Differential effects of cocaine and pentobarbital on fixed-interval and random-interval performance

Reports have indicated that the behavioral effects of a drug can be related to the nondrug control rate of behavior in the absence of the drug. To investigate the purported relationship between control rate and drug rate, squirrel monkeys were trained under a fixed-interval 300-s schedule of stimulus-shock termination, a procedure that engendered a wide range of response rates. A light illuminated the experimental chamber during the fixed interval, and the first lever press after 300 s had elapsed terminated the light for 30 s and precluded an electrical stimulus to the tail. Following acute intramuscular administration of cocaine (0.03-0.56 mg/kg), overall rate increased and different control rates of responding, during different parts of the fixed interval, converged toward a common rate. Subsequently, the schedule was changed to a multiple fixed-interval 300-s random-interval 300-s schedule; performance during the random-interval component was characterized by steady responding at a uniformly high rate. Analysis of fixed-interval and random-interval performances following acute cocaine administration revealed convergence of response rates toward a common, uniform rate. Pentobarbital (0.3-10.0 mg/kg) only decreased overall rate, and different control rates of responding during the fixed interval did not converge toward a common rate. The results indicate that this type of analysis can be useful in comparing pharmacological agents from different classes and that the rate at which responding becomes uniform can provide a quantitative behavioral end point for characterizing drug effects on behavior.     

A comparison of responding maintained under second-order schedules of intramuscular cocaine injection or food presentation in squirrel monkeys.

Key pressing by squirrel monkeys was maintained under second-order schedules of either intramuscular cocaine injection or food presentation. Under one schedule, each completion of a 10-response fixed-ratio unit produced a brief visual stimulus; the first fixed-ratio unit completed after 30 minutes elapsed produced the stimulus paired with either cocaine injection or food presentation. Generally, short pauses followed by high rates of responding were maintained within the fixed-ratio units, and responding was positively accelerated over the 30-minute interval. Under another schedule, each completion of a 3-minute fixed-interval unit produced the brief stimulus; completion of the 10th fixed-interval unit produced the stimulus paired with either cocaine injection or food presentation. Generally, short pauses followed by high rates of responding were maintained within the fixed-ratio units, and responding was positively accelerated over the 30-minute interval. Under another schedule, each completion of a 3-minute fixed-interval unit produced the brief stimulus; completion of the 10th fixed-interval unit produced the stimulus paired with either cocaine injection or food presentation. Rates of responding increased within the fixed-interval units, and to a greater extent over the entire 10 fixed-interval units. Patterns of responding depended more on the schedule of reinforcement than on whether cocaine or food maintained responding. Omitting the brief stimuli following all but the last fixed-ratio or fixed-interval units decreased average rates and altered the patterns of responding. Substituting a visual stimulus that was never paired with cocaine or food following all but the last fixed-ratio or fixed-interval units decreased response rates to a lesser extent and did not substantially alter patterns of responding. When the duration of the paired stimulus was varied from .3 to 30.0 seconds, the highest response rates occurred at intermediate durations (1.0 to 10.0 seconds). The manner in which the stimulus changes affected performances depended more on the schedule of reinforcement than on whether cocaine injection or food presentation maintained responding.     

Rate changes after unscheduled omission and presentation of reinforcement

Changes in response rate similar to frustration effects were studied in a two-lever situation. Responding on one lever on a fixed-interval schedule produced access to water for 5 sec and an exteroceptive stimulus. In the presence of this stimulus, responding on another lever on a fixed-interval schedule produced access to water for 5 sec and terminated the stimulus. Occasional omission of a previously scheduled reinforcer after responding on the first lever resulted consistently in increases in rate on the second lever during the immediately succeeding interval. In another procedure, occasional presentation of a previously unscheduled reinforcer after responding on the first lever resulted consistently in decreases in rate on the second lever during the immediately succeeding interval. Changes occurred after the first omissions or presentations and were about the same in magnitude as the procedure continued over several sessions. Typically, an increase or decrease in rate was maintained throughout an entire 100-sec interval. Changes in rate on the second lever of approximately the same magnitude also occurred when rate on the first lever was near-zero under a schedule that differentially reinforced behavior other than lever pressing.     

Behavioral and pharmacological modulation of respiration in rhesus monkeys.

Changes in respiration associated with schedule-controlled behavior were determined in seated rhesus monkeys prepared with a pressure-displacement head plethysmograph for monitoring ventilation continuously during behavioral experiments. Subjects were trained to press a lever under fixed-ratio 40 and fixed-interval 300-s schedules of stimulus termination. Episodic increases in ventilation were closely associated with periods of responding under both schedules. Recurring episodes of increased ventilation occurred during fixed-ratio responding, and were separated by brief 10-s timeouts during which ventilation decreased. Under the fixed-interval schedule, both ventilation and response rate typically increased as the 300-s interval elapsed. The effects of cocaine, caffeine, and two adenosine agonists, 5'-N-ethylcarboxamidadenosine (NECA) and 2-(carboxyethylphenylamino)adenosine-5'-carboxamide (CGS 21680), on behavior and respiration were determined using a cumulative-dosing procedure. Drug-induced suppression of behavior eliminated the episodic increases in ventilation during the performance components of both schedules. Schedule-related increases in ventilation were compared to those produced by elevated levels of CO2 in inspired air. Exposure to 4% CO2 mixed in air increased ventilation in all subjects, and the combined effects of CO2 exposure and schedule-controlled responding on respiration appeared to be additive. The results suggest that behavioral activities may increase ventilation through increased metabolic demand and increased CO2 production.     

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.     

Responding in the squirrel monkey under second-order schedules of shock delivery

Lever-pressing responses were maintained in the squirrel monkey when the only consequence of responding was the delivery of a response-produced electric shock, or alternatively, a brief visual stimulus that was occasionally followed by an electric shock. When shock was produced by the first response occurring after 8 min (8-min fixed-interval schedule), a period of no responding at the beginning of the interval was followed by a gradual increase in response rate during the interval. Similar rates and patterns of responding were maintained when a 1-sec visual stimulus was produced by the first response occurring after 8 min and shock delivery followed the brief stimulus. Subsequently, patterns of positively accelerated responding were engendered during individual fixed-interval components when the first response occurring after 4 min produced a 1-sec visual stimulus and shock delivery followed the second, and later the fourth, presentation of the 1-sec stimulus. When the duration of the brief stimulus was varied over a 100-fold range from 0.1 to 10.0 sec (1) mean response rates decreased monotonically as stimulus duration increased, and (2) patterns of positively accelerated responding were least variable and response rates during the initial part of each 4-min interval were lowest at a stimulus duration of 1 sec.     

Effects of chlordiazepoxide and cocaine on concurrent food and avoidance-of-timeout schedules.

Five rats were trained on a concurrent schedule in which responses on one lever produced a food pellet on a random-interval 30-s schedule during 10 s of food availability associated with distinctive exteroceptive stimuli. Responses on another lever postponed for 20 s the presentation of a 50-s timeout, during which all stimuli were extinguished and the schedule contingencies on the food lever were suspended. The response rates maintained by the random-interval schedule exceeded those maintained by the avoidance contingency, but both provided a stable baseline to assess the behavioral effects of different drugs. Low doses of cocaine hydrochloride (1 and 3 mg/kg) did not affect food-reinforced responding or avoidance response rates. Intermediate doses (5.6, 10, and 13 mg/kg) produced a dose-dependent decrease in food-maintained and avoidance response rates, and both types of responding were virtually eliminated after administration of the highest doses (17 and 30 mg/kg) of cocaine. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased food-maintained and avoidance response rates, and both rates decreased systematically after 10 and 30 mg/kg of this drug. The effects of cocaine and chlordiazepoxide on response rates maintained by avoidance of timeout from food presentation were unlike those reported when subjects responded to avoid shock presentation. The results of this experiment thus provide evidence to suggest that the effects of drug administration on avoidance behavior may be a function of the nature of the consequent event to be avoided.     

Behavior controlled by scheduled injections of cocaine in squirrel and rhesus monkeys.

Rates and patterns of key-press responding maintained under schedules in which responding resulted in intravenous injections of cocaine were studied in squirrel monkeys and rhesus monkeys. Each injection was followed by a 60- or 100-sec timeout period. Schedule-controlled behavior was obtained at appropriate cocaine doses in each species. Under FR 10 or FR 30 schedules, performance was characterized by high rates of responding (usually more than one response per second) in each ratio. Under FI 5-min schedules, performance was characterized by an initial pause, followed by acceleration of responding to a final rate that was maintained until the end of the interval. Under multiple fixed-ratio fixed-interval schedules, rates and patterns of responding appropriate to each schedule component were maintained. Responding seldom occurred during timeout periods under any schedule studied. At doses of cocaine above or below those that maintained characteristic schedule-controlled behavior, rates of responding were relatively low and patterns of responding were irregular. Characteristic fixed-interval responding was maintained over a wider range of cocaine doses than characteristic fixed-ratio responding. Complex patterns of responding controlled by discriminative stimuli under fixed-ratio or fixed-interval schedules can be maintained by cocaine injections in squirrel monkeys and rhesus monkeys.     

Effects of cocaine on fixed-interval responding reinforced by the opportunity to run

Rate-dependent drug effects have been observed for operant responding maintained by food, water, heat, light onset, electrical brain stimulation, shock-stimulus termination, and shock presentation. The present study sought to determine if the effects of cocaine on lever pressing maintained by the opportunity to run could also be described as rate dependent. Seven male Wistar rats were trained to respond on levers for the opportunity to run in a wheel. The schedule of reinforcement was fixed-interval 60 s, and the reinforcing consequence was the opportunity to run for 60 s. On this schedule, overall rates of responding were low, usually below six presses per minute, and pauses frequently exceeded the 60-s interval. Despite these differences, an overall scalloped pattern of lever pressing was evident for each rat. Doses of 1, 2, 4, 8, and 16 mg/kg cocaine were administered 10 min prior to a session. Only at the 16 mg/kg dose did the responding of the majority of rats change in a manner suggestive of a rate-dependent drug effect. Specifically, lower response rates at the beginning of the intervals increased and higher rates at the end of the intervals decreased, as indicated by the fact that slopes from the regression of drug rates on control rates decreased. These data provide tentative support for the generalization of rate-dependent effects to operant responding maintained by wheel running. Differences in the baseline performance maintained by wheel running compared to those for food and water point to the need for further experimentation before this effect can be firmly established.     

Fixed-interval behavior: effects of percentage reinforcement

The percentage of fixed intervals terminating with food presentation was varied parametrically. Intervals that did not end with food were terminated by a stimulus uncorrelated with food presentation (a timeout stimulus). In Experiment I, the pigeons' response rates were an inverted U-shaped function of the percentage of food presentations: decreasing the percentage from 100% to 90%, 70%, or 50% produced an increase in response rates; lower percentages decreased the rates. The patterns of responding in the 100% condition differed from those of the other conditions. In Experiment II, the chamber was darkened after food presentations and timeouts. Response rate was directly related to the percentage of food presentations: decreasing the percentage decreased the response rate. Characteristic fixed-interval patterns of responding were maintained as long as there were occasional food presentations; pausing followed by positively-accelerated responding occurred in percentage conditions ranging from 7% to 100%. The ability to maintain fixed-interval performance with percentage reinforcement suggested that the behavioral sequences occurring in each interval may operate as unitary responses.     

Fixed-interval responding under second-order schedules of food presentation or cocaine injection.

Squirrel monkeys operated a key under second-order schedules in which every tenth completion of a 5-minute fixed interval resulted in either presentation of food or intravenous injection of cocaine. When a 2-second light was presented at the completion of the component fixed-interval schedules, positively accelerated responding developed and was maintained in each component. Over a tenfold range of doses of cocaine(30 to 300 microgram/kg/injection) and amounts of food (0.75 to 7.5 g/presentation); the second-order schedule of cocaine injection maintained higher average rates of responding than the second-order schedule of food presentation. Substituting saline for cocaine or eliminating food presentation decreased average rates of responding. When no stimulus change occurred at the completion of the first nine component fixed-interval schedules, but the 2-second light and food presentation or cocaine injection still occurred after the tenth component, only low and relatively constant rates of responding were maintained in each component. Patterns of responding characteristic of 5-minute fixed-interval schedules were maintained by the 2-second light paired with either cocaine injection or food presentation, though the maximum frequency of cocaine injection or food presentation was less than once per 50 minutes.     

Stimulus functions in chained fixed-interval schedules

Pigeons were required to complete three successive fixed-interval components to obtain food. When the same exteroceptive stimulus was correlated with the three components, responding was positively accelerated between food deliveries. When different exteroceptive stimuli were correlated with each component in a fixed sequence, prolonged pauses developed in the first component; low response rates developed in the second component; and responding was positively accelerated in the second and third components. When different exteroceptive stimuli were correlated with each component in a variable sequence, responding was positively accelerated in each component. Because the response and reinforcement contingencies were the same in all three procedures, the differences in performances must be due to the changes in the sequence of stimuli.     

Rate-dependent effects of drugs: modification by discriminative stimuli of the effects of amobarbital on schedule-controlled behavior

Food-deprived pigeons responded under a 10-min fixed-interval schedule of food presentation. During even-numbered minutes of the schedule, the discriminative stimuli were the same as those present when food was delivered. During odd-numbered minutes there was either a change in keylight color or a change in overhead illumination, either for the entire duration of the odd-numbered minutes, or for 3-sec after each response. Responding during even-numbered minutes showed the usual pattern of positive acceleration; responding during odd-numbered minutes was similarly graded, but rates were much lower. The response-rate-increasing effects of amobarbital were inversely related to control rates of responding for both even- and odd-numbered minutes. However, when the stimulus change during odd-numbered minutes was either keylight color or a change from a darkened to a brightly illuminated chamber, increases in responding were considerably less than predicted on the basis of the effects on responding during even-numbered minutes. When the stimulus change was from a darkened to a dimly illuminated chamber, control rates of responding changed little, but increases in responding during odd-numbered minutes after amobarbital were considerably greater, and of the approximate order expected on the basis of control rate.     

Fixed-interval schedules of intravenous cocaine presentation in rats

Fixed-interval schedules of intravenous cocaine presentation were examined as a function of injection dose (0.32 to 0.64 mg/kg) and interval duration (200 to 400 sec) in two rats. Cocaine was found to exert a dose-related temporal control over the initiation of responding that was unaffected by the fixed-interval contingency. Fixed-interval pause duration was linearly related to injection dose and was the same duration as the interresponse time found on continuous reinforcement schedules of cocaine presentation. The fixed-interval pause remained constant with changes in interval duration. Characteristic fixed-interval patterns of responding were observed. However, overall response rates were inversely related to injection dose and directly related to interval duration. Running response rates varied unsystematically with both variables. These findings are at variance with results typically found in studies of fixed-interval food and electric shock presentation.     

Stimulus control of responding during a fixed-interval reinforcement schedule

During training sessions, pecks by pigeons on a response key illuminated by a vertical line of white light resulted in reinforcement and an ensuing blackout according to a fixed-interval schedule. Training sessions were followed by dimensional stimulus control test sessions during which the orientation of the line present throughout the fixed interval was varied. Inverted U-shaped (excitatory) gradients of responding, with maximum responding occurring in the presence of the vertical line, were observed during the terminal part of the fixed interval. U-shaped (inhibitory) gradients of responding, with minimum responding occurring in the presence of the vertical line, were observed during the early part of the fixed interval when the preceding interval had terminated with reinforcement and blackout but not when the preceding interval had terminated with blackout only. These results suggest that the dimensional control by the stimulus present throughout the fixed interval is of a conditional variety. Whether the fixed-interval stimulus exerts inhibitory or excitatory dimensional control depends upon the presence and absence, respectively, of stimuli associated with reinforcement.     

Some effects of response-dependent clock stimuli in a fixed-interval schedule

Two experiments studied the effects of brief response-dependent clock stimuli in fixed-interval schedules of reinforcement. In the first experiment, two pigeons were exposed to a fixed-interval schedule. Two conditions were compared. In both conditions each peck on the key produced a brief stimulus. In one condition, pecks produced a different stimulus in successive sixths of the interval. This was the clock condition. In the other condition, the same stimulus was produced throughout the interval. Response rates were lower and the pause after reinforcement was longer in the clock condition. In the second experiment, a two-key optional clock procedure was used. Responding on the clock key produced one of three stimuli correlated with the three successive minutes of a fixed-interval schedule. A response on the other key produced grain at the end of the 3 min. When the final stimulus was removed from the situation and pecking produced nothing during the third minute, responding to the clock key declined to a very low rate. When the first two stimuli were removed and the third one replaced, responding to the clock key was resumed.     

Conjunctive schedules of reinforcement: I. Rate-dependent effects of pentobarbital and d-amphetamine

Key pecking of pigeons was maintained under conjunctive schedules of food presentation in which both a fixed-interval and a fixed-ratio schedule had to be completed before a peck produced food. For two pigeons, pecks on a single key completed both schedule requirements (fixed-interval 3-min, fixed-ratio 50 for one bird, fixed-interval 5-min, fixed-ratio 50 for the second). For two other pigeons, each requirement was scheduled on a separate key. On the two-key schedule, a peck after 5 min on the key scheduling the fixed-interval requirement produced food if at least 10 pecks had occurred on the ratio key (conjunctive fixed-interval 5-min, fixed-ratio 10). When each requirement was scheduled on a separate key, response rates on the fixed-ratio key were generally higher in the early portion of the interval and declined as the interval progressed; responding on the fixed-interval key, once initiated, typically remained at a constant rate throughout the interval. Responding under the single-key schedule was characterized by a high rate early in the interval; this then changed to a lower rate that continued until a peck produced food. For all pigeons, increases in response rates with pentobarbital and d-amphetamine were inversely related to the control rate of responding. When equivalent rates on each key of the two-key schedule were compared, both drugs increased rates on the fixed-ratio key less. Although the effects of both drugs were rate dependent, each drug differentially modified the pattern of responding under the single-key schedule.     

The effect of multiple SΔ periods on responding on a fixed-interval schedule: V. Effect of periods of complete darkness and of occasional omissions of food presentations

In pigeons under fixed-interval schedules of reinforcement, responding during most of the interval can be suppressed by stimulus conditions never present when a response is promptly followed by reinforcing stimuli. When the external stimuli obtaining immediately before reinforcement are presented during brief probe periods in the course of the interval, the rate of responding in the probe depends on the temporal position of the probe during the interval; the rate of responding is lower during a probe early in the interval than during one late in the interval. The present experiments show that the temporal dependency still holds (1) in birds with no experience under unmodified fixed-interval schedules, (2) when the time between probes is spent in complete darkness, and (3) when food presentations are omitted at the end of 50% of intervals. The results strengthen and extend the conclusion from previous studies that the time relations themselves are the primary control of rate of responding under fixed-interval schedules of reinforcement.     

An analysis of reinforcement history effects

Four pigeons were exposed to two tandem variable-interval differential-reinforcement-of-low-rate schedules under different stimulus conditions. The values of the tandem schedules were adjusted so that reinforcement rates in one stimulus condition were higher than those in the other, even though response rates in the two conditions were nearly identical. Following this, a fixed-interval schedule of either shorter or longer values than, or equal to the baseline schedule, was introduced in the two stimulus conditions respectively. Response rates during those fixed-interval schedules typically were higher in the presence of the stimuli previously correlated with the lower reinforcement rates than were those in the presence of the stimuli previously correlated with the higher reinforcement rates. Such effects of the reinforcement history were most prominent when the value of the fixed-interval schedule was shorter. The results are consistent with both incentive contrast and response strength conceptualizations of related effects. They also suggest methods for disentangling the effects of reinforcement rate on subsequent responding, from the response rate with which it is confounded in many conventional schedules of reinforcement.     

Effects of chlorpromazine on fixed-ratio responding: modification by fixed-interval discriminative stimuli.

Effects of chlorpromazine (1 to 100 mg/kg) were assessed on two pigeons' responding under various modifications of a multiple schedule of food delivery. During a fixed-interval component, the first response after 5 min produced food; during the subsequent, fixed-ratio component, the 30th response produced food. Modifications of the schedule entailed changes in stimulus conditions imposed during the fixed-ratio component that did not systematically alter characteristics of performance under non-drug conditions. In the first phase of the experiment, distinctive visual stimuli were correlated with each schedule component (conventional multiple schedule); chlorpromazine produced small decreases in fixed-ratio responding (20% at 30 mg/kg). When each response during the fixed-ratio component produced the stimulus correlated with the fixed-interval schedule (fixed-interval discriminative stimulus) for 1.2 s, effects of chlorpromazine were not different from those under the conventional multiple schedule. Chlorpromazine produced greater decreases in fixed-ratio responding (55% at 30 mg/kg) when either the first response of each fixed ratio changed the stimulus correlated with the fixed-ratio schedule to the fixed-interval discriminative stimulus for the remainder of the fixed-ratio component, or when the fixed-interval discriminative stimulus was presented independently of responding according to a matched temporal sequence. When the fixed-interval discriminative stimulus was present continuously during the fixed-ratio component (mixed schedule), chlorpromazine produced even more substantial decreases in fixed-ratio responding (greater than 80% at 30 mg/kg). Effects of chlorpromazine on fixed-interval responding were also modified by the schedules of fixed-interval discriminative stimulus presentation. The effects of chlorpromazine were a joint function of the stimuli prevailing during the multiple schedule and the degree to which responding influenced these stimuli.