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PubMedDate not supplied

Investigations of the cholinergic deficit hypothesis in the hippocampus of the aged rat brain with physostigmine and scopolamine.

Using histochemically demonstrated acetylcholinesterase activity and (14)C-2-deoxyglucose uptake as the respective indices, a study was set up to determine whether cerebral (hippocampal) metabolism was stimulated by a cholinergic agonist and/or inhibited by a cholinergic antagonist. For this 36 12-month-old (adult) and 48 27-month-old (aged) Fischer 344 rats were given intraperitoneal injections of physostigmine 0.05, 0.1 or 0.2 mg/kg or scopolamine 0.01, 0.03 or 0.1 mg/kg for 5 days. In the aged rats there was a slight increase in acetylcholinesterase activity after physostigmine but no convincing evidence of enhanced (14)C-2-deoxyglucose uptake. In neither age group was glucose uptake significantly reduced by scopolamine; it was in fact increased, as was - slightly but significantly - acetylcholinesterase activity. Findings for acetylcholinesterase activity and (14)C-2-deoxyglucose uptake in aged Fischer 344 rats thus do not provide firm corroboration of physostigmine-induced stimulation of mental performance found in behavioural studies, while scopolamine did not adversely affect the hippocampal variables studied. It is concluded that cholinergic agents such as physostigmine and scopolamine have only a marginal effect on the functional and metabolic deficits associated with cerebral aging.

Journal Article↗
PubMed1992

Differential effects of MK-801, NMDA and scopolamine on rats learning a four-member repeated acquisition paradigm.

The glutamatergic (NMDA) and cholinergic neurotransmitter systems have been extensively implicated as neurochemical mediators of learning processes. These two systems may differentially affect learning; for example, although both the cholinergic antagonist scopolamine and the NMDA antagonist MK-801 reduced overall accuracy of rats in a 3-member repeated acquisition paradigm, the nature of the underlying error patterns produced by the two drugs differed significantly: rats administered scopolamine produced a pattern of skipping errors, while administration of MK-801 predominantly increased perseverative errors (Cohn et al., 1992). The present experiment extended that study to examine whether a more complex task, i.e. a 4-member repeated acquisition paradigm, would alter the nature of the error patterns resulting from administration of each drug, and whether NMDA itself would increase accuracy on the repeated acquisition paradigm. MK-801 (0.05-0.3mg/kg i.p.) significantly decreased overall accuracy in a dose-dependent manner, and the rats produced a pattern of errors similar, although not identical to, that noted in the 3-member paradigm, including perseverative errors early in the sequence, but additional skipping errors at later points in the sequence. MK-801 dramatically decreased correct initiation of a sequence following an error at any point in the sequence. NMDA (10.0-30.0mg/kg) itself did not facilitate sequence acquisition, i.e. it did not affect overall accuracy. However, it was the only drug to increase the frequency of correctly reinitiating a sequence following an incorrect first or an incorrect second sequence member. Like MK-801, scopolamine (0.5-3.0mg/kg i.p.) also produced a decline in overall accuracy which was again achieved primarily through increased skipping errors. Scopolamine did not, however, interfere with correctly reinitiating a sequence either after successful completion of a sequence, or after an error. These findings suggest that cholinergic and glutamatergic compounds exert their effects on learning through different behavioral mechanisms.

Journal Article↗
PubMed1995

Effects of scopolamine and its quaternary analogue in the murine elevated plus-maze test of anxiety.

Several lines of evidence suggest that muscarinic cholinergic receptors may play a role in fear/anxiety reactions in animals. In the present study, the behavioural effects of the muscarinic receptor antagonist scopolamine (0.125-1.0mg/kg) were examined in male mice exposed to the elevated plus-maze. In contrast to scopolamine methyl bromide, which was behaviourally inert under present test conditions, scopolamine hydrobromide produced behavioural changes indicative of enhanced anxiety. The effects included a reduction in percentage of open arm entries and a marked stimulation of risk assessment measures (i.e. stretched attend postures and closed arm returns), as well as more subjective signs of enhanced fear/anxiety such as vocalisation, struggling and escape-oriented behaviour. Although scopolamine also enhanced total arm entries, perhaps suggesting a general stimulant action, this effect was specific to the closed arms and was not accompanied by systematic increases in either rearing or head-dipping. Data are discussed in relation to the possible involvement of central muscarinic substrates in risk assessment behaviour in animals and hypervigilance states in humans.

Journal Article↗
PubMed1981

Modification of novelty preferences in rats by current and prior treatment with scopolamine and methylscopolamine.

Two experimental paradigms were adopted to compare effects of scopolamine and its quaternary derivative, methylscopolamine, on the behaviour of albino rats in an exploration box comprising novel and familiar halves. Subjects tested with the first paradigm were exposed to one of the halves, injected and then observed 20 min later. Although both drugs reduced preferences for the previously inaccessible novel half, only scopolamine decreased rearing and increased ambulation. With the second paradigm, behaviour was assessed without any current drug influence. On the 2 days prior to testing the rats had been exposed to one half of the apparatus while drugged. Prior treatment with both scopolamine and methylscopolamine reduced novelty preference to the extent that the familiar half of the apparatus was preferred. Both drugs also reduced rearing (for females only) and ambulation. It was concluded that the results with both paradigms provided some support for the view that reductions in novelty preference by anticholinergic drugs arise from their aversive peripheral actions.

Animals↗
PubMed1984

Effects of scopolamine and nicotine on human rapid information processing performance.

In the first experiment, after a 10-min baseline test on a rapid information processing task, subjects received oral doses of either placebo, methscopolamine 1.2 mg, scopolamine 0.6 mg or scopolamine 1.2 mg, and 1 h later performed the task again for a 20-min period. Following scopolamine 1.2 mg, correct detections were significantly lower over the 20-min period, whereas no such decrement was observed in the other three conditions. In the second experiment a similar design was used to study the effects of nicotine 0.5 mg, 1.0 mg and 1.5 mg and placebo, except that post-drug testing was carried out 10 min after baseline due to the faster absorption of nicotine. Nicotine helped prevent both the decline in detections and the increase in reaction time which occurred over time in the placebo condition. These findings indicate that compounds with opposite effects on central cholinergic pathways produce opposite effects on the performance of a task involving rapid information processing, and are consistent with previous findings from this laboratory.

Afferent Pathways↗
PubMed1995

Dissociation between cognitive and motor/motivational deficits in the delayed matching to position test: effects of scopolamine, 8-OH-DPAT and EAA antagonists.

The effects of the muscarinic antagonists scopolamine HBr and MeBr, the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the N-methyl-d-aspartate (NMDA) antagonists MK-801 and CGS-19755 on performance of rats in a delayed matching-to-position task were examined. Pretreatment with scopolamine HBr (0.05 and 0.1 mg/kg), resulted in a delay-dependent decrease in the percentage of correct responses and discriminability (log d), but had no effect on either the latency to complete trials, or the rate of trial completion during the fixed duration session. Scopolamine MeBr (0.1 mg/kg) did not impair percent correct or increase the response latency but did decrease the rate of trial completion. 8-OH-DPAT (up to 0.3 mg/kg), had no effect on percent correct, but did induce a small decrease in discriminability. The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion. Both MK-801 (0.05 mg/kg) and CGS 19755 (10 mg/kg) induced a delay-independent impairment in percent correct, discriminability and a reduction in the rate of trial completion without affecting latency. A lower dose of CGS 19755 (5.0 mg/kg) induced a slight impairment in discriminability without significantly affecting the other measures. Taken together, these results demonstrate some dissociation between drug-induced cognitive and motor/motivational deficits in the DMTP test. However, the data question the specificity of putative cognitive impairments reported in many previous studies with the 5-HT1A agonist 8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMedDate not supplied

Scopolamine effects on delayed spatial alternation in the rat.

Rats were trained to press two levers in alternation on discrete trials spaced 10 sec apart. During the final sessions of alternation training, error responses per opportunity on the trials that followed reinforced trials (initial trials) did not differ from error responses per opportunity on repetitive (correction) trials (Experiment 1). Scopolamine did not increase the rats' tendency to perseverate: drug treatment did not cause the error responses per opportunity to increase over runs of consecutive error responses (Experiment 2). Scopolamine did not impair performance when alternation was controlled by visual stimuli present in the external environment at the time of the response (Experiment 3). The disruption in delayed alternation performance produced by scopolamine was attributed to effects on stimulus discrimination, resulting in impairment of control of responding by stimuli not present in the environment at the time of the response.

Animals↗
PubMed1992

Differential effects of scopolamine on working and reference memory depend upon level of training.

Controversy exists whether the cholinergic system in the brain is involved in working memory (WM) selectively or in both WM and reference memory (RM). Rats were trained to obtain food from four baited arms of an eight-arm radial maze. The remaining arms were never baited. Three types of errors were recorded: entry into unbaited arms (RM errors), reentry into baited arms (WM errors), and reentry into unbaited arms (WRM errors). There were no differences among three control conditions: methyl scopolamine, physiological saline, and uninjected. Scopolamine increased WM but not RM errors. When rats were trained to a higher criterion of learning, however, both WM and RM were impaired. It appears that when baseline error rate is sufficiently low RM errors under scopolamine become observable. The results suggest that the cholinergic system is involved in both WM and RM, and the selective involvement of WM is the result of insufficient training. The controversy in the literature over the involvement of the cholinergic system in WM and RM was addressed.

Animals↗
PubMed1991

Role of cholinergic systems in pain modulation: I. Impact of scopolamine on environmentally induced hypoalgesia and pain reactivity.

Scopolamine was found to block both brief shock-induced (3 0.75-s, 1.0-mA shocks) and conditioned hypoalgesia on the tail-flick test in rats. The drug also produced a general increase in pain reactivity as measured by both the tail-flick test and shock-induced vocalization. It was shown that this hyperalgesia cannot account for the effect of the drug on brief-shock or conditioned hypoalgesia. Scopolamine did not block the nonopioid analgesia observed after long shock (3 25-s, 1.0-mA shocks). When the effect of the drug on baseline levels of pain reactivity was controlled, it potentiated long shock-induced hypoalgesia. Scopolamine also increased reactivity to tactile stimulation, which suggests the hyperalgesia reflects a general increase in arousal. None of these effects were observed with methylscopolamine, which suggests they are not peripherally mediated.

Animals↗
PubMed1988

Effects of scopolamine on repeated acquisition of radial-arm maze performance by rats.

Rats repeatedly acquired the performance of selecting only the four baited arms in an automated eight-arm radial maze, with the arms containing food pellets randomly assigned prior to each session. During each 14-trial (trial: obtain all four pellets) daily session, the number of errors (selecting nonbaited arms or repeating arm selections) showed a within-session decline, and choice accuracy for the first four arm selections showed a positive acceleration across trials for all rats. An index-of-curvature statistic, calculated for total errors, was used to quantify both the within- and between-session improvement of performance. Scopolamine (0.03 to 0.3 mg/kg, ip), but not methylscopolamine (0.3 mg/kg), reduced the accuracy of the first four selections of each trial and increased total within-session errors for all rats. Session times also were increased by scopolamine. An examination of within-session accuracy showed only slight signs of improvement at the higher dosages of scopolamine. The results indicate that behavior in transition states maintained by reinforcement contingencies in the radial maze is similar to that maintained by extended chained schedules, despite the fact that some of the stimuli controlling behavior in the maze are absent at the moment behavior is emitted.

Animals↗
PubMed1990

Influence of pH on the binding of scopolamine and N-methylscopolamine to muscarinic receptors in the corpus striatum and heart of rats.

The influence of pH on the binding of scopolamine and [3H]N-methylscopolamine to muscarinic receptors in the heart and corpus striatum was investigated. The specific binding of [3H]N-methylscopolamine in the heart and corpus striatum was relatively insensitive to pH over the range of 6 through 10 but decreased markedly below pH 6.0. This reduction in binding was attributed to a reversible decrease in the observed affinity without an effect on the binding capacity. The data are consistent with the postulate that [3H]N-methylscopolamine competes with hydrogen ions for an acidic group on the muscarinic receptor that has a pKA of approximately 5.5 in both the heart and corpus striatum. When measured by competitive inhibition of the binding of [3H]N-methylscopolamine, the affinity of scopolamine decreased relative to that of [3H]N-methylscopolamine as the pH increased from 6 to 10, confirming that it is primarily the protonated form of scopolamine that binds with muscarinic receptors.

Animals↗
PubMedDate not supplied

Prenatal alcohol exposure and offspring hyperactivity: effects of scopolamine and methylscopolamine.

Rats were fed a liquid diet containing alcohol from days 6-19 of gestation. Controls were pair-fed the same diet with sucrose substituted for ethanol, or received ad lib chow and water. The activity of the offspring was observed at 10, 16, 22 or 28 days of age. Offspring exposed to alcohol prenatally were hyperactive compared to controls at 16 and 22 days, but not at 10 or 28 days. Administration of scopolamine had no effect on activity in any group at 10 days. At 16 days it reduced activity in the alcohol treated offspring but had no effect on the controls. At 22 days it led to a dose-related increase in activity in controls but had no effect on the already high levels of activity in the alcohol treated pups. At 28 days, scopolamine increased activity in all three groups. Administration of the quaternary derivative, methylscopolamine, indicated that the effects of scopolamine at 22 and 28 days were probably central in origin. These data indicate that a putative cholinergic/inhibitory system becomes functional in control pups before 22 days, but in pups exposed to alcohol prenatally development is delayed by a number of days.

Analysis of Variance↗
PubMed1975

Scopolamine effects on visual discrimination: modifications related to stimulus control.

Stumptail monkeys (Macaca arctoides) performed a discrete trial, three-choice visual discrimination. The discrimination behavior was controlled by the shape of the visual stimuli. Strength of the stimuli in controlling behavior was systematically related to a physical property of the stimuli, luminance. Low luminance provided weak control, resulting in a low accuracy of discrimination, a low response probability and maximal sensitivity to scopolamine (7.5--60 mug/kg). In contrast, high luminance provided strong control of behavior and attenuated the effects of scopolamine. Methylscopolamine had no effect in doses of 30 to 90 mug/kg. Scopolamine effects resembled the effects of reducing stimulus control in undrugged monkeys. Since behavior under weak control seems to be especially sensitive to drugs, manipulations of stimulus control may be particularly useful whenever determination of the minimally-effective dose is important, as in behavioral toxicology. Present results are interpreted as specific visual effects of the drug, since nonsensory factors such as base-line response rate, reinforcement schedule, training history, motor performance and motivation were controlled. Implications for state-dependent effects of drugs are discussed.

Animals↗
PubMed1988

The effects of acute scopolamine in geriatric depression.

In an intensive multidrug, multidose study, nine elderly depressed patients were administered 0.1, 0.25, and 0.5 mg of scopolamine hydrobromide, 1 mg of oral lorazepam, and placebo in a double-blind investigation aimed at assessing the status of the central cholinergic nervous system in geriatric depression. Significant cognitive and behavioral effects of scopolamine were observed only at the high dose (0.5 mg), while lower doses and lorazepam showed no significant differences from placebo. Cognitive deficits caused by scopolamine were in the areas of new learning, access to semantic memory, vigilance, and continuous performance. Behavioral effects consisted of activation, restlessness, and anxiety, but there was no significant effect on depressed mood. These results suggest that elderly depressed patients with mild to moderate cognitive impairment seem to be more similar to previously studied elderly controls rather than to patients with Alzheimer's disease in their reaction to short-term cholinergic blockade, and suggest that the cognitive and mood changes often seen in geriatric depression may involve factors other than disturbed muscarinic cholinergic mechanisms.

Aged↗
PubMed2001

Cholinergic modulation of pavlovian fear conditioning: effects of intrahippocampal scopolamine infusion.

Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, including Pavlovian fear conditioning. To more precisely define the role of cholinergic modulation in this process, the effect of site-specific cholinergic antagonism was assessed. Male Long-Evans rats were implanted with chronic, bilateral cannulae aimed at the dorsal hippocampus. Infusions of scopolamine hydrobromide (50 microg bilaterally) or phosphate-buffered saline (PBS) were made immediately prior to a signaled Pavlovian fear conditioning procedure. On consecutive days following training, all rats were given independent tests assessing freezing to both the training context and the tone conditional stimulus (CS). Relative to PBS infused controls, rats that received intrahippocampal infusions of scopolamine showed a significant attenuation of contextual freezing but comparable levels of freezing to the tone CS. Neither shock sensitivity nor general activity levels differed between rats infused with scopolamine or PBS. These findings suggest that fear conditioning to context, but not discrete CS, requires intact cholinergic neurotransmission in the hippocampus.

Animals↗
PubMed1982

Belladonna alkaloids and phenobarbital combination pharmaceuticals analysis I: High-performance liquid chromatographic determinations of hyoscyamine-atropine and scopolamine.

High-performance liquid chromatographic separations are described for the analysis of hyoscyamine-atropine and scopolamine in combination pharmaceutical dosage forms containing phenobarbital. A mobile phase containing 0.034 M tetramethylammonium phosphate in water-methanol (21:10, pH 2.0) separated hyoscyamine or atropine from scopolamine on an octadecylsilane column in less than 9 min. Monitoring of the column effluent at 220 nm gave a detection limit of 0.02 microgram for each alkaloid. Hyoscyamine sulfate and/or atropine sulfate were determined as total equivalent hyoscyamine sulfate, and scopolamine hydrobromide was determined as a separate entity. Data from the application of the method to commercial pharmaceutical products are also presented.

Atropine↗
PubMed1994

Solid-state stereochemistry of (-)-scopolamine hydrobromide sesquihydrate, a new polymorph of the anticholinergic drug.

The solid-state structure of (-)-scopolamine hydrobromide sesquihydrate was determined by single-crystal X-ray diffraction analysis at low temperature. (Nr,C alpha-S)-(-)-Scopolamine hydrobromide sesquihydrate gives crystals belonging to the tetragonal space group P4(3)2(1)2, and at 180 K: a = 11.870(4), c = 26.193(3) A, V = 3691(1) A3, Z = 8, R(F) = 0.062, and Rw(F) = 0.059. Thermogravimetric analysis afforded a total weight loss of approximately 6%, consistent with a loss of 1.5 molecules of water and in accord with the sesquihydrate stoichiometry found by single-crystal X-ray crystallography. The unit cell dimensions, molecular structure, basic packing arrangement [minus the full water molecule], and the crystal system are all the same as that of the P4(1)2(1)2 hemihydrate form [R(F) = 0.09] reported earlier by Pauling and Petcher. This suggests that the previously reported "hemihydrate" description of the structure should be reconsidered. In addition to partial dehydration of the sesquihydrate crystal, non-observance of the eight water molecules might have arisen from their relatively large thermal motions at ambient temperature coupled with a lack of sufficient data versus the number of variable parameters. The phenyl ring syn-to-oxirane arrangement in the sesquihydrate form is the same as that in the corresponding crystalline methyliodide quaternary ammonium salt and in (-)-(Ns,C alpha-S)-hyoscyamine [atropine] hydrobromide, but differs from the elongated anti-to-oxirane arrangement in anhydrous (Nr,C alpha-S)-(-)-scopolamine hydrobromide.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystallography, X-Ray↗
PubMed1998

Estrogen replacement attenuates effects of scopolamine and lorazepam on memory acquisition and retention.

A multiple-trial passive avoidance paradigm was used to examine and compare the ability for estrogen replacement to attenuate learning and memory deficits produced by the muscarinic antagonist scopolamine and the benzodiazepine lorazepam. The multiple-trial paradigm was used in order to distinguish effects on acquisition from effects on retention. Estrogen replacement significantly attenuated a scopolamine-induced deficit on passive avoidance acquisition, but not retention. The ability for estrogen to attenuate the effect of scopolamine on acquisition was observed only when the analysis was limited to animals with serum levels of estradiol <200 pg/ml, suggesting that higher levels of estradiol were ineffective. This observation is consistent with at least one recent study showing dose-related effects of estrogen on ChAT-like immunoreactivity in the basal forebrain and supports the hypothesis that effects of estrogen on basal forebrain cholinergic neurons can help to reduce cognitive deficits associated with cholinergic impairment. Estrogen replacement was also observed to protect against a lorazepam-induced impairment on passive avoidance retention. This effect was observed specifically in animals that received estrogen prior to and during training and was not due to any effect of estrogen on serum levels of lorazepam following acute lorazepam administration. Collectively, these data demonstrate the ability for estrogen replacement to attenuate specific pharmacologically induced impairments in learning and retention and provide additional clues as to potential mechanisms by which estrogen replacement may help to reduce cognitive deficits associated with aging and Alzheimer's disease in postmenopausal women.

Animals↗