic scopolamine exposure. Juvenile rats received daily intraperitoneal scopolamine or saline injections for one week. Play soliciting and play fighting behavior were then measured at 24 and 168 hr after drug withdrawal. Scopolamine treated juveniles engaged in markedly greater play soliciting and play fighting behavior than did controls. Drug-induced increase in muscarinic receptors and supersensitivity to endogenous acetylcholine following scopolamine withdrawal is suggested as the basis for observed differences in social play.

Acetylcholine↗