Cocaine and food as reinforcers: effects of reinforcer magnitude and response requirement under second-order fixed-ratio and progressive-ratio schedules.

Reinforcer magnitude and fixed-ratio requirement were varied under two second-order schedules. Under one, the first sequence of a fixed number of responses completed after the lapse of a 10-min fixed interval produced reinforcement. Under the second, a second-order progressive-ratio schedule, the fixed number of responses increased after each reinforcement. Either cocaine (0 to 300 micrograms/kg/inj) or food (0 to 5,700 mg/delivery) reinforcers were delivered. Under some conditions, a 2-s illumination of stimulus lights occurred on completion of each ratio sequence. Under the second-order schedule, as cocaine dose or amount of food increased, rates of responding increased; at the highest values, rates of responding decreased. Increases in the ratio requirement from 10 to 170 responses minimally decreased overall response rates. Under the second-order progressive-ratio schedule, increases in dose of cocaine or amount of food increased rates of responding; at the highest amounts of food, rates of responding decreased but response rates at the highest dose of cocaine remained relatively high. The highest ratio requirement that was completed (breaking point) depended on the dose of cocaine but was less dependent on the amount of food. Removing brief-stimulus presentations had a greater effect on completion of ratio requirements with cocaine compared to food.     

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).     

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.     

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.     

Time of supplemental feeding alters the effects of cocaine on lever pressing of rats

The present experiment assessed the effects of cocaine on the lever pressing of 4 rats maintained during 15-min sessions by a fixed-ratio 50 schedule of food reinforcement. Across phases, supplemental food was provided either immediately or 2 hr after sessions. Two rats began the experiment in the delayed-feeding condition, and 2 began the experiment in the immediate-feeding condition. Rates of lever pressing of 2 rats sometimes decreased to low levels near the ends of sessions when supplemental feeding was provided immediately, but were consistently high throughout sessions when supplemental feeding was delayed. Cocaine (1.0 to 17.0 or 30.0 mg/kg) was administered intraperitoneally 15 min prior to test sessions. In most cases, cocaine suppressed response rates at lower doses under immediate-feeding conditions. Decreases in overall response rates were correlated with dosedependent increases in the time rats spent not responding. It is suggested that delaying the time of postsession feeding increased response strength, as indicated by greater resistance to the rate-suppressive effects of cocaine.     

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.     

The effects of brief stimuli presented under a multiple schedule of second-order schedules

The effects of briefly presented stimuli paired or not paired with food reinforcement were investigated in the pigeon on a multiple schedule containing second-order schedules. A stimulus paired with food reinforcement was presented on a variable-interval schedule in one unit of the multiple schedule and either a stimulus not paired with food reinforcement or no stimuli were scheduled in the other unit. Response rates were highest when behavior was followed by the food-paired stimulus. Presentation of the food-paired stimulus at completion of each 1-min variable-interval component maintained a steady rate of responding between consecutive food presentations. Pausing following food reinforcement was greatest in the second-order schedule not containing the paired stimulus. Reversing the stimulus pairings led to a reversal of the relative response rates and patterns of responding for each stimulus.     

Differential effects of pentobarbital and cocaine on punished and nonpunished responding.

Similar rates of punished and nonpunished responding, maintained with equated rates of reinforcement, were established in pairs of rats. One subject of each pair was exposed to a random-ratio schedule of food presentation. The interreinforcement intervals for this subject comprised the intervals of a random-interval schedule of reinforcement for the other (yoked) rat. The random-ratio schedule maintained rates of responding higher than those maintained by the same rate of reinforcement schedule according to the yoked random-interval contingency. A random-ratio schedule of electric foot shock added to the random-ratio schedule of food presentation suppressed rates of responding such that similar rates of responding were observed in rats of both groups. Pentobarbital (3.0 to 17.0 mg/kg) increased punished responding at doses that had little effect on or decreased nonpunished responding, whereas cocaine (5.6 to 30 mg/kg) increased nonpunished responding at doses that decreased or did not alter punished responding. Qualitatively different effects of pharmacological agents on punished and nonpunished responding can be obtained using procedures that generate similar rates and temporal patterns of punished and nonpunished responding. The effects of pentobarbital and cocaine on responding can be determined by factors other than simply the baseline rate of responding.     

Effects of mesolimbic dopamine depletion on responding maintained by cocaine and food.

The hypothesis that mesolimbic dopamine is selectively involved in cocaine reinforcement was investigated in the rat. Animals were trained under a multiple schedule in which responding was reinforced by intravenous cocaine (0.75 mg/kg/injection) or food (45-mg pellets) under fixed-ratio 15 schedule requirements in alternate 30-min components of a 2-hr daily session. Infusion of the catecholaminergic neurotoxin 6-hydroxydopamine, but not the vehicle solution, into the region of the nucleus accumbens and olfactory tubercle produced selective reductions in cocaine self-administration without significantly altering responding maintained by food within the same sessions. This effect was reproduced in intact animals by substituting saline for cocaine in the self-administration component. These results support the hypothesis that the reinforcing effects of cocaine are dependent upon mesolimbic dopamine and demonstrate that cocaine self-administration can be disrupted in animals without altering behavior maintained by a nondrug reinforcer.     

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.     

Effects of cocaine on briefly signaled versus completely signaled delays to reinforcement.

Key pecking by 4 pigeons was maintained by a multiple schedule consisting of two variable-interval 60-s schedules wherein each food presentation followed a nonresetting 27-s delay that was either briefly signaled at its outset or completely signaled. Brief-signal duration was adjusted so that response rates maintained by the briefly and completely signaled delays of reinforcement were similar. In general, acute administration of small to intermediate doses (0.3 to 3.0 mg/kg) of cocaine produced either small increases in response rates in both components or no change, and larger doses (5.6 to 13.0 mg/kg) decreased response rates. Chronic (i.e., daily) cocaine administration (10.0 mg/kg) resulted in tolerance to the rate-decreasing effects in both components. Cocaine's effects were generally similar whether delays were completely or briefly signaled. Discontinuation of cocaine administration and subsequent removal of the delay signals also had similar effects in both components of the multiple schedule. Taken together, these results are consistent with the view that the two types of delay signals were equally effective in maintaining responding during the variable-interval schedules.     

Tolerance to the effects of cocaine on performance under behavior-correlated reinforcement magnitude

Four pigeons responded under a fixed-interval 8-min schedule of food delivery in which the amount of food delivered at the end of each interval depended on performance during the interval (i.e., a correlated schedule). Specifically, duration of access to grain was contingent upon the number of responses made during the first 4 min of the interval. This differential outcome did not affect response rates or patterning relative to performance under a simple fixed-interval 8-min schedule. Behavior under the correlated schedule was then investigated under doses of cocaine ranging from 0.3 to 10.0 mg/kg. A bitonic dose-response function was obtained for response rates and the time with head in the food hopper, whereas dose-dependent decreases were observed in the mathematical index of curvature (Fry, Kelleher, & Cook, 1960). The dose that produced the greatest increase in the head-in-hopper time was then administered prior to each session. Following repeated administration of cocaine, disruptions in response patterning were attenuated for all 4 pigeons; tolerance was also observed to the rate-increasing effects and increased head-in-hopper time for 2 pigeons after chronic cocaine administration. Tolerance therefore developed despite the fact that the initial effect of cocaine was to increase the amount of food obtained.     

Acute and chronic effects of cocaine on extinction-induced aggression.

Pigeons worked individually in a chamber containing a response key and a mirror. Pecking on the key was controlled by a multiple schedule in which a brief period of continuous food reinforcement alternated with a 5-minute period of extinction. Under baseline conditions, aggressive behavior (responding on the mirror) occurred at the onset of each extinction period. In Experiment I (acute drug administration), the aggressive behavior was decreased by doses of cocaine that had little or no effect on key pecking. Such food-reinforced responding was disrupted, however, by higher doses of cocaine. An attempt to mimic the disruptive drugs effects by a prefeeding manipulation was unsuccessful. In Experiment II (chronic drug administration), some tolerance developed to the disruptive effects of cocaine on the food-reinforced responding, except at the highest dose tested. There was no clear-cut indication of tolerance to the initial effect of cocaine on the aggressive behavior at any dose.     

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.     

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.     

Changing the response unit from a single peck to a fixed number of pecks in fixed-interval schedules

Each of three pigeons was studied first under a standard fixed-interval schedule. With the fixed interval held constant, the schedule was changed to a second-order schedule in which the response unit was the behavior on a small fixed-ratio schedule (first a fixed-ratio 10 and then a fixed-ratio 20 schedule). That is, every completion of the fixed-ratio schedule produced a 0.7-sec darkening of the key and reset the response count to zero for the next ratio. The first fixed-ratio completed after the fixed-interval schedule elapsed produced the 0.7-sec blackout followed immediately by food. These manipulations were carried out under two different fixed-interval durations for each bird ranging from 3 min to 12 min. The standard fixed-interval schedules produced the typical pause after reinforcement followed by responding at a moderate rate until the next reinforcement. The second-order schedules also engendered a pause after reinforcement, but responding occurred in bursts separated by brief pauses after each blackout. For a particular fixed-interval duration, post-reinforcement pauses increased slightly as the number of pecks in the response unit increased despite large differences in the rate and pattern of key pecking. Post-reinforcement pause increased with the fixed-interval duration under all response units. These data confirm that the allocation of time between pausing and responding is relatively independent of the rate and topography of responding after the pause.     

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

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

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

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

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.     

Tolerance to effects of cocaine on behavior under a response-initiated fixed-interval schedule

Tolerance to effects of cocaine can be modulated by schedules of reinforcement. With multiple ratio schedules, research has shown an inverse relationship between ratio requirement and amount of tolerance that resulted from daily administration of the drug. In contrast, tolerance to the effects of cocaine on behavior under multiple interval schedules generally has developed regardless of interval value. Under interval schedules reinforcement depends on the animal making one response following a time interval. Thus, as time to respond increases, the time to reinforcement decreases. On the other hand, fixed ratio schedules require a specified number of responses to be made prior to reinforcement. Therefore, delaying the initiation of responding does not coincide with a significant decrease in the time to reinforcement. In the current experiment, 6 pigeons were trained to respond under a three-component multiple schedule, with a different tandem fixed-ratio 1 fixed-interval schedule in each component. The multiple schedule required one response, which was followed by one of three fixed-interval values (5, 15, or 60 s). Thus, the multiple schedule was interval-like because after the fixed-ratio 1, only one more response was required for reinforcement, but it was also ratio-like because the length of the pause at the beginning of each interreinforcer interval affected the time until the next reinforcer. Acute administration of cocaine generally resulted in dose-dependent decreases in responding. Chronic (i.e., daily) administration of a rate-decreasing dose resulted in tolerance patterns similar to those usually obtained with multiple ratio schedules. That is, the magnitude of tolerance was related inversely to schedule size. These results suggest that delay to reinforcement from the initial response may play a role in the development of schedule-parameter-related tolerance.