Comparison of error patterns produced by scopolamine and MK-801 on repeated acquisition and transition baselines

An understanding of the differential role of cholinergic and glutaminergic systems may be limited by the failure to move the analysis of learning impairments beyond an assessment of changes in overall accuracy. This paper reports the results of two studies in which the effects in rats of scopolamine (0.5–3.0 mg/kg IP), a cholinergic antagonist, and MK-801 (0.05–0.3 mg/kg IP), an NMDA-receptor antagonist, were compared in two different repeated learning procedures and the nature of the underlying error patterns produced by each was evaluated. The first study examined drug effects upon a repeated sequence acquisition procedure and found that while both drugs decreased overall accuracy in a dose-dependent manner, the predominant error pattern varied significantly with drug; scopolamine primarily produced skipping errors within the sequence, whereas MK-801 more prominently increased perseveration on the first and second members of the sequence. In the second study, which used a repeated transition procedure, both drugs again significantly decreased overall accuracy in a dose-dependent manner, but no consistent differences in error patterning produced by the drugs were observed. Thus, while both cholinergic and NMDA systems play a role in learning, the behavioral processes underlying the changes in overall accuracy may differ, as indicated by the differential patterns of errors produced by scopolamine and MK-801 in the repeated acquisition baseline. Furthermore, the observed differences in the underlying behavioral processes of scopolamine and MK-801 in the repeated acquisition but not on the repeated transition procedure suggest that each of the two drugs may affect more than one of the variables controlling behavior, with the relative impact of drug-related changes in controlling variables depending upon the operative contingencies of the learning task.     

Delta-9-tetrahydrocannabinol impairs visual recognition memory but not discrimination learning in rhesus monkeys

The effects of orally administered delta-9-tetrahydrocannabinol (THC) were evaluated on two different learning abilities in monkeys. Visual recognition memory, known to depend on limbic system integrity, was tested by means of delayed nonmatching-to-sample and found to be significantly impaired by acute administration of 2 and 4 mg/kg THC given 1 or 2 h prior to testing. Performance was significantly impaired throughout a 21-day period of repeated administration of 4 mg/kg THC and also during a 3–5 day period that began 7–10 days after the last dose of THC. By contrast, 24-h concurrent discrimination learning, a task that monkeys with limbic lesions can perform normally, was not impaired by THC, even following doses as high as 16 mg/kg. These results suggest that THC interferes with recognition memory more than discrimination learning, possibly reflecting a selective action of THC on limbic mechanisms.Portions of this work were presented at the Annual Meeting of the Society for Neuroscience, Dallas, Texas (Aigner et al. 1985)     

Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys

RATIONALE: Early, accurate detection of degenerative neurological disorders such as Alzheimer's disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a non-human model may therefore provide an improved tool for study of the etiology and treatment of dementia. OBJECTIVE: The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs. METHODS: Seven monkeys were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 microg/kg, IM) and ketamine (0.3, 1.0, 1.78 mg/kg, IM). RESULTS: Scopolamine produced a dosexdifficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition. CONCLUSIONS: Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment, therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.     

Effects of diazepam and scopolamine on storage,retrieval and organizational processes in memory

The effects of intramuscular injections of diazepam (0.3 mg/kg) and scopolamine (8 g/kg) on memory processes and subjective moods were studied in 36 volunteers. Subjects (Ss) were tested in groups of four in a double blind procedure with treatments distributed according to a Latin square design. Lists of words were presented to Ss who were then tested with an immediate free recall test prior to drug administration. Following injection delayed free recall and recognition tests were given. Subsequently two sets of lists were presented separately and tested in the same fashion. Two of the lists in the last set were composed of words falling into distinct categories. Memory was additionally analyzed by testing immediate recall of digit sequences and employing a visual recognition test. Subjective moods were evaluated with a rating questionnaire.Both diazepam and scopolamine impaired memory functions although the action of the latter drug was more pronounced and prolonged. The deficit appeared to be in the storage process leaving retrieval processes unaffected. Scopolamine in addition interfered with organizational processes. Subjectively, scopolamine also produced a larger sedative effect than diazepam.     

Cholinergic learning deficits in the marmoset produced by scopolamine and ICV hemicholinium

Common marmosets (Callithrix jacchus) were trained to perform daily position discrimination learning tasks in a Wisconsin General Test Apparatus. Acetylcholine receptor blockade with scopolamine was found to impair position learning. Testing on the day after scopolamine treatment suggested that a task learnt under scopolamine was not encoded into long term memory. Acetylcholine depletion achieved by the intraventricular injection of hemicholinium 4 h before testing resulted in a profound impairment of position discrimination learning. It is suggested that central acetylcholine depletion in primates may provide a useful model of senile dementia.     

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.     

Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert

Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.     

Comparing the effects of scopolamine on operant and aggressive responses in squirrel monkeys

The anticholinergic drug, scopolamine, causes disinhibition or an increase in response that an animal normally suppresses. Experiment 1 confirmed this effect in squirrel monkeys. Experiment 2 explored the implications of drug-produced disinhibition on aggressive interactions. In Experiment 1, scopolamine produced increased unreinforced responding on a DRL schedule and increased responding during unreinforced (Time Out) periods. In contrast, the peripheral control drug, methyl scopolamine, caused decreased responding in both situations. In Experiment 2, social rank and drug treatment interacted. When space was restricted so that the opportunity for social interactions was maximized, scopolamine consistently increased aggressiveness in the dominant monkey and decreased aggressiveness in a submissive monkey. When space was increased so that the opportunity for social interactions was minimized, scopolamine caused decreased aggressive responses in all monkeys. Neither the effective dosage nor the drug's effect on the operant task could be easily generalized to aggressive responses.     

Effects of scopolamine,trimipramine and diazepam on explicit memory and repetition priming in healthy volunteers

The effects of scopolamine, an anticholinergic drug, of trimipramine, a tricyclic antidepressant with both anticholinergic and sedative properties, of diazepam and a placebo, on explicit memory and repetition priming were assessed using a free-recall task and a word-stem completion task. Forty-eight healthy volunteers took part in this double-blind study. Diazepam provoked a dissociation between free recall, which was profoundly impaired, and word completion, which was spared. No significant changes in memory performances were observed in the scopolamine group; however, a significant correlation between explicit and implicit memory performances was observed in this group. At the low dose used, the effects of trimipramine on memory were mild. The results suggest that the cholinergic system is involved in the priming effect.     

Improved recognition memory in monkeys following naloxone administration

The effects of naloxone on visual recognition were evaluated in five macaques trained in delayed nonmatching-to-sample with trial-unique objects. In four of the five monkeys, naloxone yielded an inverted U-shaped dose-effect curve. For each of these four animals, as well as for all five animals as a group, at least one dose within a narrow range (0.32–3.2 mg/kg) produced a significant increase in the number of objects correctly recognized. Lower doses had little effect, while the highest dose (10.0 mg/kg) tended to disrupt performance.     

Chronic neuroleptic effects on spatial reversal learning in monkeys

Cebus apella monkeys were chronically administered the antipsychotic drug fluphenazine decanoate for periods ranging from 3.5 to 5.5 years. In the present study, four of these monkeys and two controls were tested for cognitive abilities on a spatial learning task, which consisted of an original discrimination and four reversals of that discrimination. No effect of fluphenazine administration was seen in the rate of learning the original discrimination, but the carryover of learning across discrimination reversals was significantly reduced by fluphenazine. After overtraining on the original discrimination, the controls showed the normal difficulty in learning the first reversal. The fluphenazine-treated monkeys showed no such disruption. On subsequent reversals, the controls showed continually improving performance, so that on the third and fourth reversals they had near-perfect scores. On the other hand, the fluphenazine-treated monkeys showed no change over the four reversals. Unlike normal monkeys, their learning did not improve with practice. Although simple forms of learning seem to be relatively unaffected by chronic fluphenazine administration, more complex learning is disrupted.     

Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia

Two experiments examined dose-related effects of 200, 400 and 600 μg scopolamine (n = 24, SC) and 5 and 10 mg diazepam (n = 6, PO) on parallel tests of visual memory and learning taken from the CANTAB battery. Scopolamine significantly impaired accuracy of performance on a delayed matching to sample test of visual recognition memory in a dose-and delay-dependent manner, but had only marginal decremental effects on a test of visuospatial paired associates learning. Scopolamine significantly lengthened decision times in a visual search matching to sample task at the 400 and 600 μg doses, without significantly affecting accuracy. The drug also impaired performance on tests of spatial (on accuracy and response time measures) and pattern (on response time only) memory. Most of the deleterious effects on scopolamine were removed by covariance analyses with indices of subjective sedation, but the effects of delayed matching accuracy and latency remained. By contrast, diazepam significantly impaired paired associates learning but affected delayed matching to sample in a delay-independent manner. These results suggest that scopolamine can produce selective deficits in tests of short-term visual recognition memory which do not depend on overall impairments in arousal and which contrast with deficits in visual associative learning produced by diazepam. They have implications for the pharmacological modelling of dementia and memory disorders in man and for the neurochemical substrates of the short-term recognition memory and associative learning for visual stimuli. Received: 19 February 1997 / Final version: 25 April 1997     

Effects of scopolamine on acquisition of passive avoidance

Summary Scopolamine was tested for effects on acquisition of a passive-avoidance problem. First mice were given four trials 24 hours apart on a step-off apparatus. Various dose levels of the drug were studied. For one group the drug was injected i.p. 20 minutes prior to each trial, in the other immediately after. Doses of 5.0 mg/kg and higher greatly interfered with the acquisition of the response, but only when injected prior to the trial. These results failed to indicate any direct effect of the drug on the learning process. The only time the drug affected the behavior was when the animal was under its influence at the time of testing.A second experiment was conducted in which mice were trained as before but pre-injection of 5.0 mg/kg of scopolamine was used. However, the mice were injected with the drug on only some of the trials. In all, six groups were studied, and their performance compared with a group that had received scopolamine on all trials and with one that received saline on all trials. When the data were examined for evidence of dissociation, it was clear that it was not present. Further analysis showed that animals which had learned, as indicated by their performance on the early trials conducted when they were not drugged, failed to show evidence of memory when given additional trials after being drugged. This outcome clearly indicated that a major effect of scopolamine was on the performance of the animal. Also, animals which had received 1 or 2 trials while drugged and given additional trials in the nondrugged state, showed a rapid increase in latency on succeeding trials equal that of animals which had not been drugged at all.These results, in light of other research, indicate that the effect of scopolamine on this type of learning task does not appear to be through a modification of the consolidation process.A preliminary report of Experiment I was made at the Southeastern Psychological Association Annual Meeting in Atlanta, Georgia, April, 1967. Supported by NIMH Grant No. MH 12770-01 to the senior author.     

Effects of pre-training administration of scopolamine on learning and retention in the cockroach,P. americana

The muscarinic cholinergic blocker, scopolamine, has no effect on acquisition or retention of the choice behavior of the cockroach, P. americana trained to turn right or left to avoid shoch in a T-maze. Scopolamine does, however, prevent runaway habituation during training, suggesting that such habituation may be dependent on central cholinergic synapses as there are no known peripheral cholinergic receptors in cockroaches. Previous work demonstrating that no effect of scopolamine on such retention, suggests that puromycin does not produce its amnesic effect on choice behavior by interferring with central cholinergic synaptic processes.     

The effects of atropine,benactyzine, and physostigmine on a repeated acquisition baseline in monkeys

A repeated acquisition procedure was used with cynomolgus monkeys to test the effects of one anticholinesterase (physostigmine) and two anticholinergic (atropine and benactyzine) compounds on learning and performance. Learning was defined as the number of response chains (trials) required to meet a criterion of three consecutive chains at 90% accuracy or better. Measures were the number of trials to criterion and the number of errors made. Following learning, behavior was analyzed as performance. Measures were total errors after learning and errors per trial. Time-out minutes (i.e., periods of enforced no responding after errors) were analyzed separately from total session time. Atropine (0.014, 0.044, 0.14, and 0.44 mg/kg) produced large learning disruptions and performance decrements at the highest dose. Learning decrements due to benactyzine (0.057, 0.18, 0.57, and 1.82 mg/kg) were not significant and produced little effect on performance. The effect of physostigmine (0.025, 0.050, and 0.075 mg/kg on learning was not consistent. The anticholinergics increased performance errors per trial, while the anticholinesterase had little effect. Session times showed dose-related increases for all drugs and were significantly increased by the highest doses of each. The session time increases observed after the anticholinergics were interpreted to be due to both an effect on learning and an effect on response rate, whereas the anticholinesterase effect was due primarily to response suppression.     

Effects of scopolamine on variable intertrial interval spatial alternation and memory in the rat

A repeated measures procedure, variable intertrial interval (ITI) spatial alternation, was used to assess scopolamine effects on memory, and to compare effects of the drug on discrimination processes with effects on storage. Rats learned in two stages to press left and right levers in alternation on discrete trials separated by 5 different ITI's ranging from 2.5 to 40 s and presented in random order during the experimental session. In the first stage, alternating discrimination, alternation was controlled by a light on over the correct lever at the time of the trial; in the second stage, variable ITI spatial alternation, a centrally located panel light signalled all trials and alternation was controlled by stimuli from prior trials (memory). Alternation response occurrence declined moderately (but significantly) with increasing ITI duration in both the alternating discrimination and variable ITI spatial alternation stages; response occurrence was also significantly decreased by scopolamine treatment in both stages. Accuracy of alternating discrimination performance was not significantly altered by either ITI duration or scopolamine treatment. Accuracy of variable ITI spatial alternation performance on a trial varied inversely with the duration of the ITI that preceded the trial. Scopolamine treatment significantly reduced accuracy of lever pressing in variable ITI spatial alternation but did not alter the slope of the curves relating accuracy to ITI duration. These effects indicate that the drug impaired discrimination processes but did not alter memory storage.     

Reinforcing properties of clonidine in rhesus monkeys

Intravenous clonidine self-administration was studied in rhesus monkeys under condttions of limited and unlimited access. Limited access consisted of daily 2-h experimental sessions with drug available on a fixed ratio 10 schedule. For unlimited access, drug was availabe 23 h/day with each response resulting in an injection. In all animals under both conditions, responding was maintained at levels that were above those maintained by saline injections at doses between 0.3 and 10 g/kg/inj, and the number of injections taken per session depended upon the dose. Under conditions of limited access, peak self-administration rates varied between animals but averaged approximately 30 inj/session. Total session intake was occasionally in excess of 1.0 mg/kg. Under conditions of unlimited access animals frequently self-administered more than 300 inj/day and intakes averaging 3.6 mg/kg/day occurred at the highest dose tested (10 g/kg/inj). When saline was substituted for clonidine after periods of clonidine access that ranged from 10–40 days, withdrawal signs included facial flushing, refusal of preferred food, restlessness, salivation, and emesis. These signs could be reversed with IV clonidine but could not be reliably precipitated with IV naloxone.     

Acute effects of physostigmine on complex operant behavior in rhesus monkeys

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001–0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or “cognitive” impairment.     

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

Seventy volunteers were injected with diazepam (0.3 mg/kg), scopolamine (8 g/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 g/kg; methscopolamine, 8 and 16 g/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.     

Acute dose-effects of scopolamine on false recognition

RATIONALE: Recently, there has been increased research interest in the phenomenon of false recognition, in which participants claim to recognize words that had not been presented during an initial study phase but that are associatively related to presented words. Acute administration of the benzodiazepine hypnotic triazolam has been shown to decrease false recognition rates. However, no false recognition studies have examined the effects of scopolamine, an anticholinergic drug that might produce a different profile of memory-impairing effects than the benzodiazepines due to its distinct neurochemical profile. OBJECTIVE: This study was designed to examine the acute dose-effects of scopolamine on false recognition. METHODS: The effects of subcutaneously administered scopolamine (0.3 and 0.6 mg/70 kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated-measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: Scopolamine produced dose-related reductions in both true and false recognition rates, and induced a more conservative response bias relative to placebo for recollection-based ("remember") responses to studied words. CONCLUSIONS: While scopolamine's effects on false recognition are similar to those observed previously with triazolam, its effects on response bias may differ from those of triazolam.