Effects of d-amphetamine, chlorpromazine, and chlordiazepoxide on intercurrent behavior during spaced-responding schedules.

Effects of d-amphetamine, chlorpromazine, and chlordiazepoxide on lever pressing under direct control of spaced-responding schedules were compared with effects on intercurrent drinking and wheel running in the rat. Drug effects on lever pressing were systematically related to dose and were consistent for all animals; drug effects on intercurrent behavior were generally different for each animal. In the case of lever presses, increasing doses of d-amphetamine first increased and then decreased response rate, increasing doses of chlorpromazine produced graded decreases in response rate, and doses of chlordiazepoxide up to 40 mg/kg produced no effect on response rate. These data are discussed in context with the concept of schedule control, and it is suggested that the behavioral pharmacology of intercurrent behavior be explored as a useful procedure in the experimental analysis of intercurrent behavior.     

Molecular analyses of the effects of d-amphetamine on fixed-interval schedule performances of rats.

A series of doses (0.5 to 2.0 mg/kg) of d-amphetamine was administered to rats whose lever pressing was maintained by fixed-interval 30-s, 60-s, or 120-s schedules of reinforcement by sucrose delivery. Under both saline and d-amphetamine conditions, molecular features of responding were reliably described in terms of the distribution of postreinforcement pauses and local response rate following the onset of responding. Postreinforcement pause always varied from interval to interval but, on average, shortened under the drug. Local response rate (response rate exclusive of pause time) tended to decrease under the drug, and where acceleration occurred within runs of responses, it was reduced by the drug. All of these effects were dose-related. These findings suggest that fixed-interval behavior can be analyzed effectively at a molecular level, and that the effects of d-amphetamine are best described as disruption of temporal discrimination.     

Drug effects on fixed-interval responding with pause requirements for food presentation.

In pigeons performing under a multiple schedule of food presentation, low key-pecking rates (0.18 to 0.29 responses per second) were maintained during 3-min fixed-interval components by requiring a 4-, 5-, or 6-sec pause preceding the food-delivery response (tandem DRL), while higher rates (0.70 to 1.37 responses per second) were maintained in alternative fixed-interval components by requiring a pause of no more than 40 msec preceding the food-delivery response (tandem DRH). Thus, reinforcement density was equal but overall response rates markedly different in the two schedule components. Pentobarbital (3, 10 mg/kg) had effects on overall rates of responding consistent with a rate-dependency interpretation (low rates were increased while higher rates were decreased), but d-amphetamine (0.03 to 3 mg/kg) either failed to increase low overall rates in the tandem DRL components or increased them only slightly. Effects of both drugs on local responding within the fixed-intervals were always related in an orderly way to control response rate, but the extent of rate increases produced by d-amphetamine was modifed in some birds by pause requirements such that the drug increased comparable rates less when these occurred in the tandem DRL component than when they occurred in the tandem DRH components. Control rate is an important determinant of drug effects, independent DRH components. Control rate is an important determinant of drug effects, independent of reinforcement density maintaining rates, and independent of environmental influences, such as response-spacing requirements for food presentation, that can modify the extent of some drug-produced rate changes.     

Food and amphetamine self-administration by baboons: effects of alternatives.

The effects of the availability of an alternative reinforcer on responding maintained by food pellets or fluid solutions were examined in 6 adult male baboons (Papio cynocephalus anubis). During daily 23-hr experimental sessions, baboons had concurrent access to both food pellets and fluid, with responding maintained under fixed-ratio schedules of reinforcement that varied between the two commodities. The fixed-ratio requirement, or cost, for pellets was increased when (a) no fluid, (b) a dilute dextrose vehicle, (c) 0.002 mg/kg d-amphetamine, or (d) 0.004 mg/kg d-amphetamine was available. When given nonrestricted concurrent access to food pellets and amphetamine at minimal cost (FR 2), baboons self-administered sufficient amphetamine to decrease pellet intake. Increasing the response requirement for pellets decreased pellet intake at a similar rate regardless of the available fluid and increased fluid intake in a variable manner among baboons such that there were no statistically significant increases in fluid intake. In contrast, when access to pellets was restricted to 70% of maximal intake under nonrestricted conditions, increasing pellet cost decreased pellet intake and increased fluid intake more rapidly when the high amphetamine dose was available. Thus, amphetamine was more effective as an economic substitute for pellets when access to pellets was restricted. The response cost for vehicle and both amphetamine concentrations was increased when baboons had nonrestricted and restricted access to pellets. Increasing the response requirement for fluid delivery decreased intake of all three fluids similarly under both pellet-access conditions. The results indicate that substitution between commodities with minimal commonalities can be studied under controlled laboratory conditions and is dependent upon reinforcement schedule and commodity restrictions.     

Discrimination of methadone and cocaine by pigeons without explicit discrimination training.

Pigeons were trained to peck a key on a variable-interval 2-min schedule of food reinforcement. Prior to each session, either 2.0 mg/kg methadone (n = 3), 3.0 mg/kg cocaine (n = 4), or 5.6 mg/kg cocaine (n = 2) was administered. When each pigeon's rate of pecking was stable, a range of doses of the training drug and saline were administered prior to 20-min extinction sessions separated by at least four training sessions. Rate of pecking during these extinction tests was generally an increasing function of dose, with the lowest rates obtained following saline and low doses and the highest rates obtained following doses near the training doses. Dose functions from pigeons trained with 5.6 mg/kg cocaine were steeper than those from pigeons trained with 3.0 mg/kg cocaine. Pigeons trained with methadone or 3.0 mg/kg cocaine were then given discrimination training, in which food reinforcement followed drug administration and 20-min extinction sessions followed saline administration. Rates of pecking under these conditions quickly diverged until near-zero rates were obtained following saline and high rates were obtained following drug. Discrimination training steepened dose functions for the training drugs, and the effects of several other substituted drugs depended on the pharmacology of the training drug. The pigeons trained with 5.6 mg/kg cocaine were tested with d-amphetamine, methadone, and morphine prior to discrimination training. d-Amphetamine increased rates dose dependently, and methadone and morphine did not. The results suggest that discriminative control by methadone and cocaine was established without explicit discrimination training.     

Relationship between response rate and reinforcement frequency in variable-interval schedules: II. Effect of the volume of sucrose reinforcement

Three rats were exposed to variable-interval schedules specifying a range of different reinforcement frequencies, using three different volumes of .32 molar sucrose (.10, .05, and .02 milliliters) as the reinforcer. With each of the three volumes, the rates of responding of all three rats were increasing, negatively accelerated functions of reinforcement frequency, the data conforming closely to Herrnstein's equation. In each rat the value of the constant K_H, which expresses the reinforcement frequency needed to obtain the half-maximal response rate, increased with decreasing reinforcer volume, the values obtained with .02 milliliters being significantly greater than the values obtained with .10 milliliters. The values of the constant R_max, which expresses the theoretical maximum response rate, were not systematically related to reinforcer volume. The effect of reinforcer volume upon the relationship between response rate and reinforcement frequency is thus different from the effect of the concentration of sucrose reinforcement: In a previous experiment (Bradshaw, Szabadi, & Bevan, 1978) it was found that sucrose concentration influenced the values of both constants, R_max increasing and K_H decreasing with increasing sucrose concentration.     

Relative reinforcer magnitude under a nonindependent concurrent schedule of cocaine reinforcement in rhesus monkeys.

Lever pressing by three rhesus monkeys was maintained under a two-lever concurrent schedule of cocaine reinforcement. Responding on one lever (constant-dose lever) produced a constant dose of 0.05 or 0.1 mg/kg/injection arranged according to a variable-interval 1-min schedule. Responding on the other lever (variable-dose lever) produced a comparison dose of cocaine (0.013 to 0.8 mg/kg/injection), also under a variable-interval 1-min schedule. The two variable-interval schedules were made nonindependent by arranging that the assignment of a reinforcer by one schedule inactivated the second schedule until the assigned reinforcer had been obtained. This modification ensured that the two cocaine doses were obtained with approximately equal frequency, regardless of the distribution of the subject's responding. Preference, indicated by relative response frequency on the variable-dose lever, was almost always for the larger of the doses and was a monotonic function of the comparison dose, except at the highest doses. Preferences at the highest comparison doses may have resulted from the low overall response rates exhibited at these doses. Relative response frequencies on the variable-dose lever roughly matched relative reinforcer magnitude (mg/kg/injection available on the variable-dose lever divided by the sum of mg/kg/injections available on each lever).     

Control over response number by a targeted percentile schedule: reinforcement loss and the acute effects of d-amphetamine.

Two fixed-consecutive-number-like procedures were used to examine effects of acute d-amphetamine administration on control over response number. In both procedures, rats were required to press the left lever at least once and then press the right lever to complete a trial. The consecutive left-lever presses on each trial comprised a "run." Under the targeted percentile schedule, reinforcement was provided if the current run length was closer to the target length (16) than half of the most recent 24 runs. This differentially reinforced run length while holding reinforcement probability constant at .5. A second group acquired the differentiation under the targeted percentile schedule, but were then shifted to a procedure that yoked reinforcement probability by subject and run length to that obtained under the targeted percentile schedule. The two procedures generated practically identical control run lengths, response rates, reinforcement probabilities, and reinforcement rates. Administration of d-amphetamine disrupted percentile responding to a greater degree than yoked control responding. This disruption decreased reinforcement frequency less in the former than the latter procedure. The similar baseline responding under these two procedures suggests that this difference in sensitivity was due to behavioral adjustments to drug prompted by reduction of reinforcement density in the yoked control but not the percentile schedule. These adjustments attenuate the drug's effects under the former, but not the latter, procedure.     

Effects of D-amphetamine on response acquisition with immediate and delayed reinforcement.

The present study examined in 8-hour sessions the effects of d-amphetamine (1.0, 5.6, and 10 mg/kg) on the acquisition of lever-press responding in rats that were exposed to procedures in which water delivery was delayed by 0, 8, or 16 seconds relative to the response that produced it. Both nonresetting- and resetting-delay conditions were studied. Although neither shaping nor autoshaping occurred, substantial levels of operative-lever responding developed under all conditions in which responses produced water. The lowest dose (1.0 mg/kg) of d-amphetamine either had no effect on or increased operative-lever pressing, whereas higher doses typically produced an initial reduction in lever pressing. Nonetheless, overall rates of operative-lever pressing at these doses were as high as, or higher than, those observed with vehicle. Thus, response acquisition was observed under all reinforcement procedures at all drug doses. In the absence of the drug, most responding occurred on the operative lever when reinforcement was immediate. Such differential responding also developed under both nonresetting- and resetting-delay procedures when the delay was 8 seconds, but not when it was 16 seconds. d-Amphetamine did not affect the development of differential responding under any procedure. Thus, consistent with d-amphetamine's effects under repeated acquisition procedures, the drug had no detrimental effect on learning until doses that produced general behavioral disruption were administered.     

Rapid acquisition of preference in concurrent chains: effects of d-amphetamine on sensitivity to reinforcement delay

The purpose of this study was to examine effects of d-amphetamine on choice controlled by reinforcement delay. Eight pigeons responded under a concurrent-chains procedure in which one terminal-link schedule was always fixed-interval 8 s, and the other terminal-link schedule changed from session to session between fixed-interval 4 s and fixed-interval 16 s according to a 31-step pseudorandom binary sequence. After sufficient exposure to these contingencies (at least once through the pseudorandom binary sequence), the pigeons acquired a preference for the shorter reinforcement delay within each session. Estimates of the sensitivity to reinforcement immediacy were similar to those obtained in previous studies. For all pigeons, at least one dose of d-amphetamine attenuated preference and, hence, decreased estimates of sensitivity to reinforcement immediacy; in most cases, this effect occurred without a change in overall response rates. In many cases, the reduced sensitivity to reinforcement delay produced by d-amphetamine resulted primarily from a decrease in the asymptotic level of preference achieved within the session; in some cases, d-amphetamine produced complete indifference. These findings suggest that a reduction in the sensitivity to reinforcement delay may be an important behavioral mechanism of the effects of psychomotor stimulants.     

Bias of phencyclidine discrimination by the schedule of reinforcement.

Pigeons, trained to discriminate phencyclidine from saline under a procedure requiring the bird to track the location of a color, received cumulative doses of phencyclidine, pentobarbital, or d-amphetamine with a variety of schedules of reinforcement in effect (across phases). When the same second-order schedules were used to reinforce responding after either saline or phencyclidine administration, stimulus control by phencyclidine did not depend on the schedule parameter. When different second-order schedules were used that biased responding toward the phencyclidine-correlated key color, pigeons responded on the phencyclidine-correlated key at lower doses of phencyclidine and pentobarbital than when the second-order schedule biased responding toward the saline key color. A similar but less marked effect was obtained with d-amphetamine. Attempts to produce bias by changing reinforcement magnitude (duration of food availability) were less successful. A signal-detection analysis of dose-effect curves for phencyclidine under two of the second-order schedules employed suggested that at low doses of phencyclidine, response bias is a major determinant of responding. As doses were increased, position preferences occurred and response bias decreased; at higher doses both response bias and position preference decreased and discriminability increased. With low doses of pentobarbital, responding again was biased but increasing doses produced position preference with only small increases in discriminability. At low doses of d-amphetamine responding also was biased, but bias did not decrease consistently with dose nor did discriminability increase. These experiments suggest that the schedule of reinforcement can be used to bias responding toward or away from making the drug-correlated response in drug discrimination experiments, and that signal-detection analysis and analysis of responding at a position can be used to separate the discriminability of the drug state from other effects of the drug on responding.     

Cocaine tolerance: acute versus chronic effects as dependent upon fixed-ratio size.

The effects of cocaine on operant behavior were studied by examining fixed-ratio value as a factor in the development of tolerance. Pigeons pecked a response key under a three-component multiple schedule, with each bird being exposed to fixed-ratio values that were categorized as small, medium, or large. Administered acutely, cocaine (1.0 to 10.0 mg/kg) produced dose-related decreases in overall rate of responding. Responding maintained by the largest ratio was decreased by lower doses than those required to reduce rates of responding maintained by the other two ratio schedules. Following repeated daily administration of 5.6 mg/kg of cocaine, dose-effect functions (obtained from sessions during the chronic regimen by making substitutions for the daily dose) indicated tolerance under the smaller ratios, but no tolerance or less tolerance under the largest ratio. Thus, whether tolerance developed, and the degree to which it developed, depended on the ratio value. The results are partially consistent with the notion that tolerance to drug effects on schedule-controlled behavior will develop if drug administration initially reduces reinforcement frequency, but they indicate that reinforcement loss alone is not a sufficient condition for the generation of tolerance under such conditions. The findings suggest that amount of responding required for reinforcement, or "effort," may contribute to the development of tolerance to effects of cocaine.     

Effects of d-amphetamine and cocaine on strained ratio behavior in a repeated-acquisition task.

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. When the fixed-ratio requirement for food presentation was five completions of the chain, d-amphetamine and cocaine disrupted the behavior. As the dose of each drug was increased, the overall response rate decreased, the overall accuracy was impaired (i,e., percent errors increased), and there was less within-session error reduction (acquisition). In contrast, when the fixed-ratio requirement was either 20 or 50 completions of the chain, certain doses of both drugs produced large increases in the overall response rate by eliminating the extended pausing (ratio strain) that was characteristic of the control sessions. These rate-increasing effects were accompanied by error-decreasing effects, both during acquisition and after the response chain had been acquired. Taken together, the results show that the effects of d-amphetamine and cocaine on behavior in a repeated-acquisition task can be modulated by manipulating the value of the fixed-ratio schedule maintaining the behavior.     

Fixed-interval schedule of cocaine reinforcement: effect of dose and infusion duration

Rhesus monkeys were trained on a fixed-interval 9-min limited-hold 3-min schedule of intravenous cocaine reinforcement. A 15-min timeout followed each reinforcement or limited-hold expiration. An identical schedule of food reinforcement was interspersed in the session to assess rate-modifying effects of the drug infusions not specific to drug reinforcement. In one experiment, response rate for cocaine reinforcement was shown to be a positive function of reinforcement magnitude for a dose range from 0 to 800 ug/kg/inj. At these doses, there was little effect on food reinforced responding except at the highest dose, where responding decreased. Results of the second experiment indicated that increasing the duration of the cocaine infusion produced a change in response rate similar to decreasing unit dose. The response rate change for a given increase in infustion duration was less at a unit dose of 400 ug/kg than at 200 ug/kg.     

Effects of d-amphetamine on responding under second-order schedules of reinforcement with paired and nonpaired brief stimuli.

Three pigeons were studied under a multiple schedule in which pecks in each component were reinforced according to a variable-interval 120-s second-order schedule with fixed-interval 60-s units. In the first component of the multiple schedule, the completion of a fixed interval produced either food or a 4-s change in key color plus houselight illumination. In the second component an identical schedule was in effect, but the stimulus was a 0.3-s change in key color. Both long and short brief stimuli were not paired with food presentations in Conditions 1 and 3 and were paired with food in Condition 2. There were no consistent differences in response patterns under paired and nonpaired brief-stimulus conditions when the stimulus was a 4-s change in key color accompanied by houselight illumination. However, pairing the 0.3-s key-color change with food presentations resulted in higher indices of curvature and lower response rates in the early segments of the fixed interval than when the stimulus was not paired with food presentations. Low doses of d-amphetamine (0.3 and 1 mg/kg) produced small and inconsistent increases in overall response rates, and higher doses (3 and 10 mg/kg) decreased overall response rates. d-Amphetamine altered response patterns within fixed intervals by decreasing the indices of curvature and increasing response rates in the early segments of the fixed interval. Response rates and patterns under paired and nonpaired brief-stimulus conditions were not differentially affected by d-amphetamine. Thus, evidence for the enhancement of the conditioned reinforcement effects of psychomotor stimulant drugs was not found with the second-order schedules used in the present study.     

Response suppression by visual stimuli paired with postsession d-amphetamine injections in the pigeon

Responding of pigeons, maintained under a fixed-interval 3-minute schedule of food presentation, was decreased on days that the color of the lights illuminating the food magazine was changed and d-amphetamine (1.0 mg/kg, i.m.) was injected after the session. Responding was not decreased by keylight color changes paired with postsession d-amphetamine or by postsession injections of saline. Administration of pentobarbital (3.0 to 5.6 mg/kg), but not d-amphetamine (.3 to 3.0 mg/kg), before the session increased rates of responding suppressed by drug-paired magazine lights. Responding maintained under a fixed-ratio 30-response schedule was not decreased when differently colored magazine lights were paired with a low (.3 mg/kg) postsession dose of d-amphetamine; with high (3.0 mg/kg) postsession doses, however, responding was completely suppressed after two pairings. The effects of pairing magazine stimuli with an intermediate (1.0 mg/kg) postsession dose of d-amphetamine depended upon the magnitude of prior postsession doses. After being paired with a low dose, stimuli paired with 1.0 mg/kg did not suppress responding. After being paired with a high dose, stimuli paired with 1.0 mg/kg completely suppressed responding. The suppression of food-maintained responding by stimuli paired with postsession drug administration depends upon both behavioral and pharmacological variables.     

The roles of stimulus control and reinforcement frequency in modulating the behavioral effects of d-amphetamine in the rat.

The behavioral effects of d-amphetamine have been shown to be modulated by stimulus control, with less impairment of performance occurring when control is great. When the fixed-consecutive-number schedule is used (on which at least a specified consecutive number of responses must be made on one operandum before a single response on another will produce a reinforcer), response rate tends to be invariant but reinforcement frequency is not. This study asks whether the differences in reinforcement frequency that usually accompany changes in stimulus control could themselves be responsible for the performance differences. Two versions of the fixed-consecutive-number schedule of reinforcement were combined into a multiple schedule within which stimulus control was varied but differences in reinforcement frequency were minimized by omitting some reinforcer deliveries during the component that usually had the higher reinforcement frequency. In one component, a compound discriminative stimulus was added with the eighth consecutive response on the first lever; a single response on the second lever was then reinforced. In the other component, no such stimulus was presented. With no added stimulus, large decreases occurred in the number of runs satisfying the minimum requirement for reinforcement at doses of drug that produced only minimal changes when an added stimulus controlled behavior. Thus, increased stimulus control diminishes the behavioral changes produced by d-amphetamine even when the possible contribution by baseline reinforcement rate is minimized.     

d-amphetamine and fixed-interval performance: effects of operant history.

Sixteen rats were initially exposed for 50 sessions to either a fixed-ratio 40 or an interresponse-time-greater-than-11-second food reinforcement schedule, then shifted to a fixed-interval 15-second food reinforcement schedule. Animals with fixed-ratio 40 histories lever pressed at much higher rates under the fixed-interval schedule than did animals with inter-response-time-greater-than-11-second histories. This difference persisted across 93 sessions of fixed-interval exposure. The effects of d=amphetamine were assessed after 15 and 59 sessions of fixed-interval exposure. On both occasions, the low-rate responding of animals with interresponse-time-greater-than-11-second histories was typically increased by all doses of the drug, while the high-rate responding of animals with fixed-ratio 40 histories was typically decreased by all doses of the drug. These results suggest that control response rate under the fixed-interval schedule, which may be affected by a history of responding under another schedule, is the primary determinant of the relative effects of d-amphetamine.     

Selective antagonism of the rate-decreasing effect of d-amphetamine by chlorpromazine in a repeated-acquisition task.

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. When d-amphetamine was administered alone, the overall response rate decreased and the percent errors increased with increasing doses. When a small dose of chlorpromazine, which was ineffective when given alone, was administered in combination with d-amphetamine, the rate-decreasing effect was antagonized. The antagonism was selective, however, in that the error-increasing effect of d-amphetamine was augmented by chlorpromazine. The nature of the joint effect of the two drugs thus depended on the behavioral measure: rate vs. accuracy.     

Drug effects on repeated acquisition: comparison of cumulative and non-cumulative dosing

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of a sequence 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. Each day there were four 15-minute sessions, with a 10-minute inter-session interval. Cumulative dose-effect curves for phencyclidine, pentobarbital, and d-amphetamine were obtained by giving an injection before each of the four sessions; successive injections increased the cumulative dose in equally spaced logarithmic steps. For comparison, non-cumulative doses of each drug (i.e., doses not preceded by other doses on the same day) were also tested. As the cumulative dose of each drug increased, the overall response rate decreased, the percent errors increased, and there was less within-session error reduction (acquisition). With phencyclidine and pentobarbital, the rate-decreasing and error-increasing effects tended to be greater with a non-cumulative dose than with the corresponding cumulative dose. In contrast, with d-amphetamine, the effects were considerably greater with the cumulative doses. The results indicate that although the cumulative-dosing procedure saved a substantial amount of time in determining dose-effect curves, there were quantitative differences in effects between cumulative and non-cumulative doses.