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PubMed1984

Effects of intrastriatal and intracortical scopolamine on behavior in rats.

The anticholinergic drug scopolamine (20 micrograms, 30 micrograms, 40 micrograms) or its vehicle was injected unilaterally into the dorsal anterior striatum or overlying rostral neocortex in rats in order to examine the role of each region in contralateral postural deviation and stereotyped rearing. Scopolamine-induced contralateral deviation was observed in all subjects with striatal injections (p less than 0.01), and was of the same magnitude at all dose levels. Intracortical scopolamine did not induce contralateral deviation. However, stereotyped rearing was elicited from both the striatum and neocortex (p less than 0.01) at the two highest dose levels of scopolamine. Thus the mechanisms for contralateral deviation and stereotyped rearing differ both with respect to brain region and drug sensitivity.

Analysis of Variance↗
PubMed1999

Estrogen improves working but not reference memory and prevents amnestic effects of scopolamine of a radial-arm maze.

This study investigated the effect of estrogen treatment on working memory and reference memory of female rats. In addition, the impact of estrogen on the sensitivity of these two types of memory to the cholinergic antagonist scopolamine was investigated. At 35 days of ages, rats were ovariectomized and implanted chronically with Silastic capsules containing either 25% crystalline estradiol or 100% cholesterol. Thirty days after surgery, animals were trained on an eight-arm radial maze with four arms baited to assess both working and reference memory performance. Following training, females were given scopolamine hydrobromide (0.2 mg/kg i.p.) prior to retesting on the task. Results indicated that estrogen treatment improved working memory performance during maze acquisition but did not affect reference memory performance. Scopolamine treatment impaired performance on the working memory component, but not the reference memory component, while estrogen prevented the impairment of working memory by scopolamine. Results support previous evidence that estrogen selectively enhances performance on tasks that depend on working memory.

Amnesia↗
PubMed2002

Caramiphen and scopolamine prevent soman-induced brain damage and cognitive dysfunction.

Exposure to soman, a toxic organophosphate nerve agent, causes severe adverse effects and long term changes in the peripheral and central nervous systems. The goal of this study was to evaluate the ability of prophylactic treatments to block the deleterious effects associated with soman poisoning. scopolamine, a classical anticholinergic agent, or caramiphen, an anticonvulsant anticholinergic drug with anti-glutamatergic properties, in conjunction with pyridostigmine, a reversible cholinesterase inhibitor, were administered prior to sbman (1 LD50). Both caramiphen and scopolamine dramatically attenuated the process of cell death as assessed by the binding of [3H]RoS-4864 to peripheral benzodiazepine receptors (omega3 sites) on microglia and astrocytes. In addition, caramiphen but not scopolamine, blocked the soman-evoked down-regulation of [3H]AMPA binding to forebrain membrane preparations. Moreover, cognitive tests utilizing the Morris water maze, examining learning and memory processes as well as reversal learning, demonstrated that caramiphen abolished the effects of soman intoxication on learning as early as the first trial day, while scopolamine exerted its effect commencing at the second day of training. Whereas the former drug completely prevented memory deficits, the latter exhibited partial protection. Both agents equally blocked the impairment of reversal learning. In addition, there is a significant correlation between behavioral parameters and [3H]RoS-4864 binding to forebrain membrane preparations of rats, which participated in these tests (r(21) = 0.66, P < 0.001; r(21) = 0.66, P < 0.001, -0.62, P < 0.002). These results demonstrate the beneficial use of drugs exhibiting both anti-cholinergic and anti-glutamatergic properties for the protection against changes in cognitive parameters caused by nerve agent poisoning. Moreover, agents such as caramiphen may eliminate the need for multiple drug therapy in organophosphate intoxications.

Animals↗
PubMed1994

Pavlovian inhibitory conditioning and tolerance-reversal to scopolamine-induced adipsia in rats.

In the present experiment the effect of a conditioned inhibitory stimulus on tolerance to scopolamine-induced adipsia was evaluated. Long-Evans rats were injected with 0.6 mg/kg scopolamine bromidrate in the presence of a tone or a noise, and physiological saline with a compound tone-odor. A summation test with the compound stimulus noise-odor showed a tolerance reversal effect to scopolamine adipsic effects in tolerant subjects. This reduction of tolerance was similar to adipsia produced by the first scopolamine administration, only when the odor stimulus was present. However, the inhibitory stimulus alone has no effect upon water intake. Results confirmed that a Pavlovian conditioned inhibition procedure can reduce conditioned tolerance to a drug.

Animals↗
PubMed1988

Scopolamine interactions with D1 and D2 antagonists on radial-arm maze performance in rats.

Recent evidence indicates that acetylcholine and dopamine play complementary roles in cognitive as well as motor functions. In our previous study, the dopamine receptor blocker, haloperidol, was found to attenuate the radial-arm maze choice accuracy deficit caused by the muscarinic acetylcholine receptor blocker, scopolamine. Haloperidol has activity in blocking both D1 and D2 dopamine receptor subtypes. The current study was conducted to determine whether this dopamine-acetylcholine interaction specifically involved D1 or D2 dopamine receptors. The D1 antagonist, SCH 23390, and the D2 antagonist, raclopride, were administered with a dose of scopolamine which caused choice accuracy deficits in the radial-arm maze. The scopolamine-induced deficit was reversed by SCH 23390, the D1 antagonist, indicating that D1 blockade alone is sufficient to reverse the amnestic effects of muscarinic blockade. There was no indication in this study that the D2 blocker, raclopride, had a similar effect. However, this does not mean that such an effect may not be present at other doses of raclopride or with other D2 antagonists. The present finding that D1 blockade counteracts scopolamine-induced cognitive dysfunction not only furthers the understanding of dopamine-acetylcholine relationships in cognitive function, it also suggests a promising direction for the development of treatments for cognitive dysfunction due to cholinergic loss.

Animals↗
PubMed2002

Oxiracetam prevented the scopolamine but not the diazepam induced memory deficits in mice.

In mice, the elevated plus-maze paradigm was used to investigate the effect of scopolamine hydrobromide and diazepam and their interaction with oxiracetam on the retrieval of spatial memory trace. This paradigm measures (using the transfer latency) an animal's capacity to escape from the open arm to the enclosed one. The retention session followed 24 h after the acquisition one. Experiment 1: Scopolamine (0.25 and 0.5 mg/kg) and diazepam (0.5 and 1.0 mg/kg) given 30 min before the retention session significantly prolonged the transfer latency as compared with the saline treated mice and those given the lowest dose of scopolamine (0.125 mg/kg) and diazepam (0.25 mg/kg). Experiment 2: Oxiracetam administered at doses of 3, 10 and 30 mg/kg immediately after the acquisition session prevented the scopolamine induced prolongation of the transfer latency. Thus, oxiracetam forestalled the impairment of retrieval of memory trace: the animals were able to remember the spatial configuration of the plus-maze. On the contrary, oxiracetam was not effective in the diazepam treated mice. We suggest that beneficial effect of oxiracetam might be confounded or blocked by the anxiolytic effect of diazepam.

Animals↗
PubMed1999

Rats exposed to acute pyrithiamine-induced thiamine deficiency are more sensitive to the amnestic effects of scopolamine and MK-801: examination of working memory, response selection, and reinforcement contingencies.

Pyrithiamine-induced thiamine deficiency (PTD), which has been used as a model of Wernicke-Korsakoff syndrome (WKS), produces a range of neuropathological and behavioral abnormalities in rodents. The extent of the diencephalic damage produced by this treatment varies from moderate to extreme cell loss. The magnitude of working memory impairment tends to correlate with the degree of neuropathology. In this study a PTD protocol that produces moderate thalamic pathology was used to gain further insight into the neurobehavioral consequences of thiamine deficiency. Towards this end, two distinct manipulations were conducted. First, the differential outcomes procedure (DOP), which correlates specific reinforcers with specific to-be-remembered events, was applied to an operant version of matching-to-position (MTP). This behavioral manipulation was conducted to determine if the DOP would improve memory performance in PTD-treated rats, demonstrating some intact cognitive functions. Additionally, to assess the functional integrity of the cholinergic and glutamatergic systems, normal and PTD-treated rats were administered i.p. injections of scopolamine and MK-801. It was found that the DOP enhanced memory, but not acquisition performance, in both normal and PTD-treated rats. Furthermore, when administered scopolamine, but not MK-801, rats trained with the DOP continued to outperform rats trained with a non-differential outcomes procedure (NOP). However, PTD-treated rats, regardless of training procedure (DOP, NOP), were more disrupted by the 'amnestic' effects of both scopolamine and MK-801. The differential sensitivity of treatment groups to the amnestic effects of scopolamine and MK-801 reveals insights into the neurochemical correlates of memory processes and WKS.

Acute Disease↗
PubMed2000

Scopolamine impairs memory performance and reduces frontal but not parietal visual P3 amplitude.

It has been suggested that the P3 event-related potential (ERP) may mark the operation of certain working or long-term memory processes. It has also been reported that cholinergic blockade by scopolamine induces significant memory impairment and is associated with an increased latency, as well as amplitude reduction or abolition of the auditory P3, thus supporting hypothesised links between P3 and long-term memory function. An intriguing anomaly is that, while visual P3 latency is also increased by scopolamine, amplitude is not changed. The aim of this study was to make a more detailed assessment of the effects of scopolamine on the visual P3 at a drug dose known to induce memory impairment. After drug administration, memory performance was significantly impaired and visual P3 latency was significantly increased. There was little evidence of parietal P3 amplitude reduction, but frontal P3 amplitude was significantly reduced in both target and non-target conditions. These findings, when considered in the light of a more recent study of the effects of scopolamine on auditory P3, suggest that cholinergic blockade produces a common effect in both visual and auditory modalities of significant frontal P3 amplitude reduction, but no significant parietal P3 amplitude reduction. These results are consistent with the view that there are modality-independent generators of the parietal and frontal P3. The finding of drug-induced memory impairment and modulations of frontal ERP deflections is also consistent with recent evidence of a significant role for regions of the frontal lobe in encoding and retrieval of long-term memories.

Adult↗
PubMed1999

The effects of temperature and scopolamine on N-methyl-D-aspartate antagonist-induced neuronal necrosis in the rat.

The effects of temperature and scopolamine on dizocilpine maleate-induced neuronal necrosis in the rat cingulate/retrosplenial cortex, entorhinal/olfactory cortices and the dentate gyrus were studied. Mild, protracted hypothermia (48 h at a brain temperature of 34 degrees C), induced by a servo-controlled "exposure technique" in the awake female rat, significantly reduced dizocilpine maleate (5.0 mg/kg, i.p.)-induced neuronal death in the cingulate/retrosplenial and entorhinal/olfactory cortices seven days following drug administration. Scopolamine (0.25 mg/kg, i.p.), putatively neuroprotective [Olney J. W. et al. (1991) Science 254, 1515-1518], did not reduce injury in the cingulate/retrosplenial cortex of female rats following one injection, but did following two and three doses. Scopolamine had no significant effect in the other brain regions. A temperature elevation of only 1 degree C above baseline for 48 h in awake female rats increased dizocilpine maleate-induced damage. Finally, the sex differences in N-methyl-D-aspartate antagonist toxicity were replicated and extended to other structures, and found not to be due to temperature differences. Our data show that dizocilpine maleate neurotoxicity is temperature sensitive. Scopolamine treatment needed to be prolonged in order to reduce injury, and even then was only efficacious in one of three brain regions. The results underscore the importance of using neuronal necrosis in several brain regions as the endpoint and for the use of prolonged therapeutic interventions. Furthermore, given the potential hypothermic action of other putative neuroprotective drugs, a mechanistic re-evaluation of N-methyl-D-aspartate antagonist-induced injury is needed, with precise brain temperature measurement.

Animals↗
PubMed2000

Intra-medial prefrontal cortex injections of scopolamine increase instrumental responses for cocaine: an intravenous self-administration study in rats.

The present experiments examined the effects of muscarinic cholinergic receptor blockade in the nucleus accumbens (NAC) and medial prefrontal cortex (MPC) on intravenous cocaine self-administration. Adult male Sprague-Dawley rats were implanted with chronic indwelling jugular catheters and guide cannulae stereotaxically aimed at the NAC or MPC. The rats were then given the opportunity to intravenously self-administer cocaine (0.8 mg/kg/infusion) during daily 2-h sessions. Intra-NAC microinjections of methyl-scopolamine (2, 4, 8, 16, and 32 microg/side) or vehicle did not affect either the number of lever presses made or infusions delivered. On the other hand, intra-MPC injections of scopolamine significantly increased responding, although there was only a trend for an increase in the number of cocaine infusions. The effects of intra-MPC injections of scopolamine (8 and 16 microg/side) on locomotor activity were also evaluated. Intra-MPC injections of scopolamine (16 microg/side) produced significant increases in locomotor activity. However, these same microinjections decreased locomotor activity when the animals also received cocaine (15 mg/kg, i.p.). These results suggest that cholinergic neurotransmission at muscarinic receptors in the MPC is involved in regulating cocaine-maintained responding.

Animals↗
PubMed1990

Electron-impact ionization detection of scopolamine by gas chromatography-mass spectrometry in rat plasma and brain.

Scopolamine, a muscarinic receptor antagonist, was measured in rat plasma and brain using gas chromatography-mass spectrometry with electron-impact ionization detection. Extracted scopolamine was either directly derivatized or first hydrolyzed to scopine, then derivatized with heptafluorobutyric anhydride, separated on a capillary column and quantified by mass fragmentography. Electron-impact ionization produced a common fragment peak at m/z 138 that was monitored along with trideuterated scopolamine, an internal standard (m/z 141). The method can be used to measure scopolamine concentrations of 2 ng/ml in rat plasma and 20 ng/g in rat brain.

Animals↗
PubMed2000

Scopolamine reduces sensitivity to auditory gaps in the rat, suggesting a cholinergic contribution to temporal acuity.

Prior research [Caine et al., 1981] suggested that scopolamine, a central cholinergic antagonist, may increase gap thresholds in young human listeners. If confirmed, an effect of scopolamine on gap detection might help to explain why both aged humans and aged laboratory animals have less sensitive temporal acuity on gap detection tests, as they may be presumed to have less effective cholinergic mechanisms. Here we measured the effect of scopolamine on gap detection in rats (n=8) using reflex modification audiometry, which depends on the fact that brief gaps in noise presented immediately prior to a loud noise inhibit the acoustic startle reflex. Scopolamine increased the gap threshold and reduced reflex inhibition produced by gaps that were presented at and beyond about 40 ms prior to the startle reflex, but not at shorter lead times. A peripheral antagonist had no effect at long lead times. These data indicate that central cholinergic mechanisms are involved in relatively high level perceptual processing of gaps. This conclusion is consistent with the hypothesis that temporal acuity may be compromised in the aged listener because of deficits in the efficacy of these central mechanisms.

Acoustic Stimulation↗
PubMed2001

N-tert-butyl-alpha-phenylnitrone, a free radical scavenger with anticholinesterase activity does not improve the cognitive performance of scopolamine-challenged rats.

Reversible inhibitors of acetylcholinesterase improve spatial learning and memory in animal models of cognitive impairment. Here we investigate if the beneficial effects of free radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on cognitive performance could be explained by its recently discovered anticholinesterase activity. Morris water maze experiment was performed to examine the effect of PBN on the impairment of spatial learning and memory induced by the antagonist of cholinergic muscarinic transmission scopolamine. In situ hybridization histochemistry experiment was performed to study its effects on the induction of immediate early gene expression (c-fos, c-jun) by dopamine D1 receptor agonist SKF-82958 and on the augmentation of the SKF-82958-induced expression of these genes by scopolamine. In both experiments, the effects of PBN were compared to the effects of reversible anticholinesterase physostigmine. We found that physostigmine but not PBN significantly reversed the cognitive impairment in scopolamine-challenged rats, prevented the induction of c-fos and c-jun mRNAs by SKF-82958 and attenuated the augmentation of the SKF-82958-induced expression of these genes by scopolamine. The present experiments did not reveal a significant in vivo anticholinesterase activity of PBN.

Animals↗
PubMed2000

Intravenous scopolamine is potently self-administered in drug-naive mice.

Scopolamine self-administration was investigated in an acute model using drug-naive mice. The mice could self-administer intravenous infusions contingent on nose poking and were tested in pairs using a contingent and a yoked control mouse. Upon nose poking of the contingent mouse, both mice received an intravenous infusion of either saline or scopolamine (fixed ratio 1). An inverted U-shaped unit dose-response curve was seen with the contingent mice. The unit dose at which nose poking of the contingent mice peaked (mean 375 per 30 min) was 0.1 mg/kg/infusion. Nose poking of yoked control mice also increased dose dependently, but it was significantly lower than that of the contingent mice. The apparent scopolamine-induced dose-dependent hyperactivity was, however, unlikely in itself to form the entire basis for the increase in nose poking of the contingent mice. The results demonstrate that scopolamine has acute and reinforcing properties in drug naive mice.

Analysis of Variance↗
PubMed2003

Effects of scopolamine on MEG spectral power and coherence in elderly subjects.

OBJECTIVE: Scopolamine, a muscarinic receptor antagonist, can produce temporary cognitive impairments as well as electroencephalographic changes that partially resemble those observed in Alzheimer's disease. In order to test the sensitivity of spectral power and hemispheric coherence to changes in cholinergic transmission, we evaluated quantitative magnetoencephalogram (MEG) after intravenous injection of scopolamine. METHODS: MEG of 8 elderly healthy subjects (59-80 years) were measured with a whole-head magnetometer after intravenous injection of scopolamine. An injection of glycopyrrolate, a peripheral muscarinic antagonist, was used as the placebo in a double-blind, randomized, cross-over design. Spectral power and coherence were computed over 7 brain regions in 3 frequency bands. RESULTS: Scopolamine administration increased theta activity (4-8 Hz) and resulted in the abnormal pattern of MEG desynchronization in eyes-open vs. eyes-closed conditions in the alpha band (8-13 Hz). These effects were most prominent over the posterior regions. Interhemispheric and left intrahemispheric coherence was significantly decreased in the theta band (4-8 Hz). CONCLUSIONS: Spontaneous cortical activity at the theta and alpha range and functional coupling in the theta band are modulated by the cholinergic system. MEG may provide a tool for monitoring brain dynamics in neurological disorders associated with cholinergic abnormalities.

Aged↗
PubMed2004

REM sleep and cortisol responses to scopolamine during depression and remission in women.

Baseline electroencephalographic (EEG) sleep and the EEG sleep response to scopolamine were studied in 10 adult female patients with unipolar major depressive disorder. Subjects were studied twice for two consecutive nights while depressed and, again, during remission. On the second night of each two-night session, normal saline or scopolamine (1.5 microg/kg, i.m.) was administered in a randomized, double-blind, cross-over fashion. Nocturnal urinary free cortisol (NUFC) measures also were collected. Compared to the depressed state, NUFC was significantly lower during remission. In contrast, baseline EEG sleep measures did not differ from episode to remission. Scopolamine suppressed rapid eye movement (REM) sleep to a comparable extent during the depressive episode and in remission. Scopolamine also reduced NUFC secretion during both clinical states, but to a lesser extent than REM sleep suppression. The findings suggest that the dysregulation in cholinergic systems associated with depressive illness may be persistent during remission, at least for some cholinergic systems. The results also suggest that the central cholinergic system(s) that regulate(s) REM sleep may be more sensitive to dysregulation than the cholinergic system(s) that control(s) nocturnal cortisol secretion.

Adult↗
PubMed2000

Effects of pH and dose on nasal absorption of scopolamine hydrobromide in human subjects.

PURPOSE: The present study was conducted to evaluate the effects of formulation pH and dose on nasal absorption of scopolamine hydrobromide, the single most effective drug available for the prevention of nausea and vomiting induced by motion sickness. METHODS: Human subjects received scopolamine nasally at a dose of 0.2 mg/0.05 mL or 0.4 mg/0.10 mL, blood samples were collected at different time points, and plasma scopolamine concentrations were determined by LC-MS/MS. RESULTS: Following administration of a 0.2 mg dose, the average Cmax values were found to be 262+/-118, 419+/-161, and 488+/-331 pg/ mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At the 0.4 mg dose the average Cmax values were found to be 503+/-199, 933+/-449, and 1,308+/-473 pg/mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At a 0.2 mg dose, the AUC values were found to be 23,208+/-6,824, 29,145+/-9,225, and 25,721+/-5,294 pg x min/mL for formulation pH 4.0, 7.0, and 9.0, respectively. At a 0.4 mg dose, the average AUC value was found to be high for pH 9.0 formulation (70,740+/-29,381 pg x min/mL) as compared to those of pH 4.0 (59,573+/-13,700 pg x min/mL) and pH 7.0 (55,298+/-17,305 pg x min/mL) formulations. Both the Cmax and AUC values were almost doubled with doubling the dose. On the other hand, the average Tmax, values decreased linearly with a decrease in formulation pH at both doses. For example, at a 0.4 mg dose, the average Tmax values were 26.7+/-5.8, 15.0+/-10.0, and 8.8+/-2.5 minutes at formulation pH 4.0, 7.0, and 9.0, respectively. CONCLUSIONS: Nasal absorption of scopolamine hydrobromide in human subjects increased substantially with increases in formulation pH and dose.

Absorption↗
PubMed1994

Estrogen and estrogen-progesterone treatments counteract the effect of scopolamine on reinforced T-maze alternation in female rats.

The purpose of the experiments was to determine if steroid hormone treatments would attenuate the effect of the muscarinic receptor blocker scopolamine on a memory task. Ovariectomized rats were trained first to alternate for food reward between the arms of a T maze. Following training, females treated with scopolamine hydrobromide (0.2 mg/kg ip) did not alternate correctly between the arms of the T maze and responded at chance levels. However, when estradiol benzoate (25 micrograms) was administered 72, 48, and 24 hr before testing alone or in combination with progesterone (500 micrograms) administered 4-6 hr before testing, females alternated successfully between the arms of the T maze following scopolamine administration. Results indicate that gonadal steroids can completely counteract the impairment of T maze performance induced by scopolamine in female rats.

Animals↗