Effects of physostigmine on operant serial discrimination/reversal learning in rats.

Two experiments examined the effects of physostigmine on acquisition and performance of operant serial reversals by rats. In Experiment 1, four groups of rats (n = 6/group) were injected with either vehicle or 0.03 mg/kg physostigmine five minutes prior to each session, or vehicle or 0.5 mg/kg physostigmine immediately after each session of a three-stimulus (bright, dim or flashing light) repeated discrimination/reversal procedure. Rats treated with physostigmine pre- or postsession learned significantly more reversals over 50 sessions than animals injected with vehicle. Experiment 2 used only two discriminative stimuli, a light and a 2,500 Hz tone. Following establishment of a stable daily reversal baseline, postsession injections of physostigmine significantly increased the number of trials to criterion on the next session compared to each subject's control baseline. Results are attributed to enhanced between-session transfer of previously learned discriminated instrumental responses by physostigmine-treated animals.

Effects of scopolamine on components of delayed response performance in the rat.

The effects of scopolamine and methyl scopolamine on working memory processes were investigated in a paired trial, go-no go delayed response procedure in which rats initiated their own trials. Drug effects were examined concurrently on performance at three delays--no, 0, and 2.5 sec. Scopolamine disrupted no-delay (discrimination) performance in a dose-related manner. Scopolamine also progressively reduced performance at 0-delay and 2.5 sec delay more than at no-delay, but only at the highest administered dose (0.5 mg/kg). Scopolamine affected sensitivity, but not response bias. Although both scopolamine and methyl scopolamine reduced the probability of trial initiation, only scopolamine disrupted accuracy of performance on the initiated trials.

Central cholinergic involvement in working memory: effects of scopolamine on continuous nonmatching and discrimination performance in the rat.

Rats were trained to stable baselines of lever pressing on a variable intertrial interval continuous nonmatching to sample schedule (CNM) or on an analogous discrimination schedule. Scopolamine reduced accuracy of CNM performance to a similar extent over the three intertrial (retention) intervals: 2.5, 5, and 10 s, results indicating that the drug did not affect the time-dependent process of retention in working memory. When baseline levels of performance accuracy were similar in the CNM and discrimination tasks (but stimulus discriminability was greater in the CNM task), scopolamine reduced accuracy equally in the two procedures. Effects of scopolamine on accuracy of noncorrection trial CNM performance were simulated by reducing stimulus discriminability; however, scopolamine disrupted CNM correction trial performance much more than did reductions in stimulus discriminability. It is concluded that scopolamine's effects on working memory are not limited to possible effects on stimulus discrimination: Scopolamine may also affect retrieval of response rules from reference memory.

Effects of pesticides and drugs on working memory in rats: continuous delayed response.

Effects of four pesticides (carbaryl, propoxur, chlordimeform, and deltamethrin) and four reference drugs (physostigmine, scopolamine, methscopolamine, and chlordiazepoxide) were measured in two delayed response, working memory procedures: go-no go alternation in which rats initiated their own trials, and spatial reversals. Four of these compounds (carbaryl, propoxur, physostigmine, and scopolamine) were also tested in a go-no go alternation procedure in which animals did not initiate their trials. The pesticides and physostigmine did not selectively affect working memory in any of the procedures: low doses only moderately decreased response accuracy, whereas higher doses suppressed responding indiscriminately. The pesticides and physostigmine had similar effects on go-no go alternation (i.e., working memory) and analogous go-no go discrimination performance. Effects on go-no go alternation performance did not depend on whether the animals initiated their own trials. Scopolamine, in contrast, appeared to disrupt working memory. It profoundly disrupted accuracy at doses that only moderately decreased over-all responding and impaired go-no go alternation accuracy much more than discrimination accuracy.

Effects of pesticides and drugs on working memory in rats: continuous non-match.

Effects of four pesticides (carbaryl, propoxur, chlordimeform, and deltamethrin) and two reference drugs, physostigmine and chlordiazepoxide, were measured on the performance of rats trained on a continuous non-match (CNM) delayed comparison, working memory procedure. These same compounds were also tested in analogous, large and small stimulus difference discrimination (i.e., non working-memory) procedures. The effects of the pesticides and physostigmine on CNM performance were qualitatively similar, and also similar to their effects on discrimination performance. As dosage of these compounds increased, only small effects on accuracy were observed, followed at still larger doses by an abrupt and non-selective decrease in all responding. The pesticides and physostigmine did not selectively affect working memory: the magnitude of their effects did not increase with intertrial interval, and the compounds were equally effective in disrupting discrimination and CNM performance. Effects of chlordiazepoxide on performance in the CNM and discrimination control procedures differed qualitatively from those of the pesticides and physostigmine.

Behavioral methods for measuring effects of drugs on learning and memory in animals.

This review describes methods for measuring effects of drugs on learning and memory in animals, proceeding from relatively simple nonassociative learning (habituation) to classical and instrumental conditioning, and concluding with complex measures for measuring learning and memory repeatedly in the individual animal. Procedures for separating drug effects specific to learning and memory from non-specific effects on activity, motivation, sensory and motor capacity, etc., were emphasized. For each method, selected experimental examples were presented which described the action of drugs on learning and memory, elucidated the behavioral processes involved in the drug effects, or illustrated methodological points. The various procedures used to measure drug effects on learning and memory in animals have yielded a bewildering array of often-contradictory results. Quantitative differences in effectiveness of drugs in the different procedures are common. Drugs (for example, the nootropics) that alter learning or memory in a few procedures may be totally without activity in many others. How are these discrepancies to be interpreted? The apparent inconsistencies in the data can, for the most part, be understood in terms of the nature of learning and memory. "Learning" and "memory" are hypothetical processes presumed to underlie enduring changes in behavior resulting from the organism's interaction with environmental stimuli. Given such a broad definition, the prevalence of inconsistencies in the data is hardly surprising. It is unlikely that the same mechanisms should underlie all of the wide variety of behavioral changes included under the rubrics "learning" or "memory." (For a contrary view, based on consistencies among results obtained in the diverse procedures, see Zornetzer). How, then, should drug effects on learning and memory be identified or measured? The first step, of course, is to rule out those drug effects that do not conform to the definition of learning or memory. This review has described strategies and procedures by which this can be accomplished. However, even when this is done there is no single procedure that can detect drug effects on learning and memory in general, nor, in view of the heterogeneous behaviors involved, is it likely that such a universal procedure will ever be found. Thus, a multi-faceted strategy will be required. Some of the simpler procedures described in this review may be adequate for the initial identification of interesting effects.(ABSTRACT TRUNCATED AT 400 WORDS)

A reappraisal of scopolamine effects on inhibition.

A series of related experiments was conducted to examine the effects of scopolamine on discrimination performance in the presence or absence of a stimulus signalling non-reinforcement. In Experiment 1, rats trained to respond on 1 of two levers in the presence of a 1000-Hz tone and on the other lever in the presence of a 3000-Hz tone were not reinforced when white noise was added to 1 of the tones. Pairing white noise with the other tone during an extinction session demonstrated that the white noise had become a conditioned inhibitory stimulus. In Experiment 2, scopolamine decreased responding and discrimination accuracy on the excitatory (reinforced) trials, and increased responding on the inhibitory (non-reinforced) trials. The magnitude of the drug's effect was similar on excitatory and inhibitory trials. Using combination of visual and auditory discriminative stimuli, Experiment 3 confirmed the results of Experiment 2. These experiments show that scopolamine disrupts animals' ability to discriminate, and that scopolamine-induced increases in non-rewarded responses cannot be attributed solely to a disinhibitory effect of the drug as Carlton (1969) and others have claimed.

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 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.

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.

Discrete trial analysis of drug action.

Discrete trial procedures permit exact control or description of the time of occurrence of stimuli, the probability of response occurrence, and the patterning of responses. They also make possible the experimental manipulation of the composition of the stimuli controlling behavior. The use of discrete trial procedures is illustrated here in an examination of the effects of scopolamine, a representative cholinergic blocker, on several aspects of behavior: Memory. Response alternation experiments, in which the spacing of discrete trials varies within the experimental session, show that, whereas accuracy of responding is consistently poorer under drug, the decline of accuracy with time since last trial is similar for drugged and nondrugged animals. Thus the drug does not affect memory "storage". Inhibition. Experiments in which discrete trials are presented in pairs, such that the correct response on Trial 2 of the pair is contingent upon Trial 1 events, show how the "disinhibiting" effect of scopolamine (as indicated by enhanced responding on "no go" trials) is augmented by increasing the time gap between Trial 1 and Trial 2, or by minimizing controlling stimuli on Trial 1. Discrimination. A variety of experiments suggest that scopolamine decreases the "detectability" of stimuli. Detectability effects, along with disinhibition observed under certain specific conditions, constitute the prinicipal behavioral actions of scopolamine observed with discrete trial procedures.

Discrete-trial alternation in the rat.

The acquisition and maintenance by rats of single alternation, double alternation, and four other repeating patterns of reinforced and non-reinforced trials was studied in a discrete-trial lever-pressing situation. The rats learned all these patterns in a small number of experimental sessions. Single alternation was learned more rapidly than the more complex patterns. Rate of learning single and double alternation decreased moderately as inter-trial interval increased. Abrupt changes in the scheduling of trials, either by doubling the inter-trial interval or by shifting from fixed to variable trial spacing, temporarily disrupted the patterned performance. Two hypotheses concerned with the means by which the rats could have learned to conform to the pattern were examined: (1) "timing" of the interval between successive reinforcements; and (2) control of responding on a trial by the outcome of preceding trials, depending on the consistency with which these outcomes were associated with reinforced or non-reinforced trials in the pattern and on how many trials back these outcomes occurred. The second hypothesis accounted for the relative frequency of errors on trials at various locations in the sequences, and predicted most of the changes in error frequency observed in experiments in which "inter-trial stimuli" were added to the sequences.