Cholinergic drug effects on a delayed conditional discrimination task in the rat

The centrally acting cholinergic antagonist scopolamine (0.025-0.10 mg/kg ip) and the peripherally acting cholinergic antagonist methyl-scopolamine (0.01-0.10 mg/kg) dose dependently impaired discriminability independent of delay in a delayed conditional discrimination task that precludes use of mediating behavior. This indicates that scopolamine does not specifically affect working memory. Drugs that enhance cholinergic transmission neither improved discriminability nor attenuated scopolamine-induced impairments. In a post hoc analysis scopolamine was found to impair discriminability in a delay-dependent manner in rats that performed at a high level in pretest sessions. Methyl-scopolamine impaired performance independently of delay in these rats. The authors suggest that a ceiling effect at short delays produced this Drug x Delay interaction of scopolamine in the best performing rats.     

Effects of the potassium channel blockers, apamin and 4-aminopyridine, on scopolamine-induced deficits in the delayed matching to position task in rats: a comparison with the cholinesterase inhibitor E2020

The effects of the muscarinic antagonists, scopolamine HBr and MeBr, a cholinesterase inhibitor, E2020, and K+ channel blockers, 4-aminopyridine (4-AP) and apamin, on the performance of rats in a delayed matching to position (DMTP) task were examined. The percentage of correct choices (choice accuracy), number of trials completed and intertrial intervals were measured. Discriminability and response bias were also calculated, using signal detection analysis. Scopolamine HBr (0.1 mg/kg), but not scopolamine MeBr (0.1 mg/kg), significantly and consistently reduced the choice accuracy and discriminability, but neither affected the other measurements. E2020 (0.03-1.0 mg/kg) had no effect on the baseline performance in the DMTP task, but at 1.0 mg/kg, it significantly attenuated the deficits in choice accuracy induced by scopolamine. 4-AP (0.001-0.1 mg/kg) had no effect on either baseline performance or deficits induced by scopolamine. Apamin (0.1-0.4 mg/kg) had no effect on choice accuracy and discriminability. Apamin also failed to attenuate the scopolamine-induced deficits. When administered in combination with scopolamine, apamin at 0.4 mg/kg significantly decreased the number of trials completed and increased the intertrial interval relative to that of the control group. Taken together, these results demonstrate that K+ channel blockers (4-AP and apamin), unlike a cholinesterase inhibitor (E2020), fail to reverse the scopolamine-induced deficits in the DMTP task.     

Acquisition, retention, and extinction of operant discriminations in rats with nucleus basalis magnocellularis lesions.

Effects of bilateral ibotenic acid lesions of nucleus basalis magnocellularis (NBM) and scopolamine treatment on different aspects of learning and memory in an operant discrimination task were assessed. In Experiment 1, NBM lesions impaired acquisition performance. In Experiment 2, scopolamine lowered response rates but did not affect discrimination accuracy in lesioned or control rats. In Experiment 3, although pretrained rats showed transient increases in commission errors, percentage correct responding remained above chance levels after lesion. During extinction in Experiment 4, operant responding diminished more quickly in pretrained NBM-lesioned rats than in controls, but subsequent reacquisition performance was equivalent in both groups. Results suggest the NBM is importantly involved in discrimination learning, but cholinergic activity may be less critical for memory retention than for acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sequential effects in pigeon delayed matching-to-sample performance.

Five pigeons were tested in a 3-alternative delayed matching-to-sample task in which 2nd choices were permitted following 1st-choice errors. Sequences of responses both within and between trials were examined in 3 experiments. In Exp I, the sample information contained in 1st-choice errors was not sufficient to account for the observed pattern of 2nd choices. This implies that 2nd choices following 1st-choice errors are based on a 2nd examination of the contents of working memory. Proactive interference was found in Exp II in the form of a dependency, beyond that expected on the basis of trial-independent response bias, of 1st-choices from 1 trial on the 1st-choice emitted on the previous trial. Samples from the previous trial did not exert a significant influence on later trials. The magnitude of the intertrial association (Exp III) did not depend on the duration of the intertrial interval. In contrast, longer intertrial intervals and longer sample durations facilitated choice accuracy by strengthening the association between current samples and choices. Results are incompatible with a trace-decay and completion model; they suggest that multiple influences act simultaneously and independently to control delayed matching-to-sample responding. These influences include memory for the choice occurring on the previous trial, memory for the sample, and general effects of trial spacing. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Bridging temporal gaps between CS and US in autoshaping: Insertion of other stimuli before, during, and after CS.

In 4 experiments, female White Carneaux pigeons were exposed to key-light illuminations separated from food delivery by 12–60 sec. Approach to the key light did not develop on conventional trace-conditioning arrangements but occurred consistently whenever some auditory or visual stimulus filled the CS–UCS gap (serial conditioning) or was always present except during the gap. The CS approach was strong only when the stimulus present during the intertrial interval remained on until the termination of CS; if the stimulus ended at CS onset, conditioning did not occur. Although discriminability of CS–UCS gaps from intertrial periods seemed necessary for conditioning to occur in the absence of close CS–UCS contiguity, the outcome of the final experiment indicates that such discriminability was not sufficient for conditioning. Results are discussed in terms of possible 2nd-order conditioning effects and the changes in the associative strength of the "local context" existing when the CS appears, which may lead to superconditioning of CS. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Context reinforcement degrades discriminative control: A memory approach.

This study measured effects of context reinforcement on a visual discrimination. Five pigeons responded to 1 key in the presence of 6 shorter wavelengths and to another key for 6 longer wavelengths. Psychometric functions provided measures of discriminative sensitivity (d') and overall stimulus control. Sensitivity and control were slightly but significantly better when 20% of correct choices yielded reinforcement than when 5% did. Reinforcement of pecks to the sample stimulus reduced control substantially and sensitivity slightly; noncontingent reinforcement during intertrial intervals also reduced control, whether such reinforcement was signaled or not. Accuracy was excellent during an extinction session, but it fell substantially when reinforcement for sample pecks was added during choice extinction. Simulations based on a memory model of the discrimination process reproduced most of the experimental findings. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of phencyclidine, pentobarbital, and d-amphetamine on the acquisition and performance of conditional discriminations in monkeys

In each of two components of a multiple schedule, monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was therefore conditioned upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One composition of the multiple schedule was a repeated-acquisition task where the discriminative stimuli for left- or right-lever responses changed each session (learning). In the other component, the discriminative stimuli for left- or right-lever responses were the same each session (performance). Phencyclidine, pentobarbital, and d-amphetamine each produced dose-related decreases in the overall rate of responding in both components of the multiple schedule. At high doses each drug increased the percent errors in each component. At lower doses, however, the three drugs produced selective effects on accuracy. Errors were increased in the learning component at lower doses than those required to disrupt the discrimination in the performance component. A signal detection analysis of the data revealed that none of the drugs tested increased errors by selectively affecting either discriminability or bias.     

Interactions between 192-IgG saporin and intraseptal cholinergic and GABAergic drugs: Role of cholinergic medial septal neurons in spatial working memory.

Rats were administered 192-IgG saporin (SAP) or vehicle into the medial septum-vertical limb of the diagonal band (MS-vDB). Starting 1 week later, the effects of intraseptal scopolamine, oxotremorine, and muscimol were tested in a T-maze alternation task. Choice accuracy in the absence of infusions did not differ between control and SAP-treated rats. Intraseptal scopolamine or muscimol impaired the choice accuracy of SAP-treated but not control rats. Oxotremorine impaired accuracy similarly in control and SAP-treated rats. The enhanced effects of scopolamine and muscimol produced by SAP are consistent with the hypothesis that cholinergic MS-vDB neurons are used in spatial working memory. The finding that SAP alone did not alter choice accuracy provides further evidence that cholinergic MS-vDB neurons are not necessary for spatial working memory. Thus, cholinergic MS-vDB neurons are involved in but not necessary for spatial working memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Testosterone potentiates scopolamine-induced disruptions of nonspatial learning in gonadectomized male rats.

Whereas research into the effects of the gonadal hormones on learning and memory has primarily focused on estrogen in females, recent evidence suggests that testosterone can also modulate learning in males through an interaction with the cholinergic system. In the present study, the interactive effects of testosterone and scopolamine (0.1- 0.32 mg/kg), a muscarinic receptor antagonist, on complex behavioral processes were investigated in male rats trained to respond under a multiple schedule of repeated acquisition and performance. In the acquisition component, subjects acquired a different 3-response sequence each session, whereas in the performance component, they responded on the same 3-response sequence each session. Although gonadectomy did not disrupt responding in either component, gonadectomized rats were less sensitive to the disruptive effects of scopolamine on both response rate and accuracy. In contrast, after receiving exogenous testosterone replacement, these gonadectomized males were more sensitive to the behavioral disruptions produced by scopolamine (i.e., the effects of scopolamine were similar to those obtained in gonadally intact males). These results suggest that testosterone replacement can enhance scopolamine-induced behavioral effects in gonadectomized male rats responding under a multiple schedule of repeated acquisition and performance, a finding that is in contrast to those previously found for certain spatial tasks. Furthermore, the present findings suggest that testosterone may decrease the activity of the cholinergic system during nonspatial tasks and thereby work in concert with the antagonism produced by scopolamine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of cholinergic blockade on performance of rats in the water tank navigation task and in a radial water maze.

Tested the disruptive effect of cholinergic blockade under conditions in which either the working memory or the spatial mapping requirements of the behavioral task were emphasized. In Exp I, 13 male hooded rats were trained in an 8-arm radial water maze to asymptotic performance. When delays of 5, 10, 20, and 40 min were inserted between Choice 4 and Choice 5, incidence of errors in Choices 5–8 increased after pretrial (20 min) intraperitoneal scopolamine (0.2 mg/kg) faster than under control conditions and approached chance level with the 40-min delay. Scopolamine after Choice 4 or pretrial methylscopolamine was ineffective. In Exp II, 30 Ss were trained in a Morris water tank. Acquisition was impaired by pretrial injection (20 min) of 0.1 and 0.2 mg/kg scopolamine, but a higher dose (1.0 mg/kg) was required to impair overtrained performance. In a working memory version of the navigation task, scopolamine administered 20 min before the 1st trial deteriorated retention tested 40 min later at a dose of 1.0 but not at 0.4 and 0.2 mg/kg. It is concluded that the disruptive effect of scopolamine is proportional to the demands on the working memory component of the task, whereas the use of an overtrained mapping strategy is relatively resistant to cholinergic blockade. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of muscarinic cholinergic receptor blockade in the rat anterior cingulate and Prelimbic/Infralimbic cortices on spatial working memory

Previous findings indicate that cholinergic input to the medial prefrontal cortex may modulate mnemonic processes. The present experiment determined whether blockade of muscarinic cholinergic receptors in the rodent anterior cingulate and prelimbic/infralimbic cortices impairs spatial working memory. In a 12-arm radial maze, a working memory for spatial locations task was employed using a continuous recognition go/no-go procedure. Rats were allowed to enter 12 arms for a reinforcement. Of the 12 arm presentations, 3 or 4 arms were presented for a second time in a session that did not contain a reinforcement. The number of trials between the first and second presentations of an arm ranged from 0 to 6 (lags). Infusions of scopolamine (1, 5, and 10 microgram), a muscarinic cholinergic antagonist, into the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, significantly impaired spatial working memory in a lag- and dose-dependent manner. The deficit induced by scopolamine (10 microgram) was attenuated by concomitant intraprelimbic/infralimbic injections of oxotremorine (2 microgram) a muscarinic cholinergic agonist. A separate group of rats was tested on a successive spatial discrimination task. Injections of scopolamine (1, 5, and 10 microgram) into the prelimbic/infralimbic cortices did not impair performance on the spatial discrimination task. These findings suggest that muscarinic transmission in the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, is important for spatial working memory.     

Glucose attenuation of memory impairments.

The performance of pigeons in a short-term memory procedure (delayed matching-to-sample) was studied over a range of retention intervals from 0.2 s to 24.0 s. The authors examined the ability of 3 dose levels of glucose (0, 50, and 100 mg/kg) to alleviate memory impairments produced by administration of scopolamine (0.03 mg/kg), by a reduction in the sample–response requirement and by interpolating retroactive interference in the retention interval (houselight illumination). Glucose administration attenuated the deficit produced by scopolamine and by the reduced sample–response requirement, by reversing the decrement in accuracy at 0 delay. Glucose did not, however, reverse the increase in rate of forgetting generated by retroactive interference. The results suggest that the mode of action by which glucose is able to attenuate drug-induced and behavioral impairments in memory may be through an effect on attentional or encoding processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sources of proactive interference in animal memory.

Events occurring before each trial in delayed matching-to-sample tasks can proactively interfere with accurate matching on the trial. Matching performance by pigeons was examined in a two-alternative delayed matching-to-sample procedure that permitted analysis of performance on two-trial sequences where the relation between the Trial N and Trial N?–?1 stimuli was manipulated. In Experiment 1, temporal variables of intertrial interval, delay interval on Trial N, and delay interval on Trial N?–?1 were varied. In Experiment 2, the effects of illuminating the intertrial interval were examined. The results suggested that there are two independent sources of proactive interference in delayed matching-to-sample performance: a general effect of intertrial-interval duration and a specific intertrial-agreement effect. The intertrial-agreement effect was influenced by both the choice stimulus on Trial N?–?1, and by the sample stimulus on Trial N?–?1. We suggested that one-process theories of proactive interference in delayed matching-to-sample performance could not account for these data and that a two-process theory of memory is required. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by hippocampal muscarinic blockade in rats

To clarify the interactions between hippocampal cholinergic and adrenergic systems in working memory function of rats, the effects of hippocampal muscarinic receptor blockade combined with noradrenaline depletion on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task, whereas the 0.32 microgram/side dose of scopolamine did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg IP caused a marked reduction in hippocampal noradrenaline concentration, but it had no effect on working memory errors. Intrahippocampal administration of 0.32 microgram/side scopolamine, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted animals. These results suggest that hippocampal muscarinic/noradrenergic interactions are involved in neural processes mediating working memory function of rats.     

Externalizing psychopathology and behavioral disinhibition: Working memory mediates signal discriminability and reinforcement moderates response bias in approach–avoidance learning.

Research has suggested that reduced working memory capacity plays a key role in disinhibited patterns of behavior associated with externalizing psychopathology. In this study, participants (N = 365) completed 2 versions of a go/no-go mixed-incentive learning task that differed in the relative frequency of monetary rewards and punishments for correct and incorrect active-approach responses, respectively. Using separate structural equation models for conventional (hit and false alarm rates) and signal detection theory (signal discriminability and response bias) performance indices, distinct roles for working memory capacity and changes in payoff structure were found. Specifically, results showed that (a) working memory capacity mediated the effects of externalizing psychopathology on false alarms and discriminability of go versus no-go signals; (b) these effects were not moderated by the relative frequency of monetary rewards and punishments; (c) the relative frequency of monetary rewards and punishments moderated the effects of externalizing psychopathology on hits and response bias for go versus no-go responses; and (d) these effects were not mediated by working memory capacity. The findings implicate distinct roles for reduced working memory capacity and poorly modulated active approach and passive avoidance in the link between externalizing psychopathology and behavioral disinhibition. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Intraventricular galanin impairs delayed nonmatching-to-sample performance in rats.

Galanin is a neuroactive peptide that coexists with acetylcholine in the basal forebrain region. Galanin inhibits cholinergic functions in vitro and in vivo and has been shown to impair performance in some memory tasks. The present study compared the effects of galanin with the effects of scopolamine (a muscarinic antagonist) and ketamine and MK-801 (both NMDA receptor antagonists) on performance of an operant, spatial, delayed nonmatching-to-sample task in rats. Choice accuracy was impaired in a dose-dependent but delay-independent manner by galanin, scopolamine, and MK-801 but was not systematically influenced by ketamine. Measures of session duration, trials completed, discrimination accuracy, perservation, within-trial error distribution, and operant lever pressing were also analyzed. These results support observations that galanin disrupts performance in memory tasks requiring delayed responding but that the disruption is not specific to mnemonic capabilities. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chorda tympani transection and selective desalivation differentially disrupt two-lever salt discrimination performance in rats

Water-restricted rats were trained to press 1 of 2 levers if a sampled stimulus was NaCl and the other lever if the stimulus was KCl (0.05, 0.1, or 0.2 M). Responses were reinforced with water. After training, the average rate of correct responses was 90%. Performance was unchanged following sham surgery. Chorda tympani (CT) transection reduced average discrimination performance to 67.7% correct, and extirpation of the sublingual and submaxillary salivary glands reduced average performance to 80% correct. Although selective desalivation moderately reduced discriminability, a disrupted salivary environment does not explain the effects of CT transection. More likely, the discrimination deficit in CT-transected rats reflects a loss of critical taste input conveyed by the CT about salts.     

Spatial delayed matching-to-sample performance by rats: Learning, memory, and proactive interference.

Nine Sprague-Dawley rats were trained in a 3-alternative delayed matching-to-sample task in which the samples were rewarded forced choices of 1 arm of a 3-arm starburst maze, and retention was indicated by returning to that arm following a delay or retention interval. If the S made an error on its 1st free choice of a trial, the chosen arm was blocked off, and the S was allowed a 2nd choice between the remaining 2 arms. Ss quickly acquired this task. Exp II showed that choice accuracy was lower with 1-min retention intervals than with immediate tests. In Exp III, there was evidence for 2 separable proactive interference effects. The degree to which prior events influenced responding decreased as the intertrial interval increased. Choice accuracy improved with increasing intertrial interval and declined with increasing retention interval durations. Additionally, choice accuracy was higher when the sample from the previous trial matched the sample from the current trial and lower when they did not match. These results suggest that encoding information about visited spatial locations is a gradual process rather than an all-or-none process in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Time and context effects on performance in a Pavlovian discrimination reversal.

Five conditioned suppression experiments with rats explored retention interval and context effects in discrimination reversal learning. In the discrimination phase, a tone (T) was paired with shock, and a houselight-off stimulus (L) was presented alone; in the reversal phase, T was extinguished and L was paired with shock. Discrimination training made L a latent inhibitor but not a conditioned inhibitor. A 28-day delay after the reversal caused spontaneous recovery to T but had no effect on L. A context switch before the reversal caused more rapid conditioning to L but did not affect extinction to T. A return to the original context after the reversal had occurred in a different context renewed suppression to T and latent inhibition to L; contextual control was strong 21 days later. Tests in a neutral context indicated that each training context controlled performance to T and L. A memory retrieval framework may begin to integrate the effects of context and time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Selective Lingual Gustatory Deafferentation on Suprathreshold Taste Intensity Discrimination of NaCl in Rats.

In rats, chorda tympani nerve transection (CTX) greatly increases the detection threshold of sodium chloride (NaCl) and severely disrupts salt discriminability. Here it is shown that CTX has surprisingly little effect, if any, on suprathreshold intensity discrimination. Glossopharyngeal nerve transection (GLX), which has no reported effect on salt sensibility, also did not affect performance. Rats were tested in a 2-response, operant taste intensity discrimination task. Difference thresholds for CTX rats were only slightly higher (-0.15 log/10 unit) than those for GLX and sham-transected rats, when 0.05 M served as the standard, and did not significantly differ when 0.1 M NaCl was the standard. Although the perceived intensity of NaCl might be reduced by CTX, input from remaining taste nerves sufficiently maintains the relative discriminability of suprathreshold NaCl concentrations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)