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PubMed1998

Muscarinic-receptor antagonist scopolamine rescues hippocampal neurons from death induced by glutamate.

Cultured hippocampal neurons were used to test the hypothesis that modulation of muscarine receptors can modify glutamate-induced neurodegeneration. Treatment of hippocampal cultures with scopolamine (1 nM to 1 mM) under glutamate incubation had beneficial effect on neuronal viability. Thus, blockade of muscarinic-receptor sites increased the threshold for glutamate neurotoxicity. These data show that interactions between the NMDA, muscarinic receptors and their corresponding neurotransmitter inputs to hippocampal neurons may play a crucial role in neurodegeneration.

Animals↗
PubMed2003

Loss of anti-cataleptic effect of scopolamine in mice lacking muscarinic acetylcholine receptor subtype 4.

Motor dysfunction associated with dyskinesia can be caused by imbalance between dopaminergic and cholinergic actions. Antimuscarinic agents are used to treat extrapyramidal symptoms in Parkinson's disease and extrapyramidal side effects of antipsychotics. These therapeutic effects are mediated by blockade of the striatal muscarinic receptors, which comprise five distinct subtypes (M(1-5)). To evaluate the role of muscarinic M(4) receptors, we have generated mutant mice lacking this subtype (muscarinic M(4) receptor-knockout mice) and analyzed their cataleptic responses induced by haloperidol (an animal model of extrapyramidal side effects). While the muscarinic M(4) receptor-knockout mice developed the cataleptic response normally, systemic administration of scopolamine could not suppress the cataleptic response. These results suggest that acute, but not chronic, blockade of muscarinic M(4) receptors plays important roles in the therapeutic effects of antimuscarinic agents.

Animals↗
PubMed1997

Effects of ginsenosides on maze performance and brain choline acetyltransferase activity in scopolamine-treated young rats and aged rats.

In young adult rats with scopolamine-induced cognitive impairment, choline acetyltransferase activity was increased in the medial septum, but not in the diagonal band, caudate and hippocampus, 30 min after the injection of ginsenosides Rg1 or Re. Rb1 and Rd had no effect on choline acetyltransferase activity. Aged rats showed a smaller number of initial correct responses in the radial-arm maze and a lower choline acetyltransferase activity in the medial septum, diagonal band, caudate and hippocampus than did young adult rats. Repeated i.p. injections of Rg1 increased the number of initial correct responses and the activity of choline acetyltransferase in the medial septum, but not in the diagonal band, caudate and hippocampus, in aged rats. These results suggest that Rg1 and Re may contribute the ameliorative effects through an increase of choline acetyltransferase activity in the medial septum.

Aging↗
PubMed2003

Preparation of a molecularly imprinted polymer for the solid-phase extraction of scopolamine with hyoscyamine as a dummy template molecule.

Molecularly imprinted polymers (MIPs) selective for scopolamine were produced using hyoscyamine (a close structural analogue) as template molecule. The produced polymers were used as media for solid-phase extraction, exhibiting selective binding properties for the analyte from biological samples. Human and calf urine and serum were processed on the MIP under various extraction protocols. The best performance was observed after loading the analyte in aqueous environment facilitating retention on the MIP by non-selective hydrophobic interactions. The MIPs were subsequently washed using an optimised solvent system to enable selective desorption of the analyte. Other related and non-related compounds were accessed to evaluate molecular recognition properties. Recoveries of up to 79% were achieved for the analyte of interest from biological samples.

Animals↗
PubMed2000

Effects of prenatal AZT+3TC treatment on open field behavior and responsiveness to scopolamine in adult mice.

Treatment of pregnant seropositive women and their neonates with the nucleoside analogs (reverse transcriptase inhibitors) zidovudine (AZT), lamivudine (3TC) and their combination has become a standard of care in industrialized countries to prevent transmission of the HIV-1 virus. Animal studies indicated limited but significant behavioral changes in AZT or 3TC-prenatally exposed offspring, whereas data on the potential neurobehavioral outcomes of AZT+3TC combination are still lacking. The aim of the present study was to assess in mice prenatally exposed to AZT+3TC the functional state of cholinergic muscarinic neuroregulation at adulthood. Pregnant CD-1 mice received per orem twice daily AZT+3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) from gestational day (GD) 10 to delivery (GD 19). Locomotor activity, exploratory behavior and responsiveness to the muscarinic cholinergic blocker scopolamine (2 mg/kg) were analyzed at adulthood (PND 70) in offspring of both sexes in an open field test. Results indicated that prenatal AZT+3TC exposure does not influence responsiveness to the muscarinic cholinergic antagonist as measured by analysis of the drug's effects on locomotor and exploratory activity and different behavioral items. However, AZT+3TC-treated mice displayed higher frequency of rearing, and lower frequency and duration of self-grooming behavior, consistent with an effect on dopaminergic neurotransmission. However, this would need confirmatory experiments.

Animals↗
PubMed1997

Cognitive dysfunctions induced by scopolamine are reduced by systemic or intrahippocampal mineralocorticoid receptor blockade.

Central cholinergic blockade with scopolamine (SCOP) produces profound cognitive impairments in human and animal subjects. We hypothesized that cognitive deficits induced by cholinergic blockade originate partly from its ability to enhance reactivity to the environment, an effect that would be ameliorated by prior mineralocorticoid receptor (MR) blockade, because MR antagonists reduce reactivity to novelty. In the present study, we investigated whether or not systemic or intrahippocampal infusions of the MR antagonist spironolactone (SPIRO) would affect SCOP-induced cognitive impairments in a water maze task. Adult male Lister hooded rats (350-450 g) served as subjects. In Experiment 1, rats were administered SPIRO (0 or 100 mg/kg i.p.) followed 10 min later by SCOP (0, 0.5, or 2.0 mg/kg i.p.; n = 10/group). In Experiment 2, groups of rats implanted with hippocampal cannulae received central infusions of SPIRO (50 ng/microliter; 3 microliters in total) 10 min prior to SCOP injection (2.0 mg/kg i.p.; n = 6/group). Behavioural testing started 15 min after SCOP administration and consisted of a simple water maze task in which animals were required to locate a submerged platform using spatial cues. The testing regime consisted of two phases: a) acquisition, and b) retention, 24 h later. Peripheral, but not central, injections of SPIRO enhanced water maze performance during acquisition in SCOP-treated rats, as shown by shorter latencies and shorter distances travelled to locate the hidden platform. Both peripheral and central SPIRO administration reduced the long-term retention deficits in performance in the SCOP-treated animals. These data are in general agreement with a growing body of research suggesting that corticosteroid hormones interact with central cholinergic systems to affect both physiological and behavioural responses. MR blockade may reduce an animal's reactivity to the environment and enable it to selectively filter out extraneous stimuli that it would otherwise react to, thus impairing performance.

Animals↗
PubMed1998

Modulation of spatial alternation and anxiety by septal scopolamine systemic diazepam in mice.

To investigate the behavioral consequences of benzodiazepines in subjects whose septo-hippocampal cholinergic (ACh) activity was impaired, C57BL/6 mice received an injection of 2.5 microg/0.2 microl of scopolamine into the medial septal area with an i.p. injection of 0.5 mg/kg of diazepam. The consequences of these treatments administered in combination or alone were evaluated on anxiety measured in an elevated plus-maze and on spontaneous alternation carried out in a T-maze, using two different intertrial intervals (ITI: 5s or 30s). In these conditions, only the combined treatment provoked a decrease of the anxiety level, which was associated with an impairment of spontaneous alternation restricted to the 5s ITI. Because mice were not impaired during the sequential 30s ITI, this seems to rule out the possibility that this alternation deficit resulted from a working memory loss. These results suggest an involvement of a septal ACh-GABA-A/BDZ interaction in the exaggeration of cognitive deficits produced by benzodiazepines in patients characterized by a cholinergic hypofunction.

Animals↗
PubMed1999

Two related forms of long-term habituation in the crab Chasmagnathus are differentially affected by scopolamine.

An opaque screen moving overhead elicits an escape response in the crab Chasmagnathus, which, after a few presentations, habituates for a long period (long-term habituation, LTH). Previous results distinguished two types of LTH: the (context-signal)-LTH yielded by spaced training, determined by an association between context and habituating stimulus, and cycloheximide sensitive: and the (signal)-LTH produced by massed training, context independent, and cycloheximide insensitive. Present experiments were aimed at studying the possible involvement of cholinergic mechanisms in one or both types of LTH, using the muscarinic antagonist, scopolamine (SCP). Results indicate that LTH acquired by spaced training (30 trials separated by 85 s) is blocked in a dose-dependent manner by posttraining SCP. Amnesia is shown with 100 ng SCP/g injected immediately before or after spaced training but not delayed 1-h posttraining. No effect of SCP on LTH acquired by massed training (300 trials separated by 4 s) is detected. Pretraining SCP induces a decrease in the response level at the initial trials of either a spaced or a massed training. It is concluded that the storage of (context-signal)-LTH may be selectively regulated by a muscarinic-cholinergic mechanism. However, the possibility that other cholinergic receptors would be involved in the consolidation of the (signal)-LTH is discussed.

Animals↗
PubMed2000

Scopolamine augments the efficacy of physostigmine against soman poisoning in guinea pigs.

The efficacy of the subchronically administered cholinesterase-inhibitor physostigmine (PHY) (0.025 mg/kg/h) either with or without the muscarinergic receptor antagonist scopolamine (SCO) (0.018 mg/kg/h) in counteracting soman-induced lethality and incapacitation were determined in guinea pigs. This was tested in animals that either received atropine sulphate (AS, 17.4 mg/kg i.m.) or no postintoxication therapy. Behavioral and neurophysiological readout systems were used to measure postintoxication incapacitation. Only the pretreatment with PHY alone did not offer any protection against 2x LD50 soman intoxication. Animals that received the complete treatment (PHY + SCO + AS) did not show any abberations in the performance of learned behavior. The use of AS after soman intoxication resulted in an increase of the startle response, whereas the addition of SCO to the pretreatment led to a more persistent duration of the effect in time. In case one has to rely completely on the pretreatment, the addition of SCO to PHY is life-saving. However, some postintoxication incapacitation is still present. Therefore, the pretreatment regime may perhaps further be improved by the addition of a nicotinic antagonist.

Animals↗
PubMed1992

Pressure on the snout immobilizes the spontaneously active, scopolaminized, and amphetaminized hyperactive rat.

Rats that are brought into a novel environment or that are given stimulants or anti-muscarinic drugs exhibit high levels of motor activity. Application of moderate pressure on the sides of the snout of such rats results in immediate cessation of all movements for extended time periods. Hippocampal electrocorticograms show that hippocampal slow wave activity during such induced immobility is equivalent to the hippocampal slow wave pattern typically associated with spontaneous immobility. However, neocortical activity following scopolamine administration contains more 2-6 Hz irregular activity during spontaneous than induced immobility.

Animals↗
PubMed1996

Benzodiazepine receptor stimulation blocks scopolamine-induced learning impairments in a water maze task.

Central cholinergic (ACh) blockade produces profound cognitive impairments in human and animal subjects. Our previous research demonstrated that ACh blockade exacerbates stress-induced adrenocorticotrophin (ACTH) and corticosterone (CORT) secretion, and increases anxiety-like behavior (ALB) in rats. The fact that all these responses occur following the same manipulation led us to question whether or not increases in ALB might play a part in the cognitive deficits. This issue was all the more intriguing given that anxiolytic agents such as benzodiazepines are reported to produce learning and memory impairments on their own. We reasoned that a low dose of diazepam (DZP) with no apparent cognitive effects itself, might be able to antagonize an impairment induced by scopolamine (SCOP). Adult male Lister rats (n = 6/group) were administered IP either vehicle (VEH), 0.5 mg/kg DZP, 0.25 mg/kg SCOP, or 0.5 mg/kg DZP, followed 20 min later by 0.25 mg/kg SCOP, and tested 20 min later in a water maze for latency to locate a hidden platform and for path length taken to the platform. Rats were tested in an acquisition phase (Day 1) and a retention phase (Day 2), as well as on a visually guided task. On Day 1, SCOP produced a marked acquisition deficit that was unaffected by DZP. DZP by itself had no obvious effect. However, whereas SCOP resulted in a persistent deficit on the retention task (Day 2), pretreatment with DZP prior to SCOP on Day 1 completely abolished the impairment. There were no group differences on the visually cued task. We contend that SCOP-induced cognitive deficits may, in part, be due to increases in ALB. Stimulation of benzodiazepine receptors may offset the loss of cholinergic systems underlying consolidation mechanisms, but not those mediating immediate task performance. Whether this effect of DZP relates to an action on ALB remains to be elucidated.

Animals↗
PubMed1998

The effects of intrahippocampal scopolamine infusions on anxiety in rats as measured by the black-white box test.

Hippocampal cholinergic projections mediate attention to arousing stimuli as demonstrated by behavioral, electrophysiological, and endocrine studies. We recently reported that peripheral injections of the cholinergic antagonist scopolamine (SCOP) increased anxiety-like behaviour (ALB) in rats and we sought to investigate if this response might be hippocampally mediated. Adult male, Lister Hooded rats were implanted bilaterally with hippocampal cannulae 3 weeks prior to testing. On the test day, rats were injected with vehicle (VEH; artificial CSF at 3 microl), 15 or 30 microg SCOP, 20 min prior to being placed into the white chamber of the black-white box (n = 10/group). Rats were scored for latencies to exit and reenter the white chamber, total time spent in the white chamber, intercompartmental crossings, and activity. SCOP at 30 microg significantly reduced time to exit the white arena, while both doses of SCOP elevated latencies to reenter the white chamber. There were no effects of SCOP on intercompartmental crossing, time spent in the white chamber, or on activity levels. Loss of hippocampal cholinergic function impairs processing of threatening stimuli that manifests itself as increased ALB.

Analysis of Variance↗
PubMed2001

Distribution of hyoscyamine and scopolamine in Datura stramonium.

The production of hyoscyamine and scopolamine in Datura stramonium has been investigated in the different plant parts, at different stages of their life cycle. Maximum contents were found in the stems and leaves of young plants, hyoscyamine being always the predominant component.

Atropine↗
PubMed1997

Development and validation of a capillary zone electrophoresis method for the determination of atropine, homatropine and scopolamine in ophthalmic solutions.

A capillary zone electrophoresis method is described for the simultaneous determination of atropine, homatropine and scopolamine. Successful results were obtained after optimization of the electrophoretic parameters such as buffer composition and pH. The best separation was achieved using a 100 mM Tris-phosphate running buffer at pH 7. The validation data proved that the method had the requisite selectivity, sensitivity, reproducibility and linearity to be used for the assay of these compounds in pharmaceutical formulations. Dosage of the separate drugs in ophthalmic preparations is also presented.

Atropine↗
PubMed1998

Validated capillary electrophoresis method for the determination of atropine and scopolamine derivatives in pharmaceutical formulations.

The simultaneous determination of atropine and scopolamine derivatives, which have similar structures, was investigated by using capillary zone electrophoresis. The effects of buffer pH, buffer concentration and hydroxypropyl-beta-cyclodextrin concentration on migration time and resolution of the investigated compounds were systematically studied. The selected electrophoretic buffer consisted of a 80 mM sodium citrate pH 2.5, containing 2.5 mM hydroxypropyl-beta-cyclodextrin as the complexing agent. Quantitative analysis was validated by testing the reproducibility of the method, giving a relative standard deviation less than 1 and 2% for the intermediate precision of migration times and peak area ratios, respectively. The linearity of the method was assessed between 50 and 150% of the theoretical content (coefficient of correlation greater than 0.99). The proposed method was found to be suitable and accurate for the determination of these basic drugs in pharmaceutical preparations.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Nebulized scopolamine in the management of oral dribbling: three case reports.

Difficulty swallowing saliva or its excessive production may be problematic for some patients. The resulting oral dribbling is often embarrassing. Three patients were admitted for hospice care complaining of oral dribbling. Each patient was given nebulized scopolamine hydrobromide which helped lessen the dribbling.

Administration, Inhalation↗
PubMed2000

Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial.

Bowel obstruction may be an inoperable complication in patients with end-stage cancer. Scopolamine butylbromide (SB) and octreotide (OCT) have been successfully used with the aim of reducing gastrointestinal (GI) secretions to avoid placement of a nasogastric tube (NGT); however, there have been no comparative studies concerning the efficacy of these drugs. Furthermore, there is little information about the role played by parenteral hydration in symptom control of these patients. In a prospective trial that involved all 17 inoperable bowel-obstructed patients presenting to our services with a decompressive NGT, patients were randomized to OCT 0.3 mg/day or SB 60 mg/day for 3 days through a continuous subcutaneous infusion. Clinical data, survival time, and the time interval from the first diagnosis of cancer to the onset of inoperable bowel obstruction were noted. The intensity of pain, nausea, dry mouth, thirst, dyspnea, feeling of abdominal distension, and drowsiness were assessed by means of a verbal scale before starting treatment with the drugs under study (T0) and then daily for 3 days (T1, T2, T3). Moreover, daily information was collected regarding the quantity of GI secretions through the NGT, the oral intake of fluids, the quantity of parenteral hydration, and the analgesic therapy used. The NGT could be removed in all 10 home care and in 3 hospitalized patients without changing the dosage of the drugs. OCT significantly reduced the amount of GI secretions at T2 (P = 0.016) and T3 (P = 0.020). Compared to the home care patients, the hospitalized patients received significantly more parenteral hydration (P = 0.0005) and drank more fluids (P = 0.025). There was no difference in the daily thirst and dry mouth intensity in relation to the amount of parenteral hydration or the treatment provided (OCT or SB). Independent of antisecretory treatment, the patients receiving less parenteral hydration presented significantly more nausea (T0 P = 0.002; T1 P = 0.001; T2 P = 0.003; T3 P = 0.001) and drowsiness at T3 (P < 0.5). Pain relief was obtained in all 17 patients and only two patients required an increase in morphine dose at T1. All patients with inoperable malignant bowel obstruction should undergo treatment with antisecretory drugs so as to evaluate the possibility of removing the NGT. When a more rapid reduction in GI secretions is desired, OCT should be considered as the first choice drug. Parenteral hydration over 500 ml/day may reduce nausea and drowsiness.

Aged↗
PubMed1997

Differential effects of scopolamine on neuronal survival in ischemia and glutamate neurotoxicity: relationships to the excessive vulnerability of the dorsoseptal hippocampus.

The neurodegeneration in the CA1 subfield of hippocampus exhibited a dorsal-ventral gradient of susceptibility in global ischemia (82% dorsoseptally and only 16% ventrotemporally). Scopolamine (SCOP) did not improve the neuronal damage caused by the global ischemic challenge in rats and did not reduce the infarct area after the focal MCA-occlusion in mice. No differences were observed between saline and SCOP-treated animals in the physiologic parameters, except for a slight increase in rectal temperature. In contrast, treatment of hippocampal cultures with increasing concentrations of SCOP (1 nM to 1 mM) under glutamate incubation had a beneficial effect on neuronal viability. These data show that (1) there is substantial gradient of vulnerability of the hippocampus from dorsal to ventral in global ischemia and (2) that interactions between the NMDA, muscarinic receptors and their corresponding neurotransmitter inputs to hippocampal neurons are evident in vitro and may play a crucial role in neuronal neurodegeneration. However, the mechanisms underlying the high vulnerability of dorsal hippocampus still remain enigmatic.

Animals↗