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PubMed2002

Reversal of scopolamine-induced spatial memory deficits in rats by TAK-147.

AIM: To evaluate effect of TAK-147 on spatial memory deficit induced by scopolamine. METHODS: Morris water maze was used to measure spatial memory in rats and open field test was used to analyse locomotor activity. RESULTS: In the acquisition memory process, scopolamine (0.4 mg/kg, ip) markedly increased the escape latency to the platform. Ip injection of both TAK-147 and donepezil ameliorated scopolamine-induced deficit, dose-related and significant effect was obtained at doses of 0.1-1.0 mg/kg. In the memory retrieval process, increased latency induced by scopolamine (1.5 mg/kg, ip) was also significantly reversed by treatment with TAK-147 (0.1, 0.3, and 1.0 mg/kg), donepezil (0.3 and 1.0 mg/kg), and tacrine (3 and 5 mg/kg), respectively. TAK-147 has a little potent efficacy to donepezil, and was more potent than tacrine. In the locomotor test, both TAK-147 and donepizil created no appreciable change of locomotor activities, compared with scopolamine or saline. CONCLUSION: TAK-147 plays an important role in spatial cognition, and this result provides additional evidence that TAK-147 is an ideal AChE inhibitor and is useful for the treatment of Alzheimer's disease.

Animals↗

PubMed2002

Nefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbit.

BACKGROUND: The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized. Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD. MATERIAL/METHODS: To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg) were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam. RESULTS: Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment. CONCLUSIONS: Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.

Aging↗

PubMed2004

Estrogen and progesterone improve scopolamine-induced impairment of spatial memory.

This study was conducted to investigate the effects of estrogen and progesterone on spatial memory in ovariectomized female rats, specifically, on memory impaired by the cholinergic antagonist scopolamine. Forty-one female rats were divided into five groups: ovariectomized (OVX), estrogen-treated after ovariectomy (OE), progesterone-treated after ovariectomy (OP), estrogen-progesterone-treated after ovariectomy (OEP), and the sham control group (Control). The animals were trained on an eight-arm radial maze with four arms baited to assess both working and reference memory performances. The OE and OEP groups showed significant improvement in the ability to perform a spatial memory task over the OVX group (P<0.05). Spatial memory in the OP group did not differ from that in the OVX group. After thirty-two trials were conducted and all rats learned the eight-radial maze task, scopolamine hydrobromide (0.2 mg/kg i.p.) was administered prior to retesting. After scopolamine injection, the OVX group showed an increased number of working memory errors, reference memory errors than the other groups (P<0.05). The OE, OEP and OP groups showed significant improvement in spatial impairment induced by scopolamine. These findings suggest progesterone alone or in combination with estrogen, improved scopolamine-induced impairment of working memory and reference memory as effectively as estrogen supplementation.

Analysis of Variance↗

PubMed1990

beta-Glucuronide and sulfate conjugation of scopolamine and glycopyrrolate.

The metabolism of scopolamine and glycopyrrolate was studied in 11 healthy parturients undergoing cesarean section. After a single intramuscular injection of scopolamine (5 micrograms/kg, n = 7) or glycopyrrolate (6 micrograms/kg, n = 4), the concentrations of the drugs in the urine were determined up to 8-12 h using a radioreceptor assay. This assay measures scopolamine and glycopyrrolate with their possible active metabolites. The effect of beta-glucuronidase and sulfatase incubation on the drug concentrations was also studied. The concentrations of scopolamine and/or its active metabolites were on the average 7 times higher after incubation indicating that beta-glucuronide or sulfate conjugation is an important metabolic pathway for scopolamine. On the contrary, the glycopyrrolate concentrations increased only slightly between 1 and 3 hours after the drug injection. Thus, beta-glucuronide or sulfate conjugation plays only a minor part in the metabolism of glycopyrrolate.

Female↗

PubMed1990

Differential effects of scopolamine and amphetamine on microcomputer-based performance tests.

Scopolamine (1.0 mg) and d-amphetamine (10 mg) were administered alone and in combination to 16 subjects (medical students), randomly assigned to testing sessions in a fully crossed-over (Latin square) within-subjects design. After being practiced to stability, 9 performance tests from a menu of portable microcomputer-based tests were administered double-blind over 4 weekly treatments (including a placebo). Differential effects of drugs on performance were found. Motor and perceptual speed tests appeared enhanced by d-amphetamine and not degraded by scopolamine. Two of the five cognitive tests showed reductions with scopolamine. The findings are discussed in connection with using a menu of performance tests that can have diagnostic significance for assessment of drug treatments. The effects of scopolamine in this study and others are considered in terms of a model which implies that magnitude of performance deficit depends on performance type (cognitive, motor, self-report) and dosage level. Applying the model, we offer the following summary: below 0.15 mg scopolamine is without any effect; below 0.50 mg, the effect is limited, but can be revealed by some sensitive, complex performance tests and self-report; above 1.0 mg, the effect is likely to impact on operational efficiency.

Administration, Oral↗

PubMed1989

[Transdermal scopolamine to prevent postoperative nausea and vomiting after uterine curettage and termination of pregnancy. A double-blind clinically controlled study with placebo].

A randomized double-blind clinically controlled investigation with a placebo was undertaken to investigate the prophylactic effect of transdermal scopolamine on postoperative nausea and vomiting after dilatation and curettage and termination of pregnancy. No significant difference was found between the placebo and transdermal scopolamine. On the other hand, the patients in the scopolamine group had significantly more postoperative discomforts which were attributable to the anticholinergic effect of scopolamine. Transdermal scopolamine cannot be recommended for the prophylaxis of postoperative nausea and vomiting following uterine curettage and termination of pregnancy.

Abortion, Induced↗

PubMed1986

[Effect of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on scopolamine-induced impairment of short-term memory in rats].

The effects of a few drugs, which are known to activate central nervous system, on scopolamine-induced impairment of short-term memory (STM) were studied in a delayed alternation task in rats. Rats were initially trained using a delayed alternation task in which a forced run to one arm of a T-maze was followed by a free-choice run. A correct free-choice response was defined as a turn toward the arm opposite to that in the forced run, and was rewarded with food pellets. After repeated training of the 60 sec-delayed alternation task, the treatment with scopolamine (0.2 mg/kg, ip) at 20 min before the test resulted in a significant decrement in the correct response. The scopolamine-induced impairment of STM was significantly antagonized by DN-1417 (10 mg/kg, ip) given 1 hr before the test. However, TRH (3-30 mg/kg, ip) and methamphetamine (0.2-1.0 mg/kg, ip) did not improve the scopolamine-induced impairment in the task. In rats without treatment with scopolamine, these drugs did not affect the percent correct response. These results suggest that DN-1417 may have an improving effect on the impairment of STM induced by a decreased cholinergic activity.

Animals↗

PubMed1988

Effects of transcutaneous scopolamine and depth on diver performance.

Transdermal scopolamine is an effective anti-motion-sickness medication that has less CNS side effects at normal ambient pressure than orally ingested agents. To see whether it has an effect on performance at depth, 24 healthy sport divers were exposed to depths equivalent to 5 m (1.5 ATA) and 36 m (4.8 ATA) in a dry recompression chamber, breathing air and wearing a skin patch containing either scopolamine or inactive placebo. Patches and dive depths were presented in a counterbalanced, double-blind experimental design. Tests of sentence comprehension, simple arithmetic, and manual dexterity were used to evaluate psychometric and cognitive performance. Drug side effects were recorded. The Bennett Hand Tool Dexterity Test was evaluated for its suitability for repeated measures testing, and found to be robust. Manual dexterity and sentence comprehension were significantly impaired at depth whereas arithmetic skills were not. No significant effects on diver performance from transdermal scopolamine were seen. Certain side effects such as blurred vision were more common with scopolamine than with placebo. The use of transdermal scopolamine as an antiemetic during diving operations deserves field evaluation.

Administration, Cutaneous↗

PubMed1985

The effects of TTS-scopolamine, dimenhydrinate, lidocaine, and tocainide on motion sickness, vertigo, and nystagmus.

The effects of TTS-scopolamine, dimenhydrinate, lidocaine, and tocainide on motion sickness and vertigo and on caloric and postrotatory nystagmus were evaluated in healthy volunteers. TTS-scopolamine was administered transdermally (delivering approximately 10 micrograms X h-1 scopolamine base) and 100 mg dimenhydrinate orally. Lidocaine and tocainide were administered intravenously (average plasma concentration of lidocaine 6 mol X L-1 and of tocainide 20 mol X L-1). TTS-scopolamine and dimenhydrinate significantly reduced vertigo induced by calorization of the ears, nausea provoked with Coriolis maneuvre, and nystagmus in caloric and rotatory tests. During treatment with lidocaine and tocainide no alleviation of vertigo and nausea was observed. Caloric nystagmus was reduced but rotation induced nystagmus was virtually unchanged. Presumably the motion sickness drugs act at the brain stem where TTS-scopolamine and dimenhydrinate have their target cells in the vestibular nuclei. Furthermore, the alleviation of motion sickness was linked to a decline of nystagmus. Lidocaine and tocainide, the action of which in vertigo and nausea in patients is proposed to be on the vestibular end organs and the supratentorial brain structures, consistently failed to alleviate motion sickness.

Administration, Topical↗

PubMedDate not supplied

[Effect of scopolamine on temporary connection formation and fixation in rats with altered brain noradrenaline content].

The locus coeruleus was ablated in rats or a 100 mg/kg dose of disulfiram and a 0.5 mg/kg dose of scopolamine were administered to them. Then a conditioned two-side avoidance reflex was elaborated. The locus coeruleus ablation and administration of disulfiram brought about a nearly equal reduction of noradrenaline (NA) content in the brain. Scopolamine against the background of a low NA level did not change its content. Ablation of locus coeruleus, administration of disulfiram and scopolamine did not prevent the elaboration, fixation and retention of the conditioned defensive reflex. Scopolamine introduced to animal with ablated locus coeruleus while not affecting the elaboration of defensive conditioned two-side avoidance reflex, completely prevented its retention. Administration of scopolamine to animals with a depressed NA synthesis produced a less profound amnesia.

Animals↗

PubMed1995

[Inhibitory effect and mechanism of scopolamine on respiration].

In conscious rabbits, dogs and anaesthetized dogs, the respiratory frequency (FR), tidal volume (Vt) and minute ventilation (Vm) were determined in order to confirm whether the respiratory effect of scopolamine is stimulatory or inhibitory. Arterial blood samples were taken intermittently and analyzed for Po2, Pco2 and pH. When scopolamine was injected i.c.v., i.a. and i.v., the decrease of FR, Vt, Vm and Po2 and the increase of Pco2 were observed in two animals. When the drug was given in clinical doses used for treating respiratory failure, the effect was seen still observable. The results indicate that scopolamine inhibits respiration. Moreover, it was observed that excitatory effect of pilocarpine on respiration can be antagonized by scopolamine, but the inhibitory effect of 6 beta-acetoxy nortropane can not be antagonized, on the contrary, can be coordinated. The above results suggest that respiratory inhibition induced by scopolamine may be related to blocking M1-R of the respiratory center.

Animals↗

PubMed1976

Prevention of experimental motion sickness by scopolamine absorbed through the skin.

A double-blind placebo-controlled study compared the efficacy of the antimotion sickness drug scopolamine when administered by oral or transdermal routes. A secondary purpose was to extend our bioassay involving fixed-dose combinations of the homergic drugs promethazine and ephedrine. After receiving 12 apparently identical drug-placebo treatments, eight normal male students were exposed to a slow rotation room to stressful accelerations generated by their execution of 40 head movements out of the plane of the room's rotation of 1 rpm and at 1-rpm increments until either symptoms were experienced (just short of frank motion sickness) or the 27-rpm ceiling on the test was reached. Efficacy of a drug was defined in terms of the placeborange and categorized as beneficial, inconsequential, or detrimental. The rank order of drugs with beneficial effects was: 1) promethazine 25 mg plus ephedrine 12.5 mg (86%); 2) scopolamine by mouth (75%); 3) scopolamine transdermally (63%); and 4) promethazine 12.5 mg plus ephedrine 25 mg (29%). The only detrimental effect was with scopolamine given orally. It is concluded that the advantages of the transdermal scopolamine, which include minimal side effects and prolonged effectiveness, deserve full exploitation.

Administration, Topical↗

PubMed1996

Neurokinin A and senktide attenuate scopolamine-induced impairment of spontaneous alternation performance in mice.

The effects of intracerebroventricular injections of the neurokinin-2 (NK-2) receptor agonist neurokinin A and the neurokinin-3 (NK-3) receptor agonist senktide on scopolamine (sc)-induced amnesia were investigated based on spontaneous alternation performance in mice. Spontaneous alternation performance is based on spatial working memory which produces a natural tendency to explore a less recently visited arm in a Y-maze. Neurokinin A (0.1-3 micrograms) or senktide (0.0003-0.03 microgram) alone did not influence either spontaneous alternation performance or total arm entries. However, neurokinin A (0.3 and 1 microgram) and senktide (0.003 and 0.03 microgram) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without affecting the scopolamine (1 mg/kg)-induced increase in total arm entries. Although the effects of neurokinin A (0.3 microgram) on the scopolamine-induced impairment of spontaneous alternation performance were almost completely antagonized by pretreatment with the NK-2 receptor antagonist cyclo (Gln-Trp-Phe-Gly-Leu-Met) (1 microgram), the inhibitory effects of senktide (0.003 microgram) were not influenced by pretreatment with the NK-3 receptor antagonist [Trp7, beta-Ala8]neurokinin A-(4-10). These findings suggest that neurokinin A inhibits the scopolamine-induced impairment of spontaneous alternation performance associated with working memory through the mediation of tachykinin NK-2 receptors, while senktide has some pharmacological action other than its effects on NK-3 receptors.

Amnesia↗

PubMed2003

Comparison of gastric peristalsis inhibition by scopolamine butylbromide and glucagon: evaluation by electrogastrography and analysis of heart rate variability.

BACKGROUND: Activation of glucagon receptors of the smooth muscle membrane suppresses gastric peristalsis. We evaluated autonomic nervous activity by two methods, electrogastrography (EGG) and analysis of heart rate variability, to compare the inhibiting effects of glucagon and scopolamine butylbromide on gastric peristalsis. METHODS: Heart rate variability, EGG, and blood catecholamine levels were measured before and after administration of glucagon (G group), scopolamine butylbromide (SB group), or physiological saline (C group). Autonomic nervous function was evaluated using spectral analysis of heart rate variability, and low frequency (LF) and high frequency (HF) power; the LF/HF ratios were also determined. RESULTS: After administration of scopolamine butylbromide, HF power, an index of parasympathetic nervous activity, decreased; and the LF/HF ratio, an index of sympathetic nervous activity, increased. In contrast, no significant change was observed in autonomic nervous activity after administration of glucagon. The peak power amplitudes of the EGG decreased significantly in the G and SB groups after intramuscular injection, but the difference between the groups was not significant. Furthermore, the dominant frequency increased significantly in the G and SB groups after injection. Serum catecholamine levels showed no significant changes after administration of scopolamine butylbromide or glucagon. CONCLUSIONS: Inhibition of gastric peristalsis by glucagon via glucagon receptors on smooth muscles did not influence autonomic nervous activity, unlike the results obtained after administration of scopolamine butylbromide. Therefore, glucagon may be safe for use with elderly patients and those with cardiopulmonary complications.

Adult↗

PubMed1976

An analysis of the action of atropine and scopolamine on the end-plate current of frog sartorius muscle.

The effects of atropine sulfate and scopolamine hydrobromide were investigated on the end-plate current (EPC) of frog sartorius muscle by standard voltage-clamp techniques. Both atropine and scopolamine reduced the peak EPC amplitude although scopolamine was only one-third as potent as atropine. The reduction of amplitude became more pronounced with increasing membrane hyperpolarization resulting in nonlinear current-voltage characteristics. Atropine shortened the EPC duration and decreased the voltage-sensitivity of the falling phase; the latter, however, continued to remain a single exponential function of time as in the control. Scopolamine reduced the time to peak, and in addition, converted the falling phase to a double exponential function, consisting of a rapid initial phase followed by a slow terminal phase. Both phases of fall were altered by changes in drug concentration but only the terminal phase responded appreciably to changes in membrane potential. Atropine and scopolamine were without effect on the EPC reversal potential, indicating that the drugs do not exhibit a preference for the ionic species carrying the synaptic current.

Animals↗

PubMed1987

A sensitive radioreceptor assay for determining scopolamine concentrations in plasma and urine.

A sensitive and reliable procedure for the quantitation of low picogram levels of scopolamine in plasma and urine is described. The method consists of two steps, a preparative extraction step using C18 columns (Sep-Pak), followed by an analytical quantitation step involving a muscarinic radioreceptor assay. The extraction efficiency of the C18 columns was 85-95% for both plasma and urine over a wide concentration range. When [3H]methyl scopolamine is used as a tracer, the assay can detect picogram concentrations (greater than 25 pg) of scopolamine (base) in plasma and urine. The applicability of the procedure for therapeutic drug monitoring of scopolamine was demonstrated by using the method to determine plasma levels in humans after transdermal administration.

Chromatography, Liquid↗

PubMed1977

Studies on human memory: the interactions of diazepam, scopolamine, and physostigmine.

Seventy volunteers were injected with diazepam (0.3 mg/kg), scopolamine (8 mug/kg), or placebo, followed 70 min later by another injection of physostigmine, physostigmine and methscopolamine (in case of diazepam treatment), or placebo. Physostigmine was given in two doses, 16 and 32 mug/kg; methscopolamine, 8 and 16 mug/kg. Subjects (Ss) were tested in groups of 5 in a double blind procedure with treatments distributed according to a Latin square design. Prior to treatment, Ss heard a series of lists of words, followed by an immediate recall test. Following the first injection, delayed free recall and recognition tests were given. The second drug was then injected, followed by a presentation of another two sets of lists which were tested similarly. Subjective feelings were also evaluated with a rating questionnaire. Diazepam and scopolamine did not affect recall of information which had been learned prior to drug injection. However, both drugs impaired the learning or acquisition of new information. Physostigmine, especially in its high dose, antagonized most of the memory deficits produced by scopolamine while those of diazepam remained. This is a strong indication that scopolamine acts centrally through an anticholinergic mechanism while diazepam may act through a different system.

Adult↗

PubMed1975

Scopolamine and amphetamine effects on discrimination: interaction with stimulus control.

A parametric examination of the interaction between drug-induced behavioral changes and the degree of predrug stimulus control was conducted with rats. A discretetrial simultaneous discrimination was used, with the controlling stimuli varied over 6 values of distinctiveness. The effects of graded doses of scopolamine, d-amphetamine, and methylscopolamine on these performances were studied, with both scopolamine and d-amphetamine showing no increase in error rate under strong stimulus control, and dose-related increases in error rate under weak stimulus control. The similar interaction between drug effect and stimulus control for scopolamine and d-amphetamine indicates that the interaction reflects the degree of susceptibility of the behaviors to drug action, rather than two specific drug-behavior interactions. Methylscopolamine produced a slight effect on error rate and no significant interaction with stimulus control. A decrease in the number of trials responded to was found with both scopolamine and methylscopolamine, but not with d-amphetamine.

Animals↗