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Effects of selection delays on radial maze performance: acquisition and effects of scopolamine.

The effects of post-selection confinement (delays) on both the acquisition of performance and the response to the muscarinic blocker, scopolamine, were examined in an automated version of the eight arm radial maze. Long-Evans rats, exposed to post-selection delays of 0.5 sec (n = 4) or 100 sec (n = 4) during daily training trials did not differ in either the number of trials to acquire an accurate baseline of performance or in the amount of time required to obtain all eight food pellets. However, the pattern (delta-arm scores) of within-session arm selections demonstrated by the two groups of rats differed. Rats exposed to the 0.5-sec delay typically selected arms adjacent to arms from which they exited while rats exposed to the 100-sec delay were more likely to enter arms 2-removed from the exit arm. When scopolamine (0.03 to 1.0 mg/kg) was administered prior to testing, rats in the 100-sec delay group showed a greater reduction of accuracy and a larger increase in selection latency than rats in the 0.5-sec delay group. The differential effect of delay value on delta-arm scores was also eliminated in a dosage dependent manner with scopolamine. Scopolamine methylbromide (0.3 mg/kg) was found to have little effect on performance. In summary, the results indicate that the post-selection delay procedure is a sensitive and selective test for chemical-induced dysfunctioning of spatial memory in rats.

Animals↗

Scopolamine impairs both working and reference memory in rats: a replication and extension.

Rats were trained to run in a spatial, radial maze for sucrose reward using a procedure that permitted determination of two memory functions [working memory (WM) and reference memory (RM)]. Injections of saline, 0.1, 0.4, and 0.8 mg/kg of scopolamine hydrobromide were administered using a Latin-square design; a single dose (0.4 mg/kg) of scopolamine methylbromide served as a control for peripheral drug effects. The smallest dose of scopolamine (0.1 mg/kg) had no measurable effect on performance, but as the dose was increased to 0.4 and 0.8 mg/kg there were increases in both WM and RM errors, in errors of omission, and increases in running time. These results support the view that the effects of scopolamine on performance in the radial maze is not specific for working memory, but rather the effects are more general in nature.

Animals↗

Effects of p-chlorophenylalanine and scopolamine on retention of habits in rats.

Rats were trained on a conventional maze test or on a swim-to-platform test. Retention of swim-to-platform performance 7 days later was severely impaired by posttraining treatment with a combination of p-chlorophenylalanine (PCPA) and scopolamine although neither drug alone had any effect. Retention of the maze habit was moderately impaired by scopolamine alone and severely impaired by a combination of scopolamine and PCPA, but was unaffected by PCPA alone. Polygraphic recordings confirmed previous reports that a combination of PCPA and scopolamine can abolish neocortical low voltage fast activity and hippocampal rhythmical slow activity. Combined blockade of central cholinergic and serotonergic neurotransmission in rats may provide a useful animal model of Alzheimer's disease.

Animals↗

Scopolamine increases nonreinforced behavior in an intracranial self-stimulation discrimination paradigm.

The effects of several doses of systemic scopolamine administration on brain-stimulation reward from the A10 nucleus of the ventral tegmental area (VTA) were evaluated. The intracranial self-stimulation (ICSS) task involved a two-hole nose-poke procedure allowing for the assessment of both reinforced (correct) and nonreinforced (incorrect) performance levels as a function of varying current intensities. Scopolamine (0.75, 1.5, and 3.0 mg/kg) was found not to alter the rate-intensity functions derived from descending and ascending presentation of seven current levels. However, when nonreinforced behavior was considered significant increases in error responding were evident following scopolamine injection. These results are consistent with the known disinhibitory and perseverative properties of scopolamine, and indicate that the previously reported positive actions of peripheral administration of anticholinergic drugs on ICSS likely involved a drug-induced rate-enhancement of reward-unrelated performance variables.

Animals↗

Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset.

The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT) selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment induced by the muscarinic receptor antagonist, scopolamine. For this purpose, marmosets were trained in an object discrimination task utilizing the Wisconsin General Test Apparatus. Administration of scopolamine (0.01-0.04 mg/kg, SC) caused a dose-dependent impairment in the acquisition of the object discrimination task in that marmosets required more trials to reach criterion, made more errors, and took longer to choose the objects. Administration of arecoline (0.06-0.1 mg/kg, SC) or 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol- 1-yl)methyl]-4H-carbazol-4-one,HCl.2H2O (ondansetron) (0.1-1 micrograms/kg, SC) prevented the scopolamine-induced impairment in task acquisition in that the performance of marmosets was indistinguishable from that of saline-treated animals and was significantly better than that following scopolamine/saline. From these studies, we conclude that ondansetron prevents impairment in the cognitive performance of marmosets induced by administration of scopolamine.

Animals↗

Effect of scopolamine and nootropic drugs on rewarded alternation in a T-maze.

The effects of different doses of scopolamine, and of the nootropic drugs oxiracetam and aniracetam, were investigated on the performance of male Wistar rats in a T-maze requiring a spatial discrimination in the stem (reference memory) and an alternate discrimination in the arms (working memory). Criterion (90% correct responses) was reached within 3 days of daily training for stem and 9 days for arm discrimination. Scopolamine (0.1, 0.2, 0.6, and 1.0 mg/kg, SC, 60 min before session) significantly impaired working memory, as shown by a decrease in the number of correct alternations, without affecting reference memory. Both nootropic drugs (25-50 and 100 mg/kg PO) 30 min before scopolamine) attenuated the working memory impairment induced by scopolamine.

Animals↗

Antagonism of scopolamine-induced memory impairments in rats by the muscarinic agonist RU 35,926 (CI-979).

The promnesic effects of RU 35,926 (CI-979), a muscarinic receptor agonist, were evaluated on memory impairments induced by the muscarinic antagonist scopolamine, using a radial arm maze task, in comparison with tetrahydroaminoacridine (THA), a cholinesterase inhibitor. Groups of rats were trained in a standard version of the radial maze until they had attained an asymptotic level of performance. The animals were then retested with one trial a day. Twenty minutes before each retest, the rats were given subcutaneous administration of 0.1 mg/kg scopolamine. Oral administration of RU 35,926 (0.02, 0.05, 0.1, 0.2, and 0.5 mg/kg) 30 min before memory retest markedly reduced or suppressed the scopolamine-induced deficit. This reduction was evidenced by a significant decrease in the different types of errors and an increase in the number of correct responses. THA (3 mg/kg, intraperitoneally or orally) given 20 min to testing also significantly reduced or suppressed the scopolamine-induced deficits. These results show that RU 35,926 possesses the capacity to reduce memory impairments induced by a deficit of cholinergic transmission in the rat.

Animals↗

Nicotine reverses scopolamine-induced impairment of performance in passive avoidance task in rats through its action on the dopaminergic neuronal system.

Interest has recently focused on tobacco and/or nicotine in relation to senile dementia of the Alzheimer type because the population of patients with this disease among tobacco smokers is significantly smaller than in nonsmokers. We investigated whether, in relation to the dopaminergic neuronal system, nicotine was effective in ameliorating the impairment of performance in passive avoidance tasks in rats induced by scopolamine, an inhibitor of muscarinic acetylcholine receptors. Scopolamine and nicotine were coadministered to rats 30 min before the acquisition trial. Some rats received scopolamine alone; they showed much shorter step-through latency (STL) than the control group in the retention test. Nicotine significantly prolonged the decreased STL induced by scopolamine. The effects of nicotine were inhibited by the preadministration of mecamylamine, SCH 23390, and (-)sulpiride, which are nicotinic acetylcholine, D1, and D2 receptor antagonists, respectively. These results suggest that nicotine, by activating the nicotinic acetylcholinergic and dopaminergic neuronal systems, ameliorates the impairment of performance in the passive avoidance task induced by a muscarinic acetylcholine receptor blocker.

Animals↗

Age-dependent effects of NGF and scopolamine on suckling behavior of neonatal mice.

Nerve growth factor (NGF) influences the neurochemical differentiation of central cholinergic neurons of developing rodents. In this study, NGF was given intracerebrally to mice on different postnatal days (days 5 and 7, or days 8 and 10). Pups were tested for suckling behavior 24 h after the second NGF injection, following systemic administration of either the muscarinic cholinergic antagonist scopolamine or saline solution. Scopolamine significantly impaired nipple attachment on day 11 but not on day 8, and decreased locomotor activity in 11-day pups. NGF given on days 5 and 7 increased paddling and treading on day 8, and this effect was more pronounced in scopolamine injected pups. Pretreatment with NGF on days 8 and 10 decreased activity levels in 11-day pups. The differences in the effects of scopolamine at successive ages suggest that distinct portions of the cholinergic system mature at different rates and that sensitivity to NGF is age dependent. NGF appears to influence functional maturation of that portion of the cholinergic system involved in the regulation of locomotor activity.

Aging↗

Effects of St-587 and prazosin on water maze and passive avoidance performance of scopolamine-treated rats.

The present experiments were designed to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and passive avoidance performance. Pretraining administration of scopolamine, a muscarinic antagonist, markedly impaired the acquisition of water maze task (a hidden platform version) as well as retention of this task. The drug also impaired slightly navigation to a visible platform. Pretraining subcutaneous administration of St-587 (alpha-1 agonist) at 2000 micrograms/kg slightly improved the water maze navigation to a hidden platform in control rats, but its effect was not augmented in scopolamine-treated rats. Pretraining administration of prazosin (alpha-1 antagonist) 1000 micrograms/kg or 2000 micrograms/kg did not significantly potentiate the scopolamine (muscarinic cholinergic antagonist)-induced (doses 200 micrograms/kg and 100 micrograms/kg, pretraining intraperitoneal injection) deficit in water maze navigation. Pretraining administration of prazosin at doses 1000 micrograms/kg and 2000 micrograms/kg or St-587 at doses 1000 micrograms/kg and 2000 micrograms/kg did not have any significant influence on scopolamine-induced (200 micrograms/kg or 400 micrograms/kg) disruption in passive avoidance performance. These findings suggest that alpha-1 adrenergic mechanisms do not participate or are not the most important component of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. The analysis of results indicates that activation of alpha-1 adrenoceptors might facilitate the acquisition of water maze task in its initial phase, for instance, switching from wall hugging strategy to an active exploration strategy. Furthermore, the present data suggest that muscarinic cholinergic blockade may affect both mnemonic and nonmnemonic processes in rats.

Adrenergic alpha-Agonists↗

Amitriptyline and scopolamine in an animal model of depression.

Adult male Sprague-Dawley rats were subjected to acute (95 dB white noise) or chronic stress, or their combination. In comparison with unstressed controls, stressed rats were more active upon several measures of open field activity. A history of chronic stress eliminated the acute stress induced activation. Concurrent treatment of chronically stressed rats with amitriptyline or scopolamine, or with a combination of both drugs resulted in selective behavioral improvement (i.e., in motor activity, latency, defecation) for amitriptyline and combined treatment rats, with significant restoration of the normal behavioral response. Scopolamine however was only marginally effective. A higher dose of scopolamine proved effective, but only with a marked disruption of baseline activity. Examination of plasma corticosterone titers indicated that chronic stress induced an elevation of basal levels and that this was reversed by amitriptyline, scopolamine, and combined drug treatment. Thus while behavioral depression and elevated corticosteroids may covary they are not identically mediated.

Amitriptyline↗

Scopolamine-induced deficits in spontaneous alternation performance: attenuation with lateral ventricle injections of glucose.

This experiment determined whether centrally administered glucose can attenuate scopolamine-induced deficits in spontaneous alternation performance. All rats were surgically prepared with indwelling cannulae directed at the lateral ventricle. Thirty min prior to alternation tests, rats received systemic (ip) injections of saline or scopolamine (3 mg/kg). Ten or thirty min prior to training, the rats also received a direct injection into the lateral ventricle of either artificial cerebrospinal fluid (CSF) or glucose (3 micrograms in 1 microliter). Scopolamine significantly impaired spontaneous alternation performance relative to controls. Additional treatment with ICV glucose 30 min, but not 10 min prior to testing, significantly attenuated the scopolamine-induced deficit. These results add support to the view that glucose acts directly on brain systems to attenuate behavioral effects of cholinergic antagonists.

Animals↗

Scopolamine-induced muscarinic supersensitivity in normal man: changes in sleep.

Scopolamine (6 microgram/kg) was administered on 3 consecutive mornings to normal human subjects. Sleep recordings obtained at night (when the central anticholinergic effect of the morning scopolamine was no longer present) indicated a significant reduction in latency to REM-sleep onset on the nights following the second and third injections. This effect is opposite to the direct pharmacological action of nighttime administration of scopolamine (i.e., prolongation of REM latency). In addition, total sleep time and sleep efficiency were reduced, and sleep latency was increased. Furthermore, scopolamine pretreatment on 2 consecutive mornings also potentiated the REM-inducing effect of arecoline, a central muscarinic agonist. These data are consistent with the development of cholinergic supersensitivity following cholinergic blockade.

Adult↗

NGF and cholinergic control of behavior: anticipation and enhancement of scopolamine effects in neonatal mice.

Male mouse pups of the Swiss-CD1 strain received on postnatal days 2 and 4 either an intracerebroventricular (i.c.v.) administration of 30 micrograms murine nerve growth factor (NGF) or cytochrome c. Pups were then tested for suckling behavior on their anesthetized multiparous dam on day 5, following intraperitoneal (i.p.) administration of either the muscarinic cholinergic antagonist scopolamine (2 mg/kg) or saline solution (0.9%). Scopolamine produced a significant increase in latency time to suckle, while reducing the time pups spent attached to the nipple. NGF exposure enhanced scopolamine effects on latency to suckle as well as on time spent attached to the nipple. More striking, NGF pups showed a marked hyperactivity after scopolamine, an effect which normally appears only around weaning time. These results support the hypothesis that NGF plays a crucial role in the functional maturation of central cholinergic mechanisms involved in the control of behavior.

Animals↗

Effects of intracranial injections of scopolamine on olfactory conditioning retrieval in the honeybee.

The role of the cholinergic system on learning abilities and memory performance has been investigated in the honeybee. The behavioural experiment was the olfactory conditioning of the proboscis extension reflex, elicited by an antennal sucrose stimulation. Intracranial scopolamine (0.5 mg/kg) or saline injections (0.25 microliter) were given at different times before or after a one trial learning session in order to interfere with acquisition of information, storage or recall processes. Neither scopolamine injections, ranging from 20 min to 5 min prior to the acquisition task, nor post-trial drug injections given in the same time-window, impaired the retention performance measured one hour after conditioning. Scopolamine injected 20 min after a learning session induced a time-dependent decrease of information retrieval, as was seen in retention testing performed from 5 min to one hour after injection. Then, the amnestic effect of intracranial scopolamine injection seems to be related to a specific and temporary inhibition of recall processes. We can conclude that, in the present task, muscarinic-like receptors are involved in information retrieval but not in acquisition or consolidation processes.

Animals↗

Peripherally injected scopolamine differentially modulates acetylcholine release in vivo in the young and aged rats.

The effect of intraperitoneal administration of scopolamine (1 mg/kg) on acetylcholine (ACh) release in vivo in 3- and 24-month-old freely behaving rats was investigated in the cerebral cortex, hippocampus and striatum by means of transverse microdialysis. In the parietal cortex, the increase in ACh release after scopolamine administration was significantly greater in the old than in the young rats, reaching a maximum increase of about 600 and 300% in the old and young animals, respectively. In the hippocampus, scopolamine caused a larger increase in ACh release in the young (+900%) than in the old rats (+600%). In the striatum of aged rats, a 40% increase occurred only at 40 min after scopolamine administration while in the striatum of young animals the increase lasted for at least 2 h, reaching a maximum of about 100%. These findings demonstrate that the modulation of ACh release in vivo is affected in a different manner in the cerebral cortex than in the hippocampus and striatum by aging.

Acetylcholine↗

Selective antagonism by pirenzepine and N-methyl-scopolamine on muscarinic receptor subtypes of the rat vas deferens.

1. The effects of pirenzepine and N-methyl-scopolamine on the responses to ACh in the isolated rat vas deferens were studied. 2. Pirenzepine was inactive at the M2-ACh receptor. 3. N-methyl-scopolamine was a competitive antagonist (pA2 = 8.76) at M2-ACh receptor, alone or in the presence of pirenzepine. 4. Pirenzepine and N-methyl-scopolamine were both non-competitive antagonists at M1-ACh receptor. 5. The mixture of pirenzepine and N-methyl-scopolamine did not alter the type of antagonism demonstrated by each drug at the M1-ACh receptor.

Animals↗

Negative and positive effects of intracerebroventricular scopolamine on memory in mice undergoing passive avoidance and escape tests.

The effects of intracerebroventricular administration of scopolamine on memory and learning in the conscious, freely moving mouse were evaluated using step-down passive avoidance and water maze tests. A new technique was used that allows convenient injection into the cerebral ventricles without disturbing the animal's behavior. No significant changes in locomotor activity were observed after low doses of scopolamine (0.1 and 1.0 microgram). However, 10 micrograms produced an increase in locomotor activity, while 100 micrograms caused an initial decrease followed by an increase in activity. In the passive avoidance test, scopolamine significantly impaired memory acquisition at doses higher than 1.0 microgram, consolidation at a dose of 100 micrograms, and retrieval at doses of 10 and 100 micrograms. In contrast, a dose of 0.1 microgram significantly improved consolidation and retrieval. In the water maze with a bridge, scopolamine either impaired memory acquisition, consolidation, and retrieval, or had no significant effect in the dose range tested. These results suggest that there are differences in the process of memory formation in the passive avoidance and escape tests.

Animals↗