Donald M. Thompson

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.

Repeated acquisition as a behavioral baseline

The Boren (1963) technique for studying variables affecting acquisition with an individual-S design was modified and used with pigeons. The sensitivity and reversibility of the steady-state baseline were demonstrated by temporarily removing the different Stimuli correlated with the different members of the chain. This “tandem” probe produced a substantial increase in the number of learning errors.

Transition to a steady state of repeated acquisition

Pigeons obtained food reinforcement via a four-response chain that require pecking different keys in the presence of different colors. The sequence of correct key positions changed from session to session. Errors gradually decreased across sessions until a constant minimum range of variability in error levels was reached (steady state). Other characteristics of the transition and steady state of repeated acquisition (e.g., within-session rate of error reduction) were described.

Phencyclidine in combination with pentobarbital: Supra-additive effects on complex operant behavior in pigeons☆

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. The response chain was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When phencyclidine was administered alone, the overall response rate decreased and the percent errors increased with increasing doses. Similar effects were found with a high dose of pentobarbital alone. When phencyclidine was administered in combination with pentobarbital, the phencyclidine dose-effect curves for rate and accuracy shifted to the left as the dose of pentobarbital was increased. Combinations of phencyclidine with a high dose of pentobarbital produced supra-additive effects; i.e., the effects on rate and accuracy were greater than expected from simple addition of the effects of each drug given alone. These results extend the generality of previous findings in patas monkeys in a similar repeated-acquisition task.

Intravenous diazepam in humans: Effects on acquisition and performance of response chains

A technique based upon an individual-subject design was used to investigate the effects of intravenous diazepam on the acquisition and performance of response chains in humans. In each of two conditions subjects were required to emit a different sequence of ten responses in a predetermined order on three levers. The conditions alternated within each session under a multiple schedule. In the performance condition the sequence of responses was the same each session. The second condition was a repeated-acquisition task. In this condition subjects were required to learn a different sequence of responses each session. Diazepam produced dose-dependent decreases in the overall rate of responding in each subject under both conditions. In two of the three subjects tested, errors were increased in the learning condition at doses lower than those required to disrupt accuracy in the performance condition. In one subject, accuracy in both the learning and performance conditions was equisensitive to the disruptive effects of diazepam. These data are consistent with the effects of the benzodiazepines in analogous animal procedures. Furthermore, the data suggest that the behavioral effects of intravenous diazepam may exhibit marked variations across subjects at clinically relevant doses (5-10 mg).

Repeated acquisition of behavioral chains: Effects of methylphenidate and imipramine

A method involving repeated acquistion of behavioral chain was used to assess the effects of methylphenidate and imipramine in individual animals. Pigeons obtained food for completing a 4-response chain, which was changed from session to session. Learning was defined by the decrease in errors across trials within a session; overall accuracy was measured by total errors per session. For comparison, the drug tests were also conducted under a performance condition, in which the 4-response chain was the same from session to session. In general, both drugs increased total errors per session as a function of dose under both the learning and performance conditions. The error-increasing effect was greater with imipramine than with methylphenidate and was detected at lower doses under the learning condition than under the performance condition. Under the learning condition, the higher doses of both drugs decreased the rate of within-session error reduction. Although neither drug enhanced accuracy at any of the doses tested, the lower doses of methylphenidate slightly decreased total trial time under both the learning and performance conditions.

Phenycyclidine in combination with d-amphetamine: Differential effects on acquisition and performance of response chains in monkeys ☆

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When phencyclidine was administered alone, overall response rate decreased and percent errors increased in both components with increasing doses. d-Amphetamine alone generally decreased rate and increased errors in learning, but increased rate and had no effect on accuracy in performance. When phencyclidine was administered in combination with d-amphetamine, the phencyclidine dose-effect curves tended to shift to the left as the dose of d-amphetamine was increased. The extent to which the curves shifted, however, depended on both the schedule component and the behavioral measure. For example, with accuracy, the shift was more evident in learning than in performance. Combinations of phencyclidine with a high dose of d-amphetamine generally produced supra-additive effects: i.e., the effects on rate and accuracy were greater than expected from simple addition of the effects of each drug given alone.

Effects of opioids and phencyclidine in combination with naltrexone on the acquisition and performance of response sequences in monkeys

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 under 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). Heroin, methadone, cyclazocine and phencyclidine each produced dose-related decreases in overall response rate. At high doses which produced equivalent rate-decreasing effects, cyclazocine and phencyclidine generally produced greater disruption of accuracy in the learning component than did heroin or methadone. Naltrexone 5.6 microgram/kg shifted to the right by approximately 1/2-log unit the heroin and methadone dose-effect curves, but produced little or no change in the cyclazocine dose-effect curves. At 56 micrograms/kg naltrexone completely antagonized both the rate-decreasing and error-increasing effects of heroin and methadone. The same dose of naltrexone tended to produce greater antagonism of the effects of cyclazocine on accuracy than on rate, which was shifted by only 1/4-log unit. In contrast, naltrexone failed to antagonize the effects of phencyclidine on either rate or accuracy. Thus it would appear that while cyclazocine and phencyclidine produce similar disruptions in the accuracy of a discrimination, the effects of each are differentially sensitive to antagonism by naltrexone.

Cocaine self-administration in pigeons

Pigeons with chronic indwelling intravenous catheters responded under a multiple schedule of food and cocaine presentation. In one component, responding was maintained by food presentation under a fixed-ratio (FR 50) schedule, whereas in the other component, responding was maintained under the same schedule by IV infusions of cocaine (0.03 or 0.1 mg/kg/injection). A 30-s timeout followed each cocaine infusion. Components alternated after 3 presentations of either food or cocaine, and each session was terminated after 18 cocaine infusions or 2 h, whichever occurred first. In general, under baseline conditions, the response rate was higher in the food component than in the drug component. Under control conditions where saline was substituted for cocaine, the response rate gradually decreased across sessions, while food-maintained responding was generally unaffected. Substituting doses lower or higher than the training dose decreased the rate of cocaine-maintained responding. Food-maintained responding only decreased at higher doses of cocaine. When blackout periods were substituted for the food component (Experiment 2), the response rate in the cocaine component decreased and then stabilized at levels well above zero. Saline substitution on this baseline produced a further decrease in the rate of FR responding. In Experiment 3, the effects of pretreatment with haloperidol (0.056 or 0.1 mg/kg) on both food- and cocaine-maintained responding were examined using a multiple schedule similar to that used in Experiment 1. Each dose was given for a period of 7-10 days. In general, haloperidol dose-dependently decreased both the overall rate of cocaine-maintained responding and the percent of available reinforcers obtained, while having little or no effect on food-maintained responding. This research indicates that cocaine can serve as a reinforcing stimulus for maintaining self-administration behavior in pigeons, and that this behavior is sensitive to antagonism by haloperidol.

Effects of phencyclidine, d-amphetamine and pentobarbital on schedule-controlled behavior in rats

The effects of phencyclidine, d-amphetamine, and pentobarbital on responding maintained under a multiple fixed-interval (FI) 3-min fixed-ratio (FR) 30 schedule of food presentation were studied in rats. Phencyclidine (0.32-7.5 mg/kg) had a biphasic effect on overall response rate in both components; response rate increased and then decreased as the dose was increased. The FR was slightly more sensitive to the rate-decreasing effects of phencyclidine than the FI. The effects of d-amphetamine (0.1-7.5 mg/kg) on overall response rate were qualitatively similar to those of phencyclidine. The FI tended to be slightly more sensitive than the FR to the rate-increasing effects of d-amphetamine. Pentobarbital (1-18 mg/kg) produced little or no rate-increasing effects in the FR at low doses and decreased FR response rate at higher doses. In the FI, pentobarbital produced small increases in overall rate at intermediate doses while decreasing response rate at higher doses. The FR tended to be more sensitive than the FI to the rate-decreasing effects of pentobarbital. Unlike d-amphetamine and pentobarbital, phencyclidine produced smaller rate-increasing effects when the dose-effect curves were redetermined. Within the FI, the effects of phencyclidine and d-amphetamine on response rate were generally independent of the control rate of responding.