Differential effects of scopolamine on working and reference memory of rats in the radial maze

Anticholinergics have often been found to impair choice accuracy in the radial maze. Some researchers have suggested that this indicates involvement of cholinergically innervated structures in cognitive mapping while others argue that these structures mediate working memory. However, most results are open to either interpretation since the baiting method did not allow a distinction between reference and working memory errors. To further test these hypotheses this study examined the effects of systemic scopolamine on radial maze performance, using a 4-out-of-8 baiting procedure. Food-deprived Wistar rats were pretrained until working memory choice accuracy stabilized to a criterion of 87% or better. Scopolamine (0.1, 0.4 and 0.8 mg/kg, IP, 30 min before a session) significantly increased the number of working memory errors (re-entries into baited arms) whereas reference memory errors (entries into never baited arms) did not change significantly. Observed deficits appeared not to be attributable to a drug-induced disruption of motivational systems. Results confirm the behavioural similarities between the memorial effects of hippocampectomy and anticholinergics, and implicate cholinergically innervated structures in working memory.     

Estrogen and NMDA receptor antagonism: effects upon reference and working memory.

Since both estrogen and NMDA receptor antagonists act on the hippocampus CA1 region and behaviorally affect hippocampal memory tasks, we examined how estrogen depletion (ovariectomy) and NMDA receptor antagonism interact upon spatial memory of the mouse. After ovariectomy or sham operation, mice were given a 2-week recovery before behavioral tests began under the influence of vehicle or (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP 2, 5 and 10 mg/kg) intraperitoneal injections. CPP is a competitive, full NMDA receptor antagonist. Spatial reference memory was tested by the water maze, spatial working memory was tested by the radial arm maze, while overall locomotive activity was monitored by the Y-maze. Results from the water maze and the Y-maze did not show any spatial reference memory or activity differences between sham-operated and ovariectomized mice. The radial arm maze, however, highlighted some working memory differences between intact and ovariectomized mice. CPP treatment impaired dose dependently--the performance of ovariectomy and sham-operated mice equally on both water maze and radial arm maze, while the drug had no effect on Y-maze performance. These results suggest that short term estrogen deprivation has no effect upon spatial-reference memory, while it impairs spatial working memory. This effect is probably not mediated by NMDA receptors.     

Modelling working and reference memory in rats: effects of scopolamine on delayed matching-to-position(1,2)

A model of working and reference memory in rats is described, based on a discrete-trial operant procedure with concurrent components of spatial matching (for working memory) and nonspatial discrimination (for reference memory). On each trial in the matching component, rats received food for pressing one of two retractable levers after a delay if that lever had been presented in the prior sample phase of the trial. On each trial in the discrimination component, food was delivered if the rat pressed a lever illuminated by a cue light after the delay interval. The model was tested with scopolamine (0.10 to 0.56 mg/kg, ip), which reduced matching accuracy in a dose-related manner. Linear slope and intercept estimates of retention gradients showed that intercepts declined and slopes remained unchanged with increasing scopolamine dose. In contrast, scopolamine had no significant effect on nonspatial discrimination accuracy, indicating a relative insensitivity of reference memory to cholinergic blockade. Because the matching component involved spatial cues and the discrimination component did not, a second group of rats was trained to discriminate between the spatial locations of two levers, to compare the effects of scopolamine on spatial and nonspatial discriminations. Scopolamine at the same doses caused a small, consistent decrease in spatial discrimination accuracy, suggesting that spatial discrimination was more sensitive to disruption by scopolamine than was nonspatial discrimination. The combined delayed matching-to-position/nonspatial discrimination procedure appears to provide a useful technique for characterizing mnemonic effects of drugs and toxicants in rats.     

Differential effects of delta 9-THC on spatial reference and working memory in mice

RATIONALE: Marijuana remains the most widely used illicit drug in the U.S., and recent attention has been given to putative therapeutic uses of marijuana and cannabinoid derivatives. Thus, developing a better understanding of delta9-THC (tetrahydrocannabinol)-induced mnemonic deficits is of critical importance. OBJECTIVES: These experiments were conducted to determine whether delta9-THC has differential effects on spatial reference and working memory tasks, to investigate its receptor mechanism of action, and to compare these effects with those produced by two other compounds--scopolamine and phencyclidine--known to produce mnemonic deficits. In addition, the potency of delta9-THC in these memory tasks was compared with its potency in other pharmacological effects traditionally associated with cannabinoid activity. METHODS: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of delta9-THC were assessed using standard tests of hypomotility, antinociception, catalepsy, and hypothermia. RESULTS: delta9-THC disrupted performance of the working memory task (3.0 mg/kg) at doses lower than those required to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These performance deficits were reversed by SR 141716A. The effects of delta9-THC resembled those of scopolamine, which also selectively disrupted the working maze task. Conversely, phencyclidine disrupted both tasks only at a dose that also produced motor deficits. CONCLUSIONS: These data indicate that delta9-THC selectively impairs performance of a working memory task through a CB, receptor mechanism of action and that these memory disruptions are more sensitive than other pharmacological effects of delta9-THC.     

A comparison of the effects of scopolamine and diazepam on working memory

Two drug models of memory dysfunction, namely the benzodiazepine and the cholinergic models, have emerged from the considerable number of studies which have examined drug effects on information processing. The reported impairments produced by administration of compounds from these two families appear to be more similar than dissimilar, and to date, direct comparisons on traditional memory tasks have failed to differentiate the models. This study compared the effects of diazepam and scopolamine on tasks associated with separable components of working memory. The results indicate that this model also fails to discriminate between the drug models; both compounds selectively impaired tasks associated with the central executive mechanism and failed to disrupt tasks associated with the articulatory loop or the visuospatial scratchpad.     

The effects of scopolamine on working memory in healthy young volunteers

Twenty healthy young adults completed a series of nonverbal and problem solving tasks in a repeated measures design involving placebo and 0.6 mg scopolamine, administered by subcutaneous injection. Subjects completed the test battery under standard presentation conditions and with concurrent articulation, which precludes verbal recoding of test material. Under standard presentation conditions, scopolamine significantly impaired performance on the problem solving task and on tasks of visuo-spatial and spatial memory; memory for abstract shapes was not impaired. Concurrent articulation impaired performance on the shape recognition and interacted with drug treatment on the problem solving task. The results suggest that scopolamine impairs working memory, and that the decrement is at the level of the central executive mechanism rather than the subsystems which it controls.     

Dissociative effects of scopolamine on working memory in healthy young volunteers

Performance on tasks of digit span, mental rotation and immediate free recall of supraspan word lists was measured before and after oral administration of 1.2 mg scopolamine or placebo to healthy young volunteers. Digit span and mental rotation were sensitive to task-specific interference from articulatory suppression and spatial tapping tasks, respectively. Neither task was affected by scopolamine when completed alone or in combination with a secondary task. A concurrent secondary task reduced immediate free recall in a nonspecific fashion (i.e., spatial tapping or articulatory suppression impaired performance equally). Scopolamine significantly reduced the number of words recalled under all conditions. The results are interpreted as evidence for selective impairment of the central executive mechanism by scopolamine without disruption of function in the articulatory loop or visuospatial scratch pad.     

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

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

Differential effects of alcohol on working memory: distinguishing multiple processes

The authors assessed effects of alcohol consumption on different types of working memory (WM) tasks in an attempt to characterize the nature of alcohol effects on cognition. The WM tasks varied in 2 properties of materials to be retained in a 2-stimulus comparison procedure. Conditions included (a) spatial arrays of colors, (b) temporal sequences of colors, (c) spatial arrays of spoken digits, and (d) temporal sequences of spoken digits. Alcohol consumption impaired memory for auditory and visual sequences but not memory for simultaneous arrays of auditory or visual stimuli. These results suggest that processes needed to encode and maintain stimulus sequences, such as rehearsal, are more sensitive to alcohol intoxication than other WM mechanisms needed to maintain multiple concurrent items, such as focusing attention on them. These findings help to resolve disparate findings from prior research on alcohol's effect on WM and on divided attention. The results suggest that moderate doses of alcohol impair WM by affecting certain mnemonic strategies and executive processes rather than by shrinking the basic holding capacity of WM.     

Pharmacological effects of cannabinoids on the reference and working memory functions in mice

Rationale

Evidence indicates cannabinoid receptor agonists impair performance in procedures to assess memory that may also be confounded by motivational or motor effects, both of which occur with cannabinoids. Thus, convergence of evidence from a variety of procedures that differ in motivation, attention, arousal and response requirements, but share a common reliance on memory, is required. There are no current reports on cannabinoid effects on mice tested in the radial arm maze.

Objectives

The objective was to determine the effects of the cannabinoid agonist CP 55940 and the dependence of any such effects on the CB1 receptor using the CB1 receptor antagonist SR 141716A on two strains of mice in the eight-arm radial maze procedure.

Methods

Male C57BL/6J (N?=?36) and C3H/HEJ (N?=?12) mice were trained to a criterion and then were treated (IP) with vehicle?+?vehicle, SR 141716A?+?vehicle, vehicle?+?CP 55940 and SR 141716A?+?CP 55940 in a fully balanced mixed design prior to further tests in the maze. Reference (long-term) and working (short-term) memory were assessed.

Results

CP 55940 impaired performance of the reference memory task in the C57BL/6J strain but not the C3H/HEJ strain; SR 141716A reversed the effect of CP 55940 on these measures. CP 55940 also increased working memory errors in the C57BL/6J mice only, which was not affected by SR 141716A.

Conclusion

The present study provides evidence for a strain-specific effect of a dose of CP 55940 on reference memory. While the cannabinoid agonist also impaired working memory in one strain, this effect was apparently not mediated by CB1 receptors.     

Differential effects of scopolamine and D-amphetamine on avoidance: Strain interactions.

In a discriminated Y-maze avoidance task it was observed that mice of the A/J strain were superior to mice of the DBA/2J strain, which in turn made more avoidance responses than C57BL/6J mice. Moreover, the A strain was also observed to acquire a discrimination problem more readily than either of the other strains. Administration of scopolamine enhanced active avoidance performance in A, but not DBA/2 or C57BL/6 mice. D-Amphetamine improved performance in both A and DBA/2 mice but had negligible effects on the performance of the C57BL/6 strain. Neither drug affected discrimination performance irrespective of strain. In an inhibitory avoidance task the C57BL/6 strain was found to perform more poorly than the A strain which was inferior to DBA/2 mice. Scopolamine disrupted performance in all three strains, while d-amphetamine was found to disrupt the performance of the A and DBA/2 strains only. The results were interpreted in terms of the role of associative and nonassociative effects of shock in modulating avoidance behavior.     

The effects of scopolamine on retrieval from semantic memory

The effects of two doses of scopolamine (0.6 and 1.2 mg p.o.) on retrieval from semantic memory in normal young volunteers were examined using tests of verbal fluency and categorization latency. A visual contrast sensitivity test, which has previously shown a scopolamine-induced impairment at these doses (Broks et al., 1988), was also administered. In agreement with the work of Dunne (1990) and others, no evidence for a scopolamine deficit in semantic retrieval was found; in fact scopolamine improved letter fluency. However, scopolamine did produce the expected decrease in visual contrast sensitivity. The doses of scopolamine used here have also been shown to impair learning and attention (Broks et al., 1988). It is possible that earlier studies which found a scopolamine deficit on semantic retrieval, did so because they used elderly subjects and/or large drug doses.     

Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats

Cannabinoid receptors in the brain (CB₁) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either Δ⁹-tetrahydrocannabinol (Δ⁹-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. Δ⁹-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic Δ⁹-THC. Despite considerable amounts of Δ⁹-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given concomitantly, CBD-rich extracts did not reverse memory deficits of the additional Δ⁹-THC-rich extract. CBD-rich extracts also did not alter Δ⁹-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of Δ⁹-THC-induced spatial memory deficits is dependent on the ratio between CBD and Δ⁹-THC.     

The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory.

Seventy college age subjects learned and recalled a series of word lists prior to being injected with methamphetamine (0.2 mg/kg or 0.3 mg/kg), scopolamine (8 microgram/kg), or a placebo. Following the injection subjects were tested for their free recall and recognition of the words and they completed a short-term digit recall task. Subjects who had previously received scopolamine were next injected with either methamphetamine (0.2 mg/kg or 0.3 mg/kg), physostigmine (32 microgram/kg), or placebo, while other subjects received a placebo injection. The above memory procedure was then repeated with a second series of word lists. In addition, subjective feelings were measured with a questionnaire. Scopolamine and methamphetamine did not affect recall of information learned prior to injection. Scopolamine did, however, impair performance in both the digit recall task and in the second series of memory tests. Physostigmine and methamphetamine alleviated most of the memory deficits and sedation produced by scopolamine. Methamphetamine alone produced subjective arousal and a small improvement in recall of words learned after injection and a large increase in incorrect responding.     

Effects of acamprosate and scopolamine on the working memory of rats in a three-panel runway task.

The aim of this study was to evaluate the effect of treatment with single (1x) and multiple (10x) doses of the anti-craving compound acamprosate (AC, calcium acetyl homotaurinate) on working memory in rats, using in a three-panel runway test. We measured tasks after the animals were treated with AC (500 mg/kg/d, i.p.); scopolamine (SC, 0.5 mg/kg/d, i.p.), a cholinergic muscarinic receptor antagonist; or both drugs concomitantly (ACSC), either for 1 day (1x) or daily for 10 consecutive days (10x). Neither 1x not 10x AC alone had a significant effect on working memory task performance, whereas treatment with SC alone had a significantly negative effect on the ability of the rats to complete the tasks. Rats receiving ACSC performed better than those receiving SC alone, making fewer errors and displaying shorter latency, similar to the performance of the control group. These observations support the hypothesis of an indirect involvement of AC in the cholinergic system.     

The effects of scopolamine and cues to forget on pigeons' memory for time.

Pigeons were trained with a 0-s delayed symbolic matching-to-sample procedure to indicate whether a houselight sample stimulus was short (2 s) or long (8 s) by pecking a red or a green comparison stimulus. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), or saline, and the delay interval was manipulated (0, 1, 3, and 9 s). Memory for time was significantly poorer following scopolamine injections than following saline injections. A significant choose-short bias was observed under scopolamine at delays as brief as 3 s, but not under saline. In Experiment 2, a brief postsample cue (a vertical or horizontal line) signaled whether the comparison stimuli would be presented or omitted on each trial. During training, comparison stimuli were always presented following the remember (R) cue, but never following the forget (F) cue. During testing, memory for time was significantly poorer on F-cue trials than on R-cue trials. A significant choose-short bias was observed on F-cue trials at the 5- and 10-s delays, but not on R-cue trials. The results suggest that anticholinergic blockade accelerates the rate at which memory for temporal events is foreshortened in working memory. This effect is similar to that produced by an explicit cue to forget the temporal sample.     

Differential effects of d-amphetamine and scopolamine on the ontogeny of rearing

Although rearing is ontogenetically an important behavior, very little is known about the neural bases of rearing. The role development of catecholaminergic and cholinergic neurons play in the ontogeny of rearing was investigated by examining rearing in infant, adolescent, and adult rats following various doses of d-amphetamine (an indirectly acting catecholaminergic agonist) and scopolamine (a cholinergic muscarinic receptor antagonist). d-Amphetamine increased rearing in infants but not in adolescents and adults. These findings suggest that activation of catecholaminergic neurons increases rearing in infants but not in adolescents or adults. Scopolamine increased rearing in adolescents and adults but not in infants, indicating that blocking transmission of cholinergic neurons increases rearing in only older rats.     

Prenatal phenytoin exposure and spatial navigation in offspring: effects on reference and working memory and on discrimination learning.

Previous research has shown that rats exposed to phenytoin (PHT) in utero demonstrate abnormal circling, decreased learning, hyperactivity, and delayed air righting reflex development. The effects of prenatal PHT on offspring learning have been found on multiple-T mazes (Biel and Cincinnati types) and on spatial navigation (Morris maze). However, the specificity of the latter effects is unknown. Herein, we tested the effects of prenatal PHT in a Morris maze using six different procedures: cued versus spatial reference memory-based learning, cued versus spatial working memory-based learning, and cued versus spatial discrimination learning. PHT-exposed offspring showed increased preweaning mortality, growth reduction, and abnormal circling as noted in previous studies. PHT offspring were separated into those exhibiting circling and those not. PHT noncircling offspring demonstrated impaired reference memory-based spatial learning (acquisition and reversal), but no other effects. By contrast, PHT circling offspring demonstrated not only impaired reference memory-based spatial learning, but also impaired cued platform learning, impaired spatial discrimination, and impaired working memory-based learning. These data confirm that prenatal PHT induces a specific reference memory-based spatial learning deficit even in asymptomatic (noncircling) offspring that is distinct from the impairment induced in littermates exhibiting the circling impairment.     

Effects of nitrendipine on reference and working memory of rats in three-panel runway.

This study was designed to investigate whether calcium-channel blocker, nitrendipine affects memory of rats in three-panel runway test. Nitrendipine (2-4 mg kg(-1), intra peritoneally (i.p.)) neither enhanced nor impaired reference and working memory performances of young adult rats. However, it improved impairment in reference memory induced by anticholinergic drug scopolamine (3 mg kg(-1), i.p.) while it had no effects on impairment in working memory induced by the same drug. The results suggest that nitrendipine may be of benefit in the treatment of memory disturbances resulted from cholinergic deficit.     

Enhancing effects of nicotine and impairing effects of scopolamine on distinct aspects of performance in computerized attention and working memory tasks in marmoset monkeys

With the CAmbridge Neuropsychological Test Automated Battery (CANTAB), computerized neuropsychological tasks can be presented on a touch-sensitive computer screen, and this system has been used to assess cognitive processes in neuropsychiatric patients, healthy volunteers, and species of non-human primate, primarily the rhesus macaque and common marmoset. Recently, we reported that the common marmoset, a small-bodied primate, can be trained to a high and stable level of performance on the CANTAB five-choice serial reaction time (5-CSRT) task of attention, and a novel task of working memory, the concurrent delayed match-to-position (CDMP) task. Here, in order to increase understanding of the specific cognitive demands of these tasks and the importance of acetylcholine to their performance, the effects of systemic delivery of the muscarinic receptor antagonist scopolamine and the nicotinic receptor agonist nicotine were studied. In the 5-CSRT task, nicotine enhanced performance in terms of increased sustained attention, whilst scopolamine led to increased omissions despite a high level of orientation to the correct stimulus location. In the CDMP task, scopolamine impaired performance at two stages of the task that differ moderately in terms of memory retention load but both of which are likely to require working memory, including interference-coping, abilities. Nicotine tended to enhance performance at the long-delay stage specifically but only against a background of relatively low baseline performance. These data are consistent with a dissociation of the roles of muscarinic and nicotinic cholinergic receptors in the regulation of both sustained attention and working memory in primates.