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PubMed1994

Pharmacological models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on word valence ratings, priming and recall.

The effects of scopolamine (0.3, 0.6 mg IM) lorazepam (2 mg oral) and placebo on word valence ratings, priming and word recall were assessed in a double-blind independent group design with 36 subjects. Subjects given active drugs rated words as having more of an affective load than subjects given placebo. Priming, as assessed in a word-stem completion task, was not significantly affected by any treatment. Word recall showed some impairment following all active treatments. Performance on the stem completion task was unrelated to subjectively rated sedation but did not relate to word-valence ratings in different ways across drug treatments. Performance on the recall task was unrelated to valence ratings but did relate to the sedative effects on lorazepam. Implications are drawn out for pharmacological models of memory dysfunction.

Adult↗
PubMed1990

Comparison of the effects of Alzheimer's disease, normal aging and scopolamine on human transient visual evoked potentials.

Transient visual evoked potentials elicited by the onset of a patterned stimulus were recorded in patients suffering from Alzheimer's disease (AD), in healthy elderly controls and in healthy young individual. The latencies and amplitudes of both the components studied were adversely affected by normal aging and one of the components, CI, but not the other, CII, showed further deterioration in AD. These changes occurred over a range of stimulus contrast levels. The changes found in AD, but not those seen in normal aging, could be mimicked by administration of the cholinergic antagonist scopolamine to young volunteers.

Adult↗
PubMed1991

Scopolamine attenuates the motor disruptions but not the attentional disturbances induced by haloperidol in a sustained attention task in the rat.

Rats were trained to perform a sustained attention task that required the subject to insert its head into a cylindrical "observation tunnel" and wait for the presentation of one of three spatially separated visual stimuli located on the upper portion of the tunnel circumference. Detection of a briefly (0.125 s) presented "correct" stimulus, followed by the rats' forward nose poke, resulted in access to a reinforcement dipper lifted through the orifice in the floor of the tunnel. Nose pokes to the two incorrect stimuli resulted in a 5-s time-out period. The task maximized attention and minimized movement requirements. Performance was characterized in terms of accuracy (i.e. errors of omission, and errors of commission), time on task, and latency to respond to the stimuli (i.e., reaction time). Haloperidol (0.04, 0.08, and 0.16 mg/kg) increased errors of omission and reaction time. However, lack of significant correlations between these two measures suggested that attentional accuracy may be independent of motor slowing produced by this neuroleptic. Scopolamine (0.2 mg/kg) alone increased both errors of omission and commission, but did not affect reaction time to correct stimuli. The sustained attention task as implemented here may be useful in the simultaneous study of classical neuroleptics desirable and undesirable CNS effects.

Animals↗
PubMed1996

[Transdermal scopolamine for prevention of postoperative nausea and vomiting. No clinically relevant result in spite of reduced postoperative vomiting in general surgical and gynecologic patients].

UNLABELLED: In a prospective double-blind trial, transdermal scopolamine (TS) was compared to placebo (P) in the prevention of postoperative nausea and vomiting (PONV) within a 48-h interval. After stratification for gender and surgical procedure, patients were randomly chosen to receive either TS or placebo. METHODS: Of 304 surgical and gynaecological patients included in this study, the data of 263 patients were evaluated (48 thyroidectomies, 15 open, and 36 laparoscopic cholecystectomies, 41 open, and 36 laparoscopic hernia repairs, 37 hysterectomies, and 50 gynaecological laparoscopies). The two groups were comparable with regard to biometrical data and duration of anaesthesia and surgery. Although anaesthesia was not standardized, there was no difference in anaesthesia techniques, drug dosage or perioperative management. Patients were evaluated once preoperatively and 2, 6, 10, 24, and 48 h postoperatively using a 100-mm visual analogue scale (VAS) for "nausea", "pain", "dry mouth", "sedation", and "blurred vision". Episodes of vomiting or retching and the need for additional antimetics (0.03 mg.kg-1 metoclopramide i.v., followed by 1 mg.kg-1 dimenhydrinat i.v., if necessary) were recorded. RESULTS: TS significantly reduced the incidence of postoperative vomiting within the first 48 h postoperatively [TS: 47 patients (36.2%) with 125 cumulative episodes vs P: 70 patients (52.6%) with 209 cumulative episodes]. Analysing the five observation intervals seperately, this difference could only be demonstrated 0-2 h and 6-10 h postoperatively. In patients suffering from emetic sequelae, TS did not reduce the frequency of vomiting significantly (mean frequency: TS: 2.7 vs P: 3.0). TS also had no significant effect on the requirement of additional antiemetics [TS:. 81 times in 46 (35.7%) patients vs P: 116 times in 58 (44.3%) patients]. Nausea as rated by the VAS was not significantly different between the two groups at any time during the postoperative observation. No relevant side-effects occurred, although there was a trend toward higher ratings of "dry mouth" in the TS group, reaching statistical significance 10 h after operation. CONCLUSION: The routine administration of TS for gynaecological and surgical patients cannot be recommended because of the lack of effect on postoperative nausea and only marginal benefit concerning postoperative vomiting.

Administration, Cutaneous↗
PubMed1997

A behavioural analysis of the delayed non-matching to position task: the effects of scopolamine, lesions of the fornix and of the prelimbic region on mediating behaviours by rats.

The delayed non-matching to position task (DNMP) is a widely used automated test of spatial memory, yet its validity has been challenged by suggestions that animals use motor mediating behaviours which facilitate correct responding. This possibility was systematically studied by analysing video recordings of rats displaying delay-dependent and delay-independent deficits following lesions or drug manipulations. Rats were first trained to perform the DNMP task and whilst untreated, a number of potential mediating behaviours were identified from the video recorded behaviour. Two independent raters recorded any apparent motor strategies and attempted to predict the response the animals made during the choice phase of the task by viewing only behaviour during the delay periods. Subsequently, the behaviour of the same animals was examined following scopolamine treatment and following lesions of the prelimbic cortex or of the fornix. The experiment confirmed previous reports of delay-dependent and delay-independent deficits under the varying conditions (drug, lesions), but also revealed that rats use clearly identifiable mediating behaviours that appear to facilitate correct responding in the DNMP task. Consequently, apparent "memory" impairments in the DNMP task, may reflect a disruption of behavioural strategies used by the animal to assist in performing the task.

Animals↗
PubMed1997

Nicotine-induced decreases in VTA electrical self-stimulation thresholds: blockade by haloperidol and mecamylamine but not scopolamine or ondansetron.

The effects of repeated daily injections of (-)-nicotine (+) hydrogen tartrate (mg kg-1 s.c.) on electrical self-stimulation of the ventral tegmental area were investigated. Nicotine reduced the frequency required to maintain half-maximal response rates with animals responding in rate-frequency threshold tests. Under these conditions, nicotine induced an increase in the total number of self-stimulation responses per session, but had no statistically significant effects on the maximal response rate. These effects of nicotine were observed by the second day of administration of this drug. Acute injections of the D2-like dopamine receptor antagonist haloperidol (0.03 mg kg-1 s.c.) and of the nicotinic acetylcholine receptor antagonist mecamylamine (1 mg kg-1 s.c.) attenuated the effects of nicotine, indicating that the observed effects involve stimulation of D2-like dopamine receptors as a result of nicotinic receptor activation. The muscarinic acetylcholine receptor antagonist scopolamine (3 mg kg-1 s.c.) and the serotonin 5-HT3 receptor antagonist ondansetron (0.01 and 0.1 mg kg-1 s.c.) did not alter the effects of nicotine. The results of this study indicate that repeated daily administration of (-)-nicotine increases the rewarding effects of electrical self-stimulation of the ventral tegmental area. These data are consistent with the proposal that repeated daily injections of nicotine positively effect a mesolimbic dopaminergic substrate of reward.

Animals↗
PubMed1998

Differentiating the effects of centrally acting drugs on arousal and memory: an event-related potential study of scopolamine, lorazepam and diphenhydramine.

The degree to which apparent amnesic effects of various centrally acting drugs are secondary to their effects on arousal remains a contentious issue. The present study uses two methods to dissociate memory and arousal effects of the cholinergic antagonist, scopolamine (SP), and the GABA-A/benzodiazepine receptor agonist, lorazepam (LZ). First, it compared their effects to those of an antihistamine, diphenhydramine (DPh), to provide an active control for arousal reduction. Second, it used the same measure--event-related potentials (ERPs)--as as a parallel index of both the arousal and cognitive effects of the drugs. Fifty participants were allocated to one of five parallel treatment groups (0.6 mg SP; 2 mg LZ; 25, 50 mg DPh; placebo). ERPs were recorded during a continuous word recognition task as well as during an "oddball" task. SP, LZ and 50 mg DPh produced a similar profile of effects on certain indices of arousal and on early components of ERPs. However, SP and LZ (but not DPh) produced marked impairments of episodic memory, and this pattern was similar to that on later components of ERPs. Memory impairments by SP and LZ were highly significant on retention in the continuous recognition task and further, no drug effects were found on response bias. Subsequent free recall was similarly very impaired by SP and LOR but not by the antihistamine. We conclude that benzodiazepines and anticholinergic drugs both reduce arousal and induce amnesia, but these effects are not interdependent. Our findings provide strong evidence for a dissociation between the effects on episodic memory and on arousal of these centrally acting compounds.

Adult↗
PubMed1998

Effects of drugs of abuse and scopolamine on memory in rats: delayed spatial alternation and matching to position.

Drugs of abuse produce amnestic effects in humans and laboratory animals in a variety of tasks. Generally, only a few compounds have been examined in any particular procedure. It was the goal of the present studies to examine drugs of abuse of different pharmacological classes in rats responding under two behavioral schedules historically employed as experimental models of memory: spatial alternation and matching to position. One group of rats responded under a single-response spatial-alternation baseline with a 10-s delay and another group responded under a matching-to-position baseline with delay values of 3, 10 and 30 s. Performance under the spatial-alternation baseline was characterized by low variability and >90% accuracy. Under the matching-to-position baseline, saline control percent accuracy was >95% at 3 s, >85% at 10 s and >70% at 30 s. Under spatial alternation cocaine, d-amphetamine, pentobarbital, diazepam, phencyclidine, scopolamine and methscopolamine produced significant (P<0.05) effects on accuracy, whereas only cocaine, d-amphetamine, pentobarbital and phencyclidine disrupted accuracy under the matching-to-position baseline. These results suggest that spatial alternation may be a more sensitive baseline for determining drug effects on working memory in the rat.

Animals↗
PubMedDate not supplied

Pirenzepine versus scopolamine methyl bromide in double-contrast barium enema study of large bowel.

To evaluate the usefulness of pirenzepine for diagnostic double-contrast barium enema study of the large bowel, pirenzepine and scopolamine methyl bromide (SMB) were compared in a single, blind, randomized trial. Sixty consecutive patients were enrolled in the study. Quantitative analysis of bowel distention was done by measuring the maximum diameter of the transverse colon before and after drug administration. Four independent observers blindly evaluated distention and mucosal coating of the large bowel and global quality of the images. No differences were found in the diagnostic performance between the two drugs. However, pirenzepine induced a slight but significantly larger distention of the large bowel (68 +/- 12 vs. 65 +/- 8 mm, p = 0.02). Heart rate and rhythm during the study were recorded by ECG. SMB induced tachycardia in all patients (from 72 +/- 15 to 98 +/- 24 beats/min, p < 0.01), whereas pirenzepine did not (from 76 +/- 13 to 78 +/- 20, p = NS). After SMB, one-patient exhibited faintness, and some patients complained of visual accommodation defects, dryness of the mouth, and dizziness. Pirenzepine had a diagnostic performance similar to SMB in avoiding adverse effects elicited by SMB.

Adult↗
PubMed2005

Treating sialorrhea with transdermal scopolamine. Exploiting a side effect to treat an uncommon symptom in cancer patients.

INTRODUCTION: Sialorrhea is a distressing symptom accompanying oral cancer and many heterogeneous cancer-related conditions (chemotherapy-induced nausea, bowel subocclusion, pharmacologic side effects), but its incidence is low in cancer patients. Conversely, it is frequent in patients with neurological damage, and some therapeutic options have been attempted such as botulinum toxins, anticholinergic agents, and surgical procedures. CASE REPORT: We report the case of an 80-year-old woman with peritoneal carcinomatosis and bowel subocclusion, suffering from distressing nausea and sialorrhea that rapidly improved using transdermal scopolamine. No relevant side effects occurred during the treatment, and the reduction of the abnormal salivation allowed the recovery of oral feeding. CONCLUSIONS: Anticholinergic drugs are classified as secondary options in the treatment of sialorrhea of patients with Parkinson's disease or cerebral palsy, owing to the relevant side effects occurring during prolonged treatments. However, they could be useful in cancer patients with bowel subocclusion, as the reduction of gastrointestinal secretions and intestinal motility (frequent side effects of anticholinergic drugs) could be effective in controlling nausea, vomiting, and abdominal pain. Moreover, the transdermal or sublingual route of administration can be of some interest, avoiding other more invasive parenteral approaches.

Administration, Cutaneous↗
PubMed1987

Separation of optical isomers of scopolamine, cocaine, homatropine, and atropine.

Different drug stereoisomers can have different physiological and therapeutic effects. Difficulties in separating optical isomers often make it impractical to market stereochemically pure products or to monitor isomeric contamination. This is not thought to be a problem with drugs isolated from biological sources (the alkaloids, for example). However, small amounts of isomeric impurities also exist in many biological systems. More importantly the isolation and purification process can cause partial or complete racimization in some cases. Great care must be taken in the handling of some drugs and an efficient, sensitive means to monitor racimization is important. Liquid chromatographic separation on a chiral beta-cyclodextrin bonded phase can be an effective technique in many cases. Its use in separating optical isomers of dl-scopolamine, dl-hyoscyamine, dl-homatropine, and dl-cocaine is discussed.

Atropine↗
PubMed1989

Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol abnormalities in depression.

Scopolamine (SCOP) (3.0 mu/kg and 6.0 micrograms/kg) and saline were administered intramuscularly at 11:00 PM to eight normal male volunteers in a randomized design, and the effects on the sleep electroencephalogram (EEG) and nocturnal cortisol secretion (via blood sampling every 15 min) were evaluated. Compared to saline, SCOP produced a significant dose-related delay in rapid eye movement (REM) latency. In contrast, neither dose of SCOP significantly affected nocturnal plasma cortisol concentrations. These results suggest that the central cholinergic system that regulates the onset of REM sleep is more sensitive to dysregulation than the cholinergic system that controls the degree of nocturnal cortisol secretion. If central cholinergic overactivity is responsible for both the REM sleep latency and cortisol abnormalities in depressed patients, then our findings with SCOP might help explain why the incidences of these abnormalities are different.

Adult↗
PubMed1984

Glucose utilization in the Papez circuit: effects of oxotremorine and scopolamine.

The [14C]2-deoxy-D-glucose technique was used to test the effects of central muscarinic stimulation or antagonism on local cerebral glucose utilization (LCGU) in the rat limbic system. Systemic administration of the muscarinic agonist oxotremorine (OXO, 0.05, 0.1 or 0.7 mg/kg, i.p.), increased LCGU in the pre- and postsubiculum, anterior nuclei of the thalamus, mammillary bodies, retrosplenial medial cortex, medial septum, postcommissural fornix and mammillothalamic tract. Scopolamine (2.5 mg/kg, i.p.) blocked these effects, and independently decreased LCGU in the pre- and postsubiculum, anterior thalamic nuclei, and retrosplenial medial cortex. The affected brain regions are components of, or are connected with, the Papez circuit.

Animals↗
PubMed1985

Differential effects of scopolamine on 3 forms of stress analgesia.

We have previously reported that non-opioid stress analgesia and two forms of opioid stress analgesia can be differentially produced in rats by varying the severity or temporal pattern of inescapable footshock. In this study, we investigated the role of muscarinic cholinergic mechanisms in mediating these 3 forms of stress analgesia. Whereas the muscarinic anticholinergic drug, scopolamine, had no effect on either non-opioid stress analgesia or opioid stress analgesia from 1 min of continuous 2.5-mA footshock, it significantly attenuated opioid analgesia from 20 min of intermittent footshock at this same intensity. The data are discussed in reference to other similarities and differences between these two forms of opioid stress analgesia.

Analgesia↗
PubMed1987

Scopolamine-disruption of radial arm maze performance: modification by noradrenergic depletion.

Administration of muscarinic cholinergic antagonists impairs performance on a variety of memory tasks. We examined the hypothesis that denervation of norepinephrine input to the forebrain would augment this effect of cholinergic antagonists. Administration of 6-hydroxydopamine into the dorsal noradrenergic bundle did not by itself alter the performance of rats on a radial maze working memory task. In Experiment 1, scopolamine, a muscarinic antagonist, impaired the performance of the NE-depleted animals more than that of animals in an operated control group. This result was again observed in Experiment 2; but here a lesion by order of dose administration interaction provided evidence for recovery from the effects of NE-depletion. In Experiment 3, it was found that NE denervation did not alter the functional status of basal forebrain cholinergic neurons as reflected in in vitro determination of sodium-dependent, high affinity choline uptake in hippocampus and cortex. These results suggest that an age-related decline in brain NE neurons, as well as further deterioration in this system in some cases of Alzheimer's disease, may contribute to the cognitive and memory deficits more typically ascribed to cholinergic dysfunction.

Adrenergic Fibers↗
PubMed1985

Distribution of cholinergic muscarinic binding sites in guinea-pig brain as determined by in vitro autoradiography of [3H]N-methyl scopolamine binding.

The distribution of muscarinic binding sites was analyzed in regions of the guinea-pig brain with semi-quantitative densitometry of [3H]N-methyl scopolamine binding, a muscarinic antagonist. In the rostral forebrain, high levels of binding were detected in the caudate putamen, nucleus accumbens and olfactory tubercle while intermediate levels of binding were observed in the medial and lateral septum, bed nucleus, and vertical and horizontal limbs of the diagonal band. The hypothalamus displayed binding that ranged from low levels in the preoptic area to intermediate levels in the mammillary nucleus. In limbic areas such as the thalamus, amygdala and hippocampus, a heterogeneous pattern of binding was evident in various subregions which tended to correspond with known innervation by cholinergic afferents. In the midbrain, binding was high in the superficial layer of the superior colliculus and the medial geniculate while intermediate binding was recorded in the lateral geniculate and the lateral aspect of the central gray. The pattern of muscarinic binding observed in the brain of the guinea-pig is similar to distributions of this binding site previously reported in the rat brain and the human brain.

Animals↗
PubMed1996

Metrifonate improves spatial navigation and avoidance behavior in scopolamine-treated, medial septum-lesioned and aged rats.

We investigated the effects of acute p.o. pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation and passive avoidance behavior. Metrifonate (10-100 mg/kg, orally, p.o.) did not improve the water maze or passive avoidance performance of young intact rats. However, in young rats metrifonate over a broad dosage range (10-100 mg/kg, p.o.) was able to alleviate the adverse effects of scopolamine (a muscarinic acetylcholine receptor antagonist; 0.4 and 2.0 mg/kg in water maze and passive avoidance study, respectively) and medial septum-lesioning on spatial reference and working memory and passive avoidance performance. In old (23-month-old) rats, a defect of water maze and passive avoidance behavior was observed. In old rats, metrifonate improved spatial reference memory function in the water maze and also passive avoidance at 10-30 mg/kg, but the 3 mg/kg dose was ineffective. Very old (27-month-old) rats had a more severe impairment of water maze performance than old rats, and metrifonate 3-30 mg/kg did not improve their spatial navigation. These results show that metrifonate may over a wide range of doses stimulate cognitive functioning, but during advanced aging neurobiological defects develop that may mask some of the therapeutic effects of metrifonate in rats.

Aging↗
PubMed1990

Characterization and agonist regulation of muscarinic ([3H]N-methyl scopolamine) receptors in isolated ventricular myocytes from rat.

Cell surface muscarinic cholinergic receptors have been characterized and quantified for the first time, in intact, isolated adult rat cardiomyocytes. The cells were previously established as functionally fully compatible with cellular responses in intact cardiac tissue. The specific binding of the hydrophilic radioligand, [3H]-NMS, (N-methyl-[3H]-scopolamine methylchloride) was found to be stereo-specific, saturable, reversible and of high affinity. Binding of [3H]-NMS demonstrated appropriate drug specificity and was positively correlated with increasing cell concentrations. Bmax for [3H]-NMS binding to ventricular myocytes, enzymatically dissociated from adult male rats, was 15.8 +/- 1.03 fmol/25 x 10(3) cells (at 4 degrees C) and KD was 0.27 +/- 0.05 nM (n = 14). Binding assays performed at a higher incubation temperature (30 degrees C) yielded a higher Bmax value (22.1 +/- 1.6 fmol/25 x 10(3) cells; n = 11; P less than 0.005 vs. Bmax at 4 degrees C) but an unchanged KD (0.23 +/- 0.06 nM). Pretreatment of myocytes with the muscarinic agonist carbachol (1 mM) at 37 degrees C resulted in a reduction (down-regulation) in specific binding of the hydrophilic ligand [3H]-NMS. The magnitude of this reduction and its rate of recovery were dependent on the time of the exposure to carbachol. Exposures of 30-60 min elicited down-regulated by 35% (Bmax = 14.29 +/- 1.66 changed to 9.5 +/- 1.79 fmol/25 x 10(3) cells, without change in KD P less than 0.01, n = 4). The down-regulation of the muscarinic receptors by carbachol was insensitive to application of bacitracin - an inhibitor of endocytosis. On the other hand preincubation with 10(-9)M atropine, a muscarinic antagonist, hindered the agonist-induced receptor "loss" from the cell surface confirming the muscarinic nature of these receptors. We conclude that our preparation of intact, isolated ventricular cardiomyocytes is ideally suited for the study of cell surface muscarinic receptor regulation under physiological and pathological conditions.

Animals↗