Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.     

The effects of diazepam and triazolam on repeated acquisition and performance of response sequences with an observing response.

Drugs often disrupt the acquisition of new response sequences at doses that fail to disrupt the performance of a previously acquired response sequence. This selective drug effect may result from differences in the control exerted by the stimuli presented after each response in the acquisition and performance sequences. To examine the function of these stimuli, an observing procedure was incorporated into a multiple schedule of repeated acquisition and performance of response sequences, in which stimulus presentations were contingent upon an observing response. Three experiments were conducted with humans. Experiment 1 compared responding with and without the observing contingency. No difference was found in the overall percentage of errors across the two conditions. Within the observing condition, observing behaviour was maintained in the acquisition component as long as errors occurred, but was not maintained in the performance component. Experiment 2 examined whether a contingency that increased errors also would increase observing in both the acquisition and performance components. Specifically, reinforcer delivery in each component was contingent upon emitting 10 correct responses and one, two, or four errors. Observing responses increased in the acquisition component as the error requirement increased, whereas observing responses in the performance component increased only when the error requirement was four. Experiment 3 assessed the effects of diazepam (0, 7.5, 15, and 30 mg/70 kg, p.o.) and triazolam (0, 0.375, and 0.75 mg/70 kg, p.o.) on repeated acquisition and performance baselines with the observing contingency. Selective drug effects were obtained in this modified procedure; that is, the percentage of errors in the acquisition component increased at doses that failed to affect the percentage of errors in the performance components. Importantly, drug effects were selective, even though observing responses were not emitted in the performance component and, hence, the stimulus presentations did not occur in that component. These findings suggest that alternative explanations for these differential effects are needed; in that regard, a response-unit account of the selective drug effects is discussed.     

Comparable Rates of Responding and Reinforcement Do Not Eliminate the Differential Effects of Ethanol on Response Chain Acquisition and Performance

Ethanol and other drugs commonly disrupt responding under repeated acquisition and performance baselines, with responding in the former condition being more sensitive to such disruption than the latter. The present study was conducted to determine if differential drug effects would occur when baseline rates of responding were comparable in the two baseline conditions. The acute effects of ethanol (0, 0.4, and 0.8 g/kg) were examined in healthy adult volunteers responding under a multiple schedule of repeated acquisition and performance of 10-response sequences. A 1-sec delay occurred after each response to keep rates of responding comparable in the acquisition and performance conditions. This delay also reduced differences in reinforcement rates between the two components. Nevertheless, responding in the acquisition condition was still more sensitive to the disruptive effects of ethanol than responding in the performance component. This differential sensitivity to ethanol was most evident in measures of accuracy of responding (e.g., percentage of errors). These findings suggest that differences in overall rates of responding and reinforcement in the repeated acquisition and performance conditions contribute little, if anything, to the differential drug effects observed on those baselines.

     

Effects of d-amphetamine, cocaine, and phencyclidine on the acquisition of response sequences with and without stimulus fading.

In each of three components of a multiple schedule, monkeys were required to emit a different sequence of four responses in a predetermined order on four levers. Sequence completions produced food on a fixed-ratio schedule. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task where the four-response sequence changed each session (learning). The second component of the multiple schedule was also a repeated-acquisition task, but acquisition was supported through the use of a stimulus-fading procedure (faded learning). In a third component of the multiple schedule, the sequence of responses remained the same from session to session (performance). At higher doses, d-amphetamine, cocaine, and phencyclidine decreased the overall rate of responding and increased the percent errors in all three components. At lower doses, however, the three drugs produced selective effects on errors. Errors were increased in the learning component at lower doses than those required to disrupt the behavior in the faded-learning component. The performance component tended to be the least sensitive to disruptive drug effects. The data are consistent with the view that stimulus fading can modulate the effects of drugs on acquisition.     

Effects of GABA modulators on the repeated acquisition of response sequences in squirrel monkeys

The present study investigated the effects of positive and negative GABA(A) modulators under three different baselines of repeated acquisition in squirrel monkeys in which the monkeys acquired a three-response sequence on three keys under a second-order fixed-ratio (FR) schedule of food reinforcement. In two of these baselines, the second-order FR schedule and the discriminative stimuli for the response sequence were manipulated ("chain-strained" and "tandem-strained"). In the third baseline condition, response-independent tail shock was presented during acquisition of the response sequence. All of these baselines maintained high error levels and produced slow rates of acquisition. Under both the chain-strained and tandem-strained conditions, the positive GABA(A) modulator triazolam (0.0032-0.1 mg/kg) and the negative GABA(A) modulators beta-CCE (ethyl-beta-carboline-3-carboxylate; 0.01-1 mg/kg), beta-CCM (methyl-beta-carboline-3-carboxylate; 0.0032-0.1 mg/kg), and FG-7142 (methyl-beta-carboline-3-carboxamide; 0.18-10 mg/kg) dose-dependently decreased overall response rate compared to administration of saline (control). Under the same two conditions, triazolam and the negative GABA(A) modulators also increased the percentage of errors; however, the effects on accuracy frequently depended on the baseline condition and the particular modulator. In contrast, triazolam only decreased errors and enhanced acquisition in the presence of concurrent response-independent tail shock when compared to saline administration under this condition. The neutral GABA(A) modulator, flumazenil (1 mg/kg), had no effect on rate or accuracy of responding when administered alone, but antagonized the rate-decreasing and error-increasing effects produced by the negative GABA(A) modulators. Together, these data suggest that the effects of both the positive and negative GABAA modulators on acquisition can be similar in squirrel monkeys (i.e., both types of modulator may produce rate-decreasing and error-increasing effects) and that their effects on acquisition depend, in part, on the environmental conditions maintaining acquisition.     

Differential antagonism of cocaine self-administration and cocaine-induced disruptions of learning by haloperidol in rhesus monkeys

Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032-0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1-0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors.     

Behavioral parameters of drug action: signalled and response-independent reinforcement

Four pigeons were initially trained under a multiple variable-interval 1-min variable-interval 1-min schedule of food reinforcement. For two of the pigeons, a signal was then presented whenever the reinforcer was available in one component; this resulted in positive contrast. For the other two pigeons, the reinforcer was presented independently of responding on a variable-time schedule in one component; this resulted in negative induction. After 30 to 50 sessions, however, a similar degree of differential responding occurred under both multiple schedules, i.e., high rates in the variable-interval component and low rates in the other component. Reinforcement frequency remained about the same in each of the schedule components. The stable performances then served as baselines for studying drug effects. In the high-rate component of both multiple schedules, small doses of d-amphetamine increased responding, whereas larger doses decreased responding. In the low-rate component of both multiple schedules, there was no rate-increasing effect at any dose of d-amphetamine; such an effect was found, however, with phenobarbital at a dose that decreased responding in the high-rate component. The drug effects thus depended on the interaction of pharmacologic variables (specific drug and dose) with behavioral variables (schedule components).     

Retention deficit after d-amphetamine treatment: memory defect or performance change?

Retention deficits in discrete trial delayed alternation and delayed matching to sample tasks following administration of d-amphetamine have been interpreted to support the view that arousal facilitates the decay of information from shortterm memory (STM) (Kesner, 1973). But since amphetamine causes numerous changes in performance, alternative explanations of the deficit are also plausible. In an attempt to separate drug effects on memory from those on performance, the effects of d-amphetamine on spatial memory in the radial maze were studied in rats. The unusually long span of accurate working memory in this setting permits drug administration within the retention interval as well as prior to the to-be-remembered event (TBRE). In rats tested at a 5-hr retention interval d-amphetamine (2 mg/kg) disrupted retention when given 0.5 hr before or 4.5 hr after the TBRE, but the same treatment 0 or 2 hr after the TBRE or 3 hr before the TBRE was without effect. At a 5-hr retention interval 3 mg/kg d-amphetamine impaired performance if given 2 hr after the TBRE, but not when given 0 hr after the TBRE or 3 hr before the TBRE. However, when the retention interval was lengthened to 7 hr, administering 3 mg/kg d-amphetamine 2 hr after the TBRE did not disrupt performance. The effects of d-amphetamine on spatial memory are best explained in terms of the well established effects of the drug on motor activity and appetite. Similar changes in performance may account for the "memory" impairments observed after amphetamine treatment in other tasks.     

Effects of D-amphetamine and ethanol on variable and repetitive key-peck sequences in pigeons

This experiment assessed the effects of d-amphetamine and ethanol on reinforced variable and repetitive key-peck sequences in pigeons. Pigeons responded on two keys under a multiple schedule of Repeat and Vary components. In the Repeat component, completion of a target sequence of right, right, left, left resulted in food. In the Vary component, 4-peck sequences differing from the previous 10 produced food. d-Amphetamine (0.1-3.0 mg/kg, i.m.) was administered in two separate phases, separated by ethanol administration (1.0-2.0 g/kg, i.g.). Under control conditions, measures of variability were high in the Vary component, and lower in the Repeat component. Following administration of the highest dose of d-amphetamine, but not ethanol, response rates decreased in both components. d-Amphetamine and ethanol tended to increase overall sequence variability in the Repeat component, and had less of an effect in the Vary component. Performance in the Repeat component during Phase 2 of d-amphetamine administration was more disrupted than during Phase 1. Measures of variability and repetition based on shifts in the relative frequency distributions of the 16 possible keypeck sequences differed from those based on the overall measure of variability, highlighting the importance of considering both molar and molecular measures when assessing the effects of drugs on reinforced variability and repetition. In addition, the shifts in the relative frequency distribution of response sequences suggest that d-amphetamine produced decrements in repeat performance by decreasing discriminative control within response sequences, whereas ethanol decreased repeat performance by decreasing discriminability between components as well as discriminative control within response sequences.     

Motor Learning as a Function of KR Schedule and Characteristics of Task-Intrinsic Feedback

Forty participants (age range = 18–35 years) practiced 1 of 2 versions of an aiming task (with or without spring resistance). Knowledge of results (KR) was provided to them either immediately or after a delay of 2 trials. Immediate KR led to significantly more accurate performance during the 80 trials in acquisition but significantly less accurate performance on a 40-trial retention test given 24 hr after practice. In addition, the spring version of the task was performed significantly less accurately than the no-spring version on the 24-hr retention test. Most important, a significant interaction on the 24-hr retention test revealed that performance of the no-spring version of the task, when KR had been given after a 2-trial delay, was significantly more accurate than performance of the other 3 combinations of task version and KR schedule. The results suggest that KR dependency in motor skill learning is related to familiarity with task-intrinsic feedback in addition to the schedule on which KR is presented.     

Motor learning as a function of KR schedule and characteristics of task-intrinsic feedback

Forty participants (age range = 18-35 years) practiced 1 of 2 versions of an aiming task (with or without spring resistance). Knowledge of results (KR) was provided to them either immediately or after a delay of 2 trials. Immediate KR led to significantly more accurate performance during the 80 trials in acquisition but significantly less accurate performance on a 40-trial retention test given 24 hr after practice. In addition, the spring version of the task was performed significantly less accurately than the no-spring version on the 24-hr retention test. Most important, a significant interaction on the 24-hr retention test revealed that performance of the no-spring version of the task, when KR had been given after a 2-trial delay, was significantly more accurate than performance of the other 3 combinations of task version and KR schedule. The results suggest that KR dependency in motor skill learning is related to familiarity with task-intrinsic feedback in addition to the schedule on which KR is presented.     

Effects of Triazolam on Performance and Sleep in a Model of Transient Insomnia

Forty-nine healthy male volunteers were each given either a placebo or one of three clinically used doses of triazolam (0.125 mg, 0.25 mg, or 0.5 mg) after viewing a film previously demonstrated to increase autonomic arousal. Subjects then attempted to sleep in an environment analogous to that experienced by air travelers. Increased duration and continuity of sleep were associated with the 0.5 mg dose of triazolam. That dose reduced the speed of performing several psychornotor tasks and impaired memory consolidation 90 min after drug administration. Except for memory tasks, accuracy of performance was not affected by any drug dose at any time, and those deficits found at 90 min postdrug intake were not evident at 6 hr or later after drug administration.     

Motivation to Lead: Research on the Motives for Undertaking Leadership Roles in the Israel Defense Forces (IDF)

Sustained flight operations are likely to produce fatigue and performance decrement in aviators. We assessed changes in cognitive performance using a workhest schedule modeled on successive long-range attack missions. Twelve subjects performed several subtests of the Unified Tri-Service Cognitive Performance Assessment Battery and the Walter Reed Performance Assess- ment Battery 18 times during a simulated sustained operation. The scenario consisted of a 9-hr planning session followed by a 4-hr rest period and a 14-hr daytime mission. After 6 hr of rest, subjects repeated this schedule with a nighttime mission. For two spatial tests, subjects showed linear increases in response rate and one of its components, error rate. Subjects appeared to change strategy as the study progressed, possibly exchanging a higher failure rate for a savings in time. Any tendency to take chances when fatigued may have serious implications for aircrew in sustained operations.     

Effects of cocaine and alcohol, alone and in combination, on human learning and performance.

The acute effects of cocaine hydrochloride (4 to 96 mg/70 kg) and alcohol (0 to 1.0 g/kg), administered alone and in combination, were assessed in two experiments with human volunteers responding under a multiple schedule of repeated acquisition and performance of response chains. Subjects were intermittent users of cocaine and regular drinkers who were not cocaine or alcohol dependent. Alcohol was mixed with orange juice and ingested in six drinks within 30 min; cocaine was administered intranasally 45 min after completion of drinking. In each component of the multiple schedule, subjects completed response sequences using three keys of a numeric keypad. In the acquisition component, a new sequence was learned each session. In the performance component, the response sequence always remained the same. Results were consistent in both experiments, despite variations in the order in which the drugs were tested alone and in combination. Alcohol administered alone increased overall percentage of errors and decreased rates of responding in the acquisition component, whereas responding in the performance component generally was unaffected. Cocaine administered alone decreased rates of responding but did not affect accuracy of responding in the acquisition component, and enhanced accuracy of responding without affecting rates of responding in the performance component. The combined doses of cocaine and alcohol attenuated the effects observed with alcohol and cocaine alone. These results suggest that, under the conditions investigated in this study, (a) alcohol produces greater behavioral disruption than cocaine or cocaine-alcohol combinations, (b) cocaine and alcohol each attenuate effects of the other, and (c) such attenuation is most pronounced for cocaine attenuating the disruptive effects of alcohol.     

Chlordiazepoxide-induced discrimination impairment

Chlordiazepoxide (5.0 and 10.0 mg/kg but not 2.5 mg/kg) administered on 10 successive sessions, significantly impaired the reinforcement-cued discrimination performance of male Sprague-Dawley rats. On three postdrug (saline) recovery sessions, groups previously treated with the drug demonstrated good recovery in discrimination performance. An analysis of response components indicated that the discrimination impairment was due to less inhibition of responding during "no-go" phases of the task by the drugged than control animals. While changes in responding during reinforcement phases may also contribute to the performance of drugged animals, no clear pattern emerges from the present study.     

Interaction of methadone, reinforcement history, and variable-interval performance.

In the present study, we examined how a reinforcement schedule history that generated high or low rates of responding influenced the effects of acute (Experiment 1) and chronic (Experiment 2) methadone administration. Initially, key-peck responses of pigeons were maintained under a variable-interval 90-s schedule of food presentation, and a methadone dose-response curve was determined with doses of 0.6, 1.2, and 2.4 mg/kg. The pigeons were then exposed, for at least 40 sessions, to either a fixed-ratio 50 schedule or a differential-reinforcement-of-low-rate 10-s schedule, or were given continued exposure to the variable-interval schedule. The methadone dose-response curve was redetermined after all pigeons again were responding under the variable-interval schedule. The effects of two different daily methadone doses (9.0 and 12.0 mg/kg/day) and withdrawal precipitated by naloxone also were assessed. Experience with a fixed-ratio or differential reinforcement of low rate schedule did not result in significantly different response rates under the variable-interval schedule and, in general, the acute effects of methadone did not have differential effects correlated with schedule history. However, for 2 of 4 subjects the rate-decreasing effects of methadone on rates of key pecking were greater following a history of low-rate responding, suggesting a possible interaction between schedule history and effects of methadone. Daily methadone administration under the variable-interval schedule revealed that pigeons with experience under the differential reinforcement of low rate schedule developed more rapid and complete tolerance to the rate-decreasing effects of methadone. Three of the 4 subjects in this group showed rate increases above drug-free baselines during chronic methadone dosing. Pigeons with a history of fixed-ratio responding also developed tolerance to the rate-decreasing effects of methadone but without the subsequent rate increases seen by subjects with low-rate histories. No subjects with variable-interval histories showed complete recovery of drug-free baselines, suggesting that interpolated training under other schedules may attenuate the rate-altering effects of chronically administered drugs. Naloxone (1.0 mg/kg), administered during the chronic methadone phase, resulted in greater disruption of responding by pigeons with a history of low-rate responding, as compared to subjects in the other two groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effects of smoked marijuana on progressive-interval schedule performance in humans.

In three experiments, 8 human subjects participated in a study of the effects of smoked marijuana on progressive-interval schedule performance. A two-component chained progressive-interval fixed-interval schedule of point delivery was used. In the progressive-interval component, the interval length began at 20 s and increased either geometrically or arithmetically (by either 20 s, 40 s, 80 s, 100 s, or 160 s) on each subsequent interval. After this interval elapsed, a single button press produced the fixed-interval component, with a total of five reinforcers of varying magnitude ($0.05, $0.20, or $0.40) available on a fixed-interval 20-s schedule. After the five reinforcer deliveries, the schedule returned to the initial progressive-interval component. Several relationships were found among rates of responding, postreinforcement pauses and drug administration in the progressive-interval component: (a) Postreinforcement pauses increased as the temporal requirements of the progressive-interval schedule increased; (b) rates of responding during successive progressive-interval components rapidly decreased to low rates of responding after the first few progressions; (c) postreinforcement pauses decreased systematically as dose of smoked marijuana increased; and (d) rates of responding increased after smoking active marijuana but not after smoking placebo cigarettes. Results are discussed in the context of behavioral control and relevance to other studies that have investigated the effects of smoked marijuana on schedule performance.     

Sequence schedules of reinforcement

The performance of pigeons was studied under a second-order schedule composed of fixed-interval components, each of which was associated with a different discriminative stimulus, the stimuli occurring in a fixed order. In one condition, food presentation followed the completion of the fourth component. This was designated a fixed-ratio sequence schedule. In another condition, responses in the first component completed after a fixed time were reinforced. This was designated a fixed-interval sequence schedule. Although the stimulus order and maximum reinforcement frequency were identical under the two schedules, considerably more responding occurred under the fixed-interval sequence schedule in all components. Relatively few food presentations occurred after responding during any but the terminal components of the fixed-interval sequence schedule, a feature independent of the parameter values investigated. In addition, while a pattern of increased responding between food presentations prevailed under both schedules, under the fixed-interval sequence schedule the rate in the terminal component was frequently less than in the penultimate component. The fixed-interval sequence schedule appeared to have several properties of simple fixed-interval schedules.     

Diazepam-induced impairment of a go-no go successive discrimination

Diazepam (2.0 and 4.0 mg/kg, but not 1.0 mg/kg) administered in eight acquisition sessions significantly impaired the light-cued successive discrimination of male Sprague-Dawley rats. In two postdrug (vehicle) sessions, groups previously treated with the drug demonstrated good recovery in discrimination. An analysis of response components indicated that the impairment was due to the failure of drugged subjects to inhibit or withhold responses during the no go periods of the task. These findings are consistent with a "disinhibitory hypothesis" of drug impairment. The similarity of the present findings to those previously reported with chlordiazepoxide suggests that such effects are a generalized characteristic of the benzodiazepine class of drugs.     

Effects of cocaine and d-amphetamine on the repeated acquisition and performance of conditional discriminations.

The acute and chronic effects of cocaine and d-amphetamine on food-reinforced behavior were investigated in pigeons responding on a two-component multiple schedule. In one component, the behavioral task consisted of the same chain of conditional discriminations each session (performance). In the other component, the chain of conditional discriminations was changed from session to session (learning). In comparison to control sessions, both acute cocaine and d-amphetamine increased errors in each component of the multiple schedule. Responding in the learning component, however, was generally disrupted at lower doses than those that affected responding in the performance component. At high doses, both drugs produced pauses in responding in each component in three of the four subjects. Pausing engendered by d-amphetamine was approximately twice as long as that under cocaine. Upon chronic administration, both the pausing and error-increasing effects of each drug diminished. Drug-induced changes in timeout responding, however, did not decrease during chronic administration. Redeterminations of the d-amphetamine dose-effect curves following chronic cocaine administration suggested the existence of cross-tolerance between cocaine and d-amphetamine. Both the acute and chronic data are consistent with the view that conditions of stimulus control may modulate the behavioral effects of drugs.