Effects of methylphenidate on response rate and measures of motor performance and reinforcement efficacy

This experiment evaluated the effects of methylphenidate on reinforced responding in rats. In each session the subjects (rats) earned reinforcement on seven different variable-interval reinforcement schedules. The average intervals varied from 108 to 3 s and provided reinforcement rates ranging from about 30 to 1100/h. Response rate was a negatively accelerated function of reinforcement rate. Low doses of methylphenidate (1.0 and 2.0 mg/kg) increased responding maintained by the four leanest schedules, but had little effect on responding maintained by the three densest schedules. In contrast, an 8.0 mg/kg dose increased responding maintained by the three densest schedules and slightly decreased responding maintained by leaner schedules. A quantitative model of reinforced responding, referred to as the matching law or response strength equation, was fitted to the data. This equation has two parameters. On the basis of previous experiments, one was used to measure changes in reinforcement efficacy and the other was used to measure changes in motor performance. The 1.0 and 2.0 mg/kg doses changed the reinforcement parameter in the same way as did increases in deprivation and reward magnitude. The 8.0 mg/kg dose changed the motor parameter in the same was as did decreases in lever weight. It was concluded that methylphenidate increases reinforcement efficacy, and that the highest dose changed the topography of responding. The results are discussed in terms of the response strength equation, the rate dependency principle, and the question of how to interpret changes in reinforcement efficacy and motor performance.     

Chlorpromazine and pimozide alter reinforcement efficacy and motor performance

This study evaluated the effects of chlorpromazine and pimozide on reinforced responding. In each session, rats were exposed to a series of five variable-interval reinforcement schedules. The response requirement was a lever press, the reward was a small portion of water, and the reinforcement rate varied from about 20 to 660 reinforcers per hour. Response rate was a negatively accelerated function of reinforcement rate, and the relationship between the two variables was described by the equation for a rectangular hyperbola (the matching law). One parameter of the hyperbola is equivalent to the asymptotic response rate and the other parameter is equivalent to the rate of reinforcement that maintains a one-half asymptotic response rate. Chlorpromazine (0.75–3.0 mg/kg) and pimozide (0.1–0.4 mg/kg) dose-dependently decreased response rates. At low doses, the response rate decreases were, for the most part, restricted to the low reinforcement rate schedules. In contrast, the highest dose tested decreased response rates at both low and high reinforcement rates. The patterns of response rate decreases resulted in dose-dependent changes in the parameters of the matching law equation. The shifts in the matching law parameters were discussed in terms of the motoric and motivational interpretations of neuroleptic-induced response rate changes. Offprint requests to: G.M. Heyman     

Effects of amphetamine on choice behavior of pigeons

Key-pecking behavior of three pigeons was maintained by concurrent variable-interval, variable-interval schedules of reinforcement. Dose-response curves of amphetamine on four operants involved in the choice situation were obtained. None of the doses of amphetamine studied produced any rate-increasing effect on responding, irrespective of the differences in control baseline rates. Responding at the changeover key was relatively more depressed than main-key responding in spite of occuring at lower rates in non-drug conditions.     

Relationship between response rates and measures of reinforcing strength using a choice procedure in monkeys

Concurrent schedules of reinforcement are increasingly being used to investigate the reinforcing strength of abused drugs. A purported advantage of concurrent schedules is that the primary dependent measure, percentage of responses emitted on the drug-associated manipulandum, is independent of the rate-altering effects of drugs. Data supporting this hypothesis are, however, rarely presented, which was one goal of this study. In addition, we tested the hypothesis that drug-induced decreases in response rates provides an additional index to characterize abuse liability of drugs. This study examined the relationship between response rate and response allocation (i.e. drug choice) when 3,4-methylenedioxymethamphetamine (MDMA, 0.03-0.3 mg/kg/inj) or cocaine (0.003-0.1 mg/kg/inj) was the alternative to food under concurrent fixed-ratio reinforcement schedules in rhesus (n=4) and cynomolgus (n=16) monkeys, respectively. Increasing doses of MDMA or cocaine resulted in increased drug choice and dose-dependent decreases in overall response rates. For both drugs, response rates on the drug-associated lever were not affected by dose and were not different from saline. Furthermore, at most doses, rates of responding on the food-associated lever were significantly higher than response rates on the drug-associated lever. Finally, MDMA but not cocaine decreased food-reinforced responding, providing evidence for potential differences between the drugs. These results demonstrate that under concurrent food-drug reinforcement schedules, response rates on the drug-associated lever are independent of measures of reinforcement, whereas disruptions in food-maintained responding may be inversely related to abuse liability.     

The effect of d-amphetamine on operant behaviour maintained under variable-interval schedules of reinforcement

Dose-response curves were obtained for the effects of d-amphetamine sulphate (0.1–3.2 mg/kg) on the operant performance of rats in variable-interval 4-min and variableinterval 20-min schedules of reinforcement. Response rates maintained under variable-interval 4-min were suppressed in a dose-dependent manner. Response rates maintained under variable-interval 20-min schedules tended to be elevated by low doses and suppressed by higher doses. The degree of response rate suppression was greater in the case of the variable-interval 4-min schedule. The results are consistent with the previously reported effect of d-amphetamine on the values of the two constants of Herrnstein's (1970) equation: the drug reduces the reinforcement frequency needed to maintain the half-maximum response rates (K _h) and lowers the maximum response rate (R _max) (Bradshaw et al. 1981 b). It is suggested that the effects of d-amphetamine on operant performance may involve two processes: an enhancement of motivation and a reduction of the capacity to respond.     

Interval and ratio reinforcement contingencies as determinants of methadone's effects

The effects of methadone hydrochloride on lever pressing rats maintained under multiple fixed-interval and fixed-ratio, or multiple variable-interval and variable-ratio reinforcement schedules equated for reinforcement density were examined. Under a multiple fixed-interval, fixed-ratio schedule overall response rate was decreased during both components but was most affected under the ratio schedule. Response rate decreases were due primarily to changes in running rate rather than pause time. Under a multiple variable-interval, variable-ratio schedule, overall response rate was also decreased by methadone, with the greatest decrease again occurring during the ratio schedule. These schedule-specific methadone effects are not due to differences in reinforcement frequency. Evidence for rate-dependency with methadone is not consistent across subjects.     

Further characterization of adjunctive behavior generated by schedules of cocaine self-administration

Rhesus monkeys (n = 5), surgically implanted with double-lumen catheters, were allowed to self-administer cocaine (0.1 or 0.3mg/kg/injection, i.v.) on one lever (COC lever) under several fixed-interval schedules of reinforcement. Responding on a second lever (SAL lever) delivered saline (i.v.) under a fixed-ratio 1 schedule. Responding on both levers was a bitonic function of interval value and cocaine dose. A variety of experimental conditions were examined to determine whether SAL lever responding could be considered to be adjunctive in nature. SAL lever responding did not change when saline injections were discontinued, suggesting that SAL lever responding was not maintained by interoceptive stimuli associated with the injection. Discontinuation of various exteroceptive stimulus changes that had occurred as a consequence of SAL lever responding also did not affect the frequency of SAL lever responding. However, when there was no stimulus change following a SAL response, response rates on that lever decreased by approximately 40-60% indicating that stimulus change played some role in the maintenance of the behavior. The introduction of change-over-delays (2-16 s) between responding on the SAL and COC levers had little or no effect on responding on the SAL lever, suggesting that SAL lever responding was not maintained by adventitious reinforcement by cocaine injections. SAL lever responding also occurred in these same monkeys when cocaine was available under fixed-time or variable-interval schedules of reinforcement. These results confirm that presentation of cocaine under interval schedules of reinforcement can generate substantial amounts of behavior (pressing the SAL lever) that is not necessary for obtaining the drug. Further, the results strongly suggest that the behavior can be classified as an adjunctive behavior that is similar to adjunctive behaviors generated by the intermittent presentation of other positive reinforcers.     

Individual differences in behavioral tolerance to amphetamine and the economic context of reinforcement loss

The economic context (i.e. an enriched vs impoverished environment) affects many drug-induced phenomena. The present study examined whether the 'experienced' economic context of operant responding was associated with the degree of tolerance to the behavioral effects of amphetamine. Eight rats lever pressed for food reinforcement under a multiple schedule consisting of several variable-interval schedules (8, 17, 55, 150, and 250 s). Amphetamine was first administered acutely (0.2, 0.8, 1.6, and 3.2 mg/kg), then chronically (dose tailored for each subject) over 30 consecutive sessions. Baseline saline injections were also administered during the acute regimen. Herrnstein's single-alternative matching equation described the rats' response rate data well under all conditions. A parameter in Herrnstein's equation (re), which has been shown to vary with experimentally-arranged contextual reinforcement, was used as the index of the experienced economic context for each subject under baseline conditions. Differences in the value of re predicted individual differences in the degree of tolerance. Under most variable-interval (VI) schedules, and when all schedules were aggregated, less tolerance accrued if the baseline context was experienced as enriched, and more tolerance accrued if the baseline context was experienced as impoverished. In terms of the reinforcement loss hypothesis, the results suggest that tolerance was not determined by reinforcement loss per se, but by how much the animal lost relative to the economic context in which the operant task was embedded.     

Effects of amphetamine and pimozide on reinforcement and motor parameters in variable-interval performance

The effects of amphetamine and pimozide were studied in rats performing on variable-interval (VI) schedules of reinforcement. In experiment 1, a five-component multiple VI schedule was used; in experiments 2 and 3, two VI schedules were presented on alternate days; a fourth experiment was carried out to validate the two VI methods. The Herrnstein matching law was used to distinguish between changes in reinforcer efficacy and changes in motor capacity. In both procedures, amphetamine, at 0.5 mg/kg, caused changes compatible with an increase in reinforcer efficacy with no change in motor capacity; higher doses (only tested in the multiple schedule) appeared further to increase reinforcer efficacy and also to decrease motor capacity. In the multiple schedule, pimozide caused changes compatible with either a decrease in reinforcer efficacy or a decrease in motor capacity, depending on the order of presentation of the schedule components; in the alternating schedule, pimozide had both effects. These discrepancies appeared to be due to changes in the effect of pimozide over time, which could not be explained either by satiation or by a gradual onset of drug action.     

DSP4 alters the effect of d-amphetamine on variable-interval performance: analysis in terms of Herrnstein's equation

The effect of d-amphetamine (0.1–3.2 mg/kg) on performance in variable-interval 1-min and variable-interval 12-min schedules of positive reinforcement was examined in ten rats treated with the selective noradrenaline neurotoxin DSP4 and 12 control rats. In the control group d-amphetamine had a dose-dependent suppressant effect on response rates maintained under variable-interval 1-min; under variable-interval 12-min, response rates were increased by low doses and suppressed by higher doses of the drug. In the case of both schedules, lower doses of d-amphetamine were more suppressant and higher doses less suppressant in the DSP4-treated group than in the control group. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum (determined by high-performance liquid chromatography) were reduced to approximately 15% of control levels in the DSP4-treated rats. The results indicate that treatment with DSP4 attenuated both the facilitatory and the suppressant effects of d-amphetamine on variable-interval performance. A formal model couched in terms of Herrnstein's (1970) equation is put forward to account for these results. It is suggested that the noradrenergic pathways emanating from the locus caeruleus are involved in both the facilitatory and suppressant effects of d-amphetamine on operant behaviour.     

Modeling the effects of fluoxetine on food-reinforced behavior

We propose a novel method to dissociate incentive motivation from memory and motor processes in instrumental performance. Components of a multiple fixed-ratio schedule of food reinforcement were adjusted to envelop the range of response requirements that maintained lever pressing by rats. We sought to manipulate motivation for food rewards with acute administrations of various doses (0-10 mg/kg) of fluoxetine, a 5-HT reuptake inhibitor that reduces food intake. A quantitative model of fixed-ratio performance derived from Killeen's (1994) Mathematical Principles of Reinforcement (MPR) provided an adequate account of data from individual rats. Decreases in response rate resulting from fluoxetine were reflected in changes in estimates of activation, indexed by MPR parameter a; estimates of working memory capacity and lever pressing duration were not systematically affected. These results support the use of MPR parameter a to index incentive motivation using multiple fixed-ratio schedules that are adjusted to individual performance.     

Effects of LSD on time-based schedules of reinforcement

The functional relationship between rate of bar-pressing and a wide range of dosages of LSD was studied under different conditions or schedules of reinforcement, i.e., variable-interval (VI), differential reinforcement of low rate (drl), and drl plus concurrent periods of punishment. In general, low doses (0.01–0.04 nig/kg of LSD) increased or facilitated responding as an inverse function of base line response rate and high doses (0.08–0.32 mg/kg) depressed behavior not already depressed by environmental contingencies.     

Rate-dependent effects of d- and l-amphetamine on schedule-controlled responding in pigeons and squirrel monkeys

The effects of d- and l-amphetamine were studied on key-pressing responses of squirrel monkeys maintained under fixed-interval schedules of electric shock presentation, and on key-pecking responses of pigeons maintained under multiple fixed-ratio, fixed-interval schedules of food presentation. Under the fixed-interval schedules, responding followed a pause and occurred at increasing rates as the interval elapsed. Both isomers produced comparable increases in rates of responding under relatively long fixed-interval schedules with small to intermediate doses; maximal effects of the d-isomer were obtained at doses one-half log unit smaller than the doses of the l-isomer. Responding of pigeons maintained under relatively short fixed-interval schedules was only decreased by either amphetamine isomer. Responding of pigeons maintained under fixed-ratio schedules occurred at the highest rates and was also only decreased by either amphetamine isomer. Decreases in response rate produced by the d-isomer were generally obtained at doses one-half log unit smaller than doses of the l-isomer that produced comparable effects. Both isomers increased responding that occurred at low rates early in the fixed-interval to a proportionally greater extent than higher rates from later in the interval. The highest rates in the fixed-interval were generally decreased. Differences in potency between the two isomers in producing rate-dependent effects were small, most noticable with larger doses, and less than the potency differences between the two isomers in producing changes in response rate.     

Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1–3.0 mg/kg) and chlordiazepoxide (3.0–30 mg/kg) increased punished responding at doses that had little effect on unpunished responding;d-amphetamine (0.3–5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding. Changeover responses were increased only moderately by the anxiolytic drugs when the punishment schedule was added to a 3-min variable-interval schedule and the alternate schedule was a 1-min variable-interval schedule without punishment; the amount of time spent in the punishment component, however, increased two-fold at the higher doses of chlordiazepoxide. When these conditions were reversed and punishment was added to the variable-interval 1-min schedule, time spent in the punishment component increased and changeover responses out of the punishment component decreased, particularly following chlordiazepoxide. Anxiolytic drugs appear to attenuate the aversiveness of stimuli correlated with punishment, but the degree of attenuation is controlled by other conditions prevailing in the presence of those stimuli.     

Changes in sensitivity of response distributions to changing reinforcement ratios during exposure to ephedrine, caffeine, and ephedrine-caffeine combinations

Changes in the sensitivity of response distributions to changes in reward distribution (reinforcer distribution sensitivity) were examined when rats were exposed to low and moderate doses of caffeine, ephedrine, and caffeine-ephedrine combinations. The data show significant decreases in sensitivity in response distributions to changes in reward schedule values during exposure to caffeine and ephedrine/caffeine combinations, whereas ephedrine alone resulted in overmatching comparable with baseline and NaCl conditions. Rats treated either with 3.0-mg/kg or 10.0-mg/kg doses of caffeine and all combinations of ephedrine at doses of 1.8 or 5.6 mg/kg with caffeine at 3.0 or 10.0 mg/kg showed reduced sensitivity in response distributions to differences in reinforcement schedule ratios. In contrast, when rats were exposed to ephedrine at 1.8 or 5.6 mg/kg, they maintained or increased the degree of overmatching. Although reinforcer distribution sensitivity was altered, drug exposure did not significantly affect the absolute rates of responding. Bias varied after exposure to caffeine, ephedrine, and their combinations, but not systematically. Finally, whereas the estimates of goodness of fit (r2) to the matching equation showed some decreases during drug exposure, these were neither statistically significant nor correlated with drug dose. These results suggest differential effects of ephedrine and caffeine on the sensitivity of response distributions to changes in reinforcement ratio distributions, with deleterious effects of caffeine and ephedrine/caffeine combinations.     

Drug effects on an effortful operant: pentobarbital and amphetamine

The behavioral effects of amphetamine and pentobarbital depend upon the conditions maintaining behavior. For example, amphetamine usually decreases the rate of operant behavior maintained by fixed ratio schedules while pentobarbital either increases it or leaves it unaffected. However, when considerable exertion is required, as in situations that require endurance, amphetamine tends to enhance performance while barbiturates degrade it. These differences complicate predictions of the effects of these two drugs on effortful operants. The present experiment was designed to characterize effortful responding behaviorally and pharmacologically. Cebus monkeys were trained to operate a lever by flexing their arms and extending their legs; this response exerted a force approximating their body weight. This operant was maintained by a multiple fixed ratio fixed interval (Mult FR FI) schedule. The two schedules maintained dramatically different response patterns. The FR schedule maintained vigorous, high rate responding characterized by a narrow IRT distribution centered at 0.5 sec. The FI schedule maintained very low overall rates of responding characterized by a variable IRT distribution with a median of 1.5 to 2 sec. Despite very low rates of responding during the FI component, no consistent rate increases appeared after amphetamine, and 0.3 mg/kg eliminated responding altogether. Pentobarbital increased overall rate but also shifted the interresponse time (IRT) distribution toward longer IRTs. The increase in overall rate arose from an earlier onset of responding during the FI component and occurred simultaneously with response slowing. The present studies do not support suggestions of a generalized enhancement of effortful performance by amphetamine or a generalized degradation by pentobarbital.     

d-Amphetamine,operant history,and variable-interval performance

The effects of d-amphetamine on the bar-pressing of rats maintained under a variable-interval schedule of water reinforcement were examined as a function of the operant history of the subjects. One group of rats initially received 51 sessions of exposure to a fixed-ratio 20 schedule, while a second group received equivalent exposure to an interresponse-time-greater-than-12-sec schedule. Mean group response rate when stable was over ten times as high under the fixed-ratio schedule as under the interresponse-time-greater-than-12-sec schedule. Response rates of the two groups largely converged across 47 sessions of exposure to a variable-interval 60-second schedule, at which time response rates for both groups appeared stable. Acute administrations of d-amphetamine sulfate similarly affected mean response rates of both groups: A 0.25 mg/kg dose did not obviously affect rate, while doses of 0.5, 1.0, and 2.0 mg/kg produced dose-dependent rate decreases. These results indicate that the efficacy of operant history as a determinant of drug effects may be limited to circumstances where current contingencies do not exercise powerful and direct control over behavior.     

Opioid drugs and timeout from avoidance

The effects of μ agonists fentanyl, methadone and morphine and kappa agonist U50,488 on behavior maintained by negative reinforcement were determined. Rats were trained on concurrent schedules in which pressing one lever postponed shock on a Sidman avoidance schedule and pressing the other lever produced signaled periods of timeout from avoidance on variable-ratio schedules. All of the μ agonists decreased responding maintained by timeout from avoidance at doses that increased or did not affect avoidance rates. The kappa agonist U50,488 decreased response rates in some rats, but increased responding in others. In no case was a selective reduction in responding on the timeout lever produced by U50,488. Thus, the previously reported selective decreases in timeout responding by morphine are also produced by μ agonists fentanyl and methadone, but not by kappa agonist U50, 488.     

COMPARISON OF THE EFFECTS OF d-AMPHETAMINE ON FI AND DRL SCHEDULE PERFORMANCE OF SELF-STIMULATING RATS

1. Six rats bar-pressed for intracranial self-stimulation in a Skinner box on fixed interval and differential reinforcement of low rate schedules with an interval parameter of 1.3 s. 2. After amphetamine timing efficiency was reduced immediately on both the schedules; it recovered after 60 min on the DRL schedule but not within 120 min on the FI schedule. Response rates increased on both the schedules. 3. The increased response rates correlated with the low efficiency on the DRL but not on the FI schedule. 4. The selective sparing of DRL performance is in line with the similarity between the effects of amphetamine and frontal cortical lesions.