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PubMedDate not supplied

Intracerebral scopolamine administration attenuates Pavlovian heart rate conditioning in the rabbit.

Scopolamine hydrobromide was injected into the septum, dorsal hippocampus, or lateral ventricles of conscious rabbits via bilateral chronic indwelling cannulas. The cardiac orienting reflex (OR) and heart rate (HR) classical conditioning were assessed. A fourth group of animals received injections of the vehicle solution into these same brain areas and were otherwise similarly trained. Scopolamine had no effect on the cardiac OR produced by unreinforced tone stimuli. The OR consisted of pronounced bradycardia that habituated over successive trials in all groups. The HR change during classical conditioning also consisted of bradycardia. However, these conditional HR changes were attenuated by scopolamine injected into the septum and lateral ventricles, but were not affected by injections into the dorsal hippocampus. These results suggest that centrally applied scopolamine may affect a central nervous system associative process, and not a mechanism directly involved in primary bradycardia.

Animals↗
PubMed2002

Self-administration of cocaine: scopolamine combinations by rhesus monkeys.

RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent dopamine (DA) uptake inhibitors with diminished reinforcing effects relative to cocaine. In addition to their effects on DA uptake, these compounds are potent muscarinic cholinergic antagonists. OBJECTIVES: The present experiments were designed to examine the hypothesis that the anticholinergic action of the BZT analogs contributes to their relatively low levels of self-administration. METHODS: Rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under either a fixed-ratio 25 (FR 25; n=5) or progressive-ratio (PR; n=5) schedule until stable responding was established. Saline, cocaine (0.0003-0.1 mg/kg per injection), scopolamine (0.001-0.1 mg/kg per injection), or various combinations of cocaine and scopolamine were then made available for self-administration. RESULTS: Cocaine maintained dose-related self-administration under both schedules whereas scopolamine did not. In the majority of cases, combinations of cocaine and scopolamine maintained less self-administration than cocaine alone. CONCLUSIONS: This study supports the hypothesis that anticholinergic actions contribute to the diminished self-administration of BZT analogs relative to cocaine. The mechanism may involve antagonism of the reinforcing effect of cocaine and/or punishment of the self-administration response by the addition of an anticholinergic component of action.

Animals↗
PubMed2003

Assessment of a combination of physostigmine and scopolamine as pretreatment against the behavioural effects of organophosphates in the common marmoset (Callithrix jacchus).

RATIONALE: There is a requirement to ensure that UK armed forces are provided with the best possible medical countermeasures to prevent or mitigate the effects of exposure to nerve agents. When pretreatments are under consideration, it is of particular importance to ensure that they do not in themselves give rise to adverse effects and do not exacerbate the effects of agent exposure. OBJECTIVES: The present study was designed to address these considerations for a combination of physostigmine and scopolamine as a potential pretreatment regimen. METHODS: Common marmosets were trained to perform a two-choice discrimination serial reversal task, and baseline data were collected. Subjects received a dose of either soman or sarin after 2 weeks of pretreatment with either saline or physostigmine and scopolamine via miniosmotic pump. RESULTS: No effects of physostigmine and scopolamine were seen on task accuracy or response rates. Neither accuracy of reversal performance nor number of responses made were significantly changed by administration of either soman or sarin subsequent to pretreatment with physostigmine/scopolamine. In the groups pretreated with saline, performance of the behavioural task, in terms of responses made, was virtually abolished on the day the OP was administered, but a significant increase in accuracy of performance was seen over the 2- to 14-day period following administration. CONCLUSIONS: A combination of physostigmine and scopolamine, which is known to protect against nerve-agent lethality, offers protection against the effects of soman and sarin on behavioural performance, as measured by a discrimination reversal task. The improved performance observed following nerve agent requires further investigation.

Animals↗
PubMed2003

Castration in rats impairs performance during acquisition of a working memory task and exacerbates deficits in working memory produced by scopolamine and mecamylamine.

RATIONALE: Although much research has focused on the effects of ovarian hormones on learning and memory in females, less information is available regarding the effects of testicular hormones on learning and memory in males. Additionally, despite evidence of an interaction of testicular hormones and the cholinergic system in areas of the brain implicated in learning and memory, no information is available regarding the behavioral consequences of that interaction. OBJECTIVES: We assessed the effect of castration in male rats on working memory during acquisition of a radial maze. We also assessed the interactive effects of castration and scopolamine, a muscarinic receptor antagonist, as well as mecamylamine, a nicotinic receptor antagonist, on behavior. METHODS: Young adult male rats were castrated or underwent sham surgeries. Beginning 10 days after surgeries, performance on a task of working memory was assessed across 24 days of acquisition in an eight-arm radial maze. Following acquisition, scopolamine and mecamylamine dose-effect curves were established. RESULTS: Castration of male rats significantly decreased arm-choice accuracy during acquisition. Castration significantly exacerbated impairments in arm-choice accuracy produced by scopolamine as well as mecamylamine, without altering the disruptive effects of the drugs on the rate at which rats entered the arms of the maze. CONCLUSIONS: These results indicate that castration in male rats impairs working memory during acquisition of a spatial maze task. Additionally, these results suggest that the absence of testicular hormones increases the sensitivity of male rats to the impairing effects of scopolamine as well as mecamylamine on working memory.

Animals↗
PubMed2006

Neutral and emotional episodic memory: global impairment after lorazepam or scopolamine.

RATIONALE: Benzodiazepines and anticholinergic drugs have repeatedly been shown to impair episodic memory for emotionally neutral material in humans. However, their effect on memory for emotionally laden stimuli has been relatively neglected. OBJECTIVE: We sought to investigate the effects of the benzodiazepine, lorazepam, and the anticholinergic, scopolamine, on incidental episodic memory for neutral and emotional components of a narrative memory task in humans. MATERIALS AND METHODS: A double-blind, placebo-controlled independent group design was used with 48 healthy volunteers to examine the effects of these drugs on emotional and neutral episodic memory. RESULTS: As expected, the emotional memory advantage was retained for recall and recognition memory under placebo conditions. However, lorazepam and scopolamine produced anterograde recognition memory impairments on both the neutral and emotional components of the narrative, although floor effects were obtained for recall memory. Furthermore, compared with placebo, recognition memory for both central (gist) and peripheral (detail) aspects of neutral and emotional elements of the narrative was poorer after either drug. CONCLUSIONS: Benzodiazepine-induced GABAergic enhancement or scopolamine-induced cholinergic hypofunction results in a loss of the enhancing effect of emotional arousal on memory. Furthermore, lorazepam- and scopolamine-induced memory impairment for both gist (which is amygdala dependent) and detail raises the possibility that their effects on emotional memory do not depend only on the amygdala. We discuss the results with reference to potential clinical/forensic implications of processing emotional memories under conditions of globally impaired episodic memory.

Adolescent↗
PubMed2001

Scopolamine fails to diminish chronic haloperidol-induced purposeless chewing in rats.

Chronic haloperidol treatment for 4-12 months gradually induces spontaneous, irregular, purposeless oral chewing movements (CMs), apparently involuntary, in some but not all treated rats. Based on phenomenologic and pharmacologic similarities, this laboratory preparation has been used as an animal model of tardive dyskinesia (TD), which is the human hyperkinetic motor syndrome associated with chronic antipsychotic administration. This putative animal model has received the most severe challenge to its validity by claims that its oral movements can be suppressed by anticholinergic treatments, since resistance to anticholinergic suppression is an accepted pharmacologic feature of TD. In this experiment, we challenged a group of haloperidol-treated rats with CMs using three doses of scopolamine (0.1, 0.3, 1.0 mg/kg) and placebo and rated the change in dyskinetic movements. Each scopolamine dose reduced CMs by a similar magnitude, without any dose effect; the saline dose also reduced CMs to an equivalent degree. Therefore, we concluded that some component of the experiment, not the scopolamine, reduced the CMs. The handling component of the procedure was identified as a likely confound, and we tested this further. Rats with CMs were handled at several levels of "severity"; and the dyskinesias were rated at 1 and 3 h later. CMs were reduced by the experimental handling, in relation to the strength of the handling. Minimal handling produced modest CM reductions with quick recovery; whereas, the "strongest" handling plus the placebo injection produced the greatest CM reduction, evident over 3 h, resembling the CM reductions seen in the scopolamine and placebo experiment. Overall, these results suggest that anticholinergic drugs do not suppress chronic haloperidol-induced rat CMs. However, the movements are sensitive to stressful handling situations, and diminish with stress. In both of these characteristics, rat CMs resemble human TD, further supporting a role for this model in studies of human TD.

Animals↗
PubMed1997

Scopolamine impairs the ability of parturient ewes to learn to recognise their lambs.

Within a 4-h period after parturition, the ewe learns the odor of her lamb that will later allow recognition of her offspring from an alien lamb. This study investigated the involvement of the cholinergic system in this olfactory learning. At parturition and 2 h later, ewes received IM injections of saline (C group, n = 21), scopolamine methylbromide (METSCOP group, 100 micrograms/kg, n = 14) a peripherally acting muscarinic antagonist, a low dose of scopolamine hydrobromide (SCOP32 group, 32 micrograms/kg, n = 15) or a higher dose of scopolamine hydrobromide (SCOP100 group, 100 micrograms/kg, n = 18). Maternal behavior was observed at parturition and selective behavior was tested after 4 h of mother-young contact. No differences in maternal behavior at parturition were found between groups. By contrast, the proportion of ewes showing selectivity was significantly lower in the SCOP100 group (7/18) than in the METSCOP group (12/14, P = 0.01), SCOP32 group (12/15, P = 0.03), or C group (17/21, P = 0.01). In addition, saline-treated ewes, after having established their selective bond, received 100 micrograms/kg scopolamine and were again tested for selectivity 20 min later. Only one out of the 17 tested ewes failed to recognize their lambs after this treatment. These results indicate that intact central muscarinic transmission of the brain is required for the learning of individual lamb odor at parturition but not for the recall of this information.

Animals↗
PubMed1999

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice.

Some experimental evidence suggests that the beneficial effects of monosialoganglioside GM1 on learning and memory could be related to an improving effect in central cholinergic function. The present study investigates the effects of GM1 on the memory impairment induced by scopolamine in rats or mice tested in passive (PA) and discriminative avoidance (DA) tasks, respectively. Wistar EPM-1 male rats and Swiss EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 7 or 14 days, respectively. Twenty-four hours after the last injection, GM1-treated animals received 1 mg/kg scopolamine (GM1-SCO) and saline-treated animals received 1 mg/kg scopolamine (SAL-SCO) or saline (SAL-SAL) IP. Twenty minutes later, the animals were submitted to PA or DA conditioning, and tests were performed 24 h later. The latency in entering the dark chamber of the PA apparatus (LD) presented by SAL-SCO rats was significantly decreased when compared to that presented by SAL-SAL animals. GM1-SCO animals showed an increased LD when compared to SAL-SCO animals and were not significantly different from SAL-SAL rats. GM1-SCO and SAL-SAL (but not SAL-SCO) mice spent significantly less time in the aversive enclosed arm of the discriminative avoidance apparatus when compared to the time spent in the non-aversive enclosed arm. The results are consistent with the interpretation that GM1 attenuates scopolamine-induced amnesia. Although not eliminating the participation of other transmitter systems, the present study indicates a possible role of central cholinergic transmission in the action of this compound on learning and memory.

Amnesia↗
PubMed1999

Moderate cortical EEG changes in apolipoprotein E-deficient mice during ageing and scopolamine treatment but not after nucleus basalis lesion.

RATIONALE: Recent studies suggest that apoE-deficient mice may have impaired central cholinergic function and neuronal recovery capacity. OBJECTIVE: We investigated whether apoE-deficient mice are more susceptible to the biochemical and EEG defects induced by ageing or nucleus basalis (NB) lesion. METHODS: ApoE-deficient and control mice were used. The baseline EEG activity and EEG response to a muscarinic acetylcholine receptor antagonist, scopolamine (0.05 and 0.2 mg/kg) and a benzodiazepine receptor agonist, diazepam (0.5 and 2.0 mg/kg), were studied during ageing. In addition, the cortical and hippocampal ChAT activities were measured in aged mice. The baseline EEG activity and EEG response to scopolamine (0.05 and 0.2 mg/kg), and cortical ChAT activity, were studied after quisqualic acid-induced unilateral NB lesion. RESULTS: The baseline EEG fast wave activity (relative alpha and beta) was higher in apoE-deficient mice. Ageing decreased relative alpha activity similarly in both strains. The scopolamine induced EEG slowing was less prominent in apoE-deficient than in control mice, and the difference between the strains became slightly clearer during ageing. The NB lesion failed to produce more severe changes in cortical EEG and ChAT activity in apoE-deficient mice. Cortical and hippocampal ChAT activity was equal in young and aged apoE-deficient and control mice. The EEG response to diazepam in young and aged mice was similar in both strains. CONCLUSIONS: The regulation of cortical EEG activity of apoE-deficient mice was somewhat altered during ageing and the response to scopolamine treatment was blunted. However, the cholinergic cells of the NB of apoE-deficient mice were not more sensitive to lesion or to ageing, suggesting that apoE does not have to be present to preserve the viability of cholinergic neurons.

Aging↗
PubMed2001

Scopolamine does not restore normal conditioned avoidance performance in raclopride-treated rats.

Several studies have shown antagonism by anticholinergics of antipsychotic-induced suppression of conditioned avoidance behavior, as well as of catalepsy, in rats. These observations provide pharmacological evidence for these behaviors mediated via nigro-striatal dopaminergic projections, as well as known dopaminergic-cholinergic interactions in the neostriatum. The objective of the present study was to examine the quality of behavioral change produced by scopolamine (0.25-1.00 mgkg(-1) s.c.) on conditioned avoidance behavior, by itself, and in combination with raclopride (0.1 mgkg(-1) s.c.) in the rat. Adult male Wistar rats were trained to perform a conditioned avoidance response requiring a brightness discrimination. A two-way avoidance shuttle-box was used with the modification that there were two passages in the partition separating the two compartments of the shuttle-box. In order to make a correct avoidance in the response to white noise conditioned stimulus, the rat had to take background light into consideration. Correct passage under dim background conditions was to the left and, with increased background lights, to the right. A weak, intermittent, electric shock (approximately 0.2 mA) was used as unconditioned stimulus. Scopolamine by itself (0.25-1.00 mgkg(-1) s.c.) disrupted the visual discrimination without affecting avoidance performance. As expected, raclopride (0.1 mgkg(-1) s.c.) produced a suppression of conditioned avoidance behavior. A dose of 1.00 mgkg(-1) of scopolamine was needed to restore raclopride-induced suppression of conditioned avoidance behavior. Thus, restoration of the avoidance behavior by scopolamine treatment was not possible at doses that allow normal performance of the visual discrimination. It is concluded that anticholinergics do not restore normal behavior after neuroleptic-induced suppression of conditioned avoidance behavior.

Animals↗
PubMed1990

Effects of transdermal scopolamine on heart rate variability in normal subjects.

A decrease in cardiac parasympathetic tone is a recognized finding in patients with ischemic heart disease, sudden cardiac death and heart failure, correlating closely with disease severity and overall survival. To study the clinical potential of vagomimetic intervention, the effect of transdermal scopolamine on fluctuations in heart rate was studied in 32 healthy adult subjects using both time-domain (mean RR interval, standard deviation of the mean RR interval, mean of the differences between consecutive RR intervals) and frequency-domain measures (spectrum analysis of 128 consecutive RR intervals) of heart rate variability. After an exposure of 24 hours, transdermal scopolamine resulted in a significant increase in all indexes tested. The increase was most pronounced in the 0.25-Hz respiratory peak of the RR interval power spectrum, compatible with a strong vagomimetic mode of action of transdermal scopolamine. Results indicate that transdermal scopolamine may have potential merit as a selective vagotonic agent in certain patients with myocardial infarction, heart failure or ventricular arrhythmias.

Administration, Cutaneous↗
PubMed1991

Chronic treatment with scopolamine and physostigmine changes nerve growth factor (NGF) receptor density and NGF content in rat brain.

Nerve growth factor (NGF) and NGF receptors were measured in cortex and hippocampus of rats treated with drugs affecting cholinergic neurotransmission. High (Kd = 0.045 nM) and low (Kd = 21 nM) affinity 125I-NGF binding sites were present in both cortical and hippocampal membranes with hippocampus containing higher numbers of both sites than cortex. Chronic treatment of rats with the muscarinic receptor antagonist scopolamine (5 mg/kg, twice daily) decreased the density of high- and low-affinity sites by 50-90% in cortical and hippocampal membranes. These changes were seen after 7 days, but not 3 days, of scopolamine treatment. Chronic infusion of physostigmine (1 mg/kg/day) using minipumps increased the number of high- and low-affinity sites in cortex 3- and 6-fold, respectively. The changes in receptor-binding parameters induced by physostigmine were transient as they were evident after 3 days of treatment, but returned to control levels after 7 days. NGF content in cortex and hippocampus was reduced by about 50% following 7, but not 3, days of chronic physostigmine infusion. In contrast, scopolamine treatment failed to change NGF levels in the cholinergic neuronal target regions but it decreased NGF content in the septal area. The content of NGF mRNA in the cortex measured by Northern blot analysis failed to change following either scopolamine or physostigmine treatment. The results suggest that the levels of NGF and NGF receptors in the target regions of cholinergic neurons are regulated by the extent of cholinergic neurotransmitter activity.

Animals↗
PubMed1993

Effects of long-stimulus intervals and scopolamine administration on hippocampal kindling.

Using the low-frequency kindling procedure, we studied the effects of periodic 2-week stimulus-free intervals and chronic scopolamine administration on hippocampal kindling seizure development. In Experiment 1, rats were divided into two groups, interval group and no-interval group. In the interval group a 2-week stimulus interval was set after every five consecutive daily stimulations until the 21st stimulation. The number of stimulating pulses required for the triggering of epileptic afterdischarge, pulse-number threshold (PNT), was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling, kindling rate, seizure parameters at the completion of kindling were recorded and compared to the values of the no-interval, control group. Our result showed that PNT at the 6th stimulation, the first stimulation after the first 2-week stimulus interval increased significantly compared to control. Other seizure parameters did not differ significantly between the two groups. In Experiment 2 scopolamine hydrobromide, 0.5 and 1.0 mg/kg i.p., was administered 1 h before each electrical stimulation until each rat showed the stage-3 seizure. PNT, ADD and BSS in the initial stage of kindling, kindling rate for the stage-3 and -5 seizures, seizure parameters at the first stage-3 and -5 were recorded and compared to the values of saline-treated, control group. Although scopolamine 1.0 mg/kg increased PNT at the 5th stimulation compared to control, no other significant changes of the seizure parameters were found by scopolamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

NMDA-but not AMPA-receptor antagonists augment scopolamine-induced spatial cognitive deficit of rats in a radial maze task.

The effect of NMDA and AMPA receptor antagonists on a scopolamine-induced spatial cognitive deficit was investigated in rats using an 8-arm radial maze. The NMDA antagonists, MK801 and CGS19755, robustly augmented scopolamine-induced deficits but had no effect on spatial cognition when administered alone. In contrast, augmentation of the scopolamine-induced deficits was not observed when the selective AMPA antagonist, YM90K, was administered with scopolamine. These results suggest that the NMDA but not AMPA subtypes of the ionotropic glutamate receptors play important roles in regulation of the central cholinergic function related to the spatial learning and memory processes.

Animals↗
PubMed1988

Acute scopolamine treatment decreases dopamine metabolism in rat hippocampus and frontal cortex.

The aim of the present study was to correlate the impairment of cognitive function induced by scopolamine with the activity of dopaminergic synapses in brain areas which are innervated by the mesocortical limbic system (e.g. hippocampus and frontal cortex) or by the mesostriatal system (e.g. striatum and nucleus accumbens). The results indicate that acetylcholine receptor blockade induced by the intraperitoneal injection of 0.5 mg/kg scopolamine resulted in a selective decrease in the content of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect appeared to be specific for the hippocampus and frontal cortex. Indeed, dopamine turnover in striatum and nucleus accumbens was not affected by scopolamine treatment. The scopolamine-induced decrease of dopamine turnover in both hippocampus and frontal cortex paralleled in terms of both time- and dose-dependence the drug-induced amnesic effects, as measured by a passive avoidance behavioral test.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Dynorphin A-(1-13) markedly improves scopolamine-induced impairment of spontaneous alternation performance in mice.

The effect of intracerebroventricular (i.c.v.) injection of dynorphin A-(1-13) on the memory process was examined in mice, using spontaneous alternation performance related to working memory in a Y-maze. Dynorphin A-(1-13) (1, 3 and 10 micrograms) influenced neither spontaneous alternation performance nor total arm entries, which are considered to reflect locomotor activity. In contrast, dynorphin A-(1-13) (3 and 10 micrograms) significantly improved the impairment of spontaneously alternation performance induced by scopolamine (1 mg/kg s.c.). Simultaneously, the scopolamine-induced increase in total arm entries was markedly attenuated by dynorphin A-(1-13) (10 micrograms). The effect of dynorphin A-(1-13) (3 micrograms) on the scopolamine-induced impairment of spontaneous alternation was almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms i.c.v.), a kappa-selective opioid antagonist. These findings suggest that dynorphin A-(1-13) improves through the mediation of kappa-opioid receptors the scopolamine-induced impairment of spontaneous alternation performance associated with working memory.

Analysis of Variance↗
PubMed1993

Effects of sustained release formulation of thyrotropin-releasing hormone on learning impairments caused by scopolamine and AF64A in rodents.

The effects of a sustained-release formulation of thyrotropin-releasing hormone (TRH-SR) on learning impairments induced by scopolamine and a cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), were examined in rodents. Subcutaneous injection of TRH-SR (2.8 mg/kg as free TRH) produced a sustained increase in immunoreactive plasma TRH levels up to about 2 weeks after dosing in rats. TRH-SR (0.56 and 2.8 mg/kg) given subcutaneously 7 days before the acquisition trial markedly ameliorated scopolamine-induced amnesia in mice, as evaluated with a passive avoidance task. Repeated administration of TRH for 7 days at doses of 0.2-5 mg/kg s.c. elicited a dose-dependent recovery from amnesia induced by scopolamine, whereas only the group treated with 5 mg/kg/day showed a significant improvement. The rats with bilateral intracerebroventricular injection of AF64A (3.75 nmol/brain) showed a significant impairment in the water maze task 2 weeks after surgery. TRH-SR (0.56 and 2.8 mg/kg) also exhibited a dose-dependent ameliorating action on the deficit. These findings indicate that TRH-SR ameliorates learning impairments produced by scopolamine and AF64A, and suggest that continuous infusion of TRH may have a potent learning and memory improving action at low doses.

Amnesia↗
PubMed1985

Interaction of choline and scopolamine in human memory.

In a previous study (1), 8 gm. of oral choline given in a single dose were found to partially reverse the amnestic and subjective effects of 0.43 mg of scopolamine. The present study determined whether similar effects could be produced by 14 gm of choline given in 4 divided doses over 24 hrs and whether choline's effects in either study were related to plasma choline concentration. Ten normal subjects were given memory tests on three separate days, once after receiving 14 gm choline and 0.35 mg scopolamine (Ch-Sc), once following placebo and scopolamine (Pl-Sc), and once following placebo and placebo (Pl-Pl). Scopolamine markedly impaired memory performance but there was no difference between the Ch-Sc and Pl-Sc conditions. Plasma choline levels were significantly elevated in the Ch-Sc condition of both the single dose and divided dose studies. There was no difference in levels between studies nor were differences in memory performance correlated with elevations in plasma choline. These results indicate that any enhancement of cholinergic activity due to increased dietary choline is transient and of small magnitude.

Acetylcholine↗