The effect of drugs on a fixed-ratio performance suppressed by a pre–time-out stimulus,

Pecking was reinforced by a fixed-ratio schedule with food, and responses during a red light produced a time out. If the bird did not respond during the red light, the light terminated and the bird could complete the FR schedule of positive reinforcement uninterrupted. The bird stopped responding during the red light sufficiently to avoid most of the possible time outs. In general, the pre–time-out stimulus suppressed responding more when the FR schedule was large than when it was small. The occurrence of the pre–time-out stimulus in the fixed ratio produced FR strain and extreme curvature atypical of normal fixed ratios of this size. Amobarbital, pentobarbital, chlorpromazine, and d-amphetamine injected when the FR performance was strained by the pre–time-out procedure produced marked increases in responding. The drug administration lowered the rate of responding only at larger doses; and then this occurred predominantly just after the injection.     

EFFECTS OF DRUGS AND DRUG COMBINATIONS IN PIGEONS TRAINED TO DISCRIMINAT AMONG PENTOBARBITAL,DIZOCILPINE, A COMBINATION OF THESE DRUGS,AND SALIN

Drugs with multiple actions can have complex discriminative‐stimulus properties. An approach to studying such drugs is to train subjects to discriminate among drug combinations and individual drugs in the combination so that all of the complex discriminative stimuli are present during training. In the current experiments, a four‐choice procedure was used to train pigeons to discriminate among dizocilpine (noncompetitive NMDA receptor blocker), pentobarbital (GABA_A receptor agonist), a fixed‐dose combination of these two drugs, and saline. Following extended training, low doses of pentobarbital or dizocilpine administered alone produced saline‐appropriate responding. Higher doses of pentobarbital produced responding on the pentobarbital‐appropriate key and higher doses of dizocilpine produced responding on the dizocilpine key. Administering the lowest doses of pentobarbital and dizocilpine together resulted in responding on the saline‐appropriate key. Increasing the dose of pentobarbital in the presence of low doses of dizocilpine produced responding primarily on the pentobarbital‐appropriate key; increasing the dose of dizocilpine in the presence of the lowest dose of pentobarbital produced responding primarily on the dizocilpine‐appropriate key. Combining the higher doses of pentobarbital and dizocilpine resulted in responding primarily on the drug‐combination key. Low doses of phencyclidine or ethanol produced responding on the saline‐appropriate key, but intermediate doses resulted in individual subjects responding predominately on either the pentobarbital key, the dizocilpine key, or the drug‐combination key depending on the subject. After the highest dose of phencyclidine or ethanol, most subjects responded predominantly on the drug‐combination key. Low doses of other drugs tested produced responding on the saline‐appropriate key. With the highest diazepam doses responding was largely confined to the pentobarbital‐appropriate key. The highest doses of dextromethorphan or dextrorphan resulted in responding on the dizocilpine key more frequently than on other keys. Across a range of doses, morphine produced responding predominantly on the saline key. The results using the four‐key procedure emphasized the role of both GABA_A and NMDA receptors in the complex discriminative stimulus properties of phencyclidine and of ethanol.     

Comparison of drug effects on fixed-ratio performance and chain performance maintained under a second-order fixed-ratio schedule.

In one component of a multiple schedule, pigeons were required to complete the same four-response chain each session by responding sequentially on three identically lighted keys in the presence of four successively presented colors (chain performance). Food presentation occurred after five completions of the chain (i.e., after 20 correct responses). Errors, such as responding on the center or right key when the left was designated correct, produced a brief timeout but did not reset the chain. In the other component, responding on a single key (lighted white) was maintained by food presentation under a fixed-ratio 20 schedule. In general, phencyclidine and d-amphetamine produced dose-dependent decreases in the overall response rates in both components. With pentobarbital, overall rate in each component generally increased at intermediate doses and decreased at higher doses. All three drugs produced dose-dependent disruptive effects on chain-performance accuracy. Phencyclidine and pentobarbital increased percent errors at doses that had little or no rate-decreasing effects, whereas d-amphetamine generally increased percent errors only at doses that substantially decreased overall rate. At high doses, all three drugs produced greater disruption of chain performance than of fixed-ratio performance, as indicated by a slower return to control responding, although the effects of d-amphetamine were less selective than those of phencyclidine or pentobarbital.     

Effects of schedule of reinforcement on a pentobarbital discrimination in rats.

The purpose of this study was to determine the effects of the schedule of reinforcement on a pentobarbital discrimination in rats. Five rats were trained to discriminate 10 mg/kg pentobarbital from saline under a multiple fixed-interval 180-s fixed-ratio 20 schedule of reinforcement. During both saline and pentobarbital training sessions, subjects emitted a higher percentage of correct responses under the fixed-ratio component as compared to the fixed-interval component of the multiple schedule. Determination of the pentobarbital dose-response curve under the fixed-ratio component resulted in a steep curve characterized by responding on the saline lever at low doses and on the drug lever at higher doses. Under the fixed-interval component, a graded dose-effect curve was produced, with considerable responding on both levers after intermediate doses of pentobarbital. The administration of phencyclidine and MK-801 resulted in an intermediate level of drug-lever responding for some subjects. Administration of d-amphetamine resulted in saline (nondrug) appropriate responding. The results of this study demonstrate that the schedule of reinforcement is a determinant of drug stimulus control, just as it is a determinant of other drug effects.     

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.     

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.     

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.     

Drug discrimination under a concurrent schedule.

Three pigeons were trained to discriminate a 5.0 mg/kg dose of pentobarbital from saline under a two-key concurrent schedule with responding on the key associated with the presession injection, under both stimulus conditions, producing four times as many reinforcers as responding on the other key. This concurrent schedule resulted in approximately 70% responding to the higher reinforcement key under the pentobarbital stimulus and approximately 30% responding to that key under the saline stimulus. During testing, then, the pigeons were able to dose-dependently emit higher (>70%) or lower (<30%) values than were established under the control conditions. Dose-response curves were determined for pentobarbital (twice), methamphetamine, phencyclidine, chlordiazepoxide, and the combination of pentobarbital and the barbiturate antagonist bemegride. The results obtained with pentobarbital and chlordiazepoxide showed that, as the dose increased, pentobarbital-appropriate responding also increased. Methamphetamine produced relatively flat dose--response curves, whereas phencyclidine administration produced inconsistent effects on responding. The combination of the training dose of pentobarbital with increasing doses of bemegride produced a decrease in pentobarbital-appropriate responding. The results also showed that the dose-response curves for pentobarbital and chlordiazepoxide, instead of being all or none, were graded functions of the drug dose.     

Drug discrimination under two concurrent fixed-interval fixed-interval schedules

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-interval (FI) 100-s FI 200-s schedule of food presentation, and later tinder a concurrent FI 40-s FI 80-s schedule, in which the FI component with the shorter time requirement reinforced responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized under the concurrent FI 100-s FI 200-s schedule, pigeons earned an average of 66% (after pentobarbital) to 68% (after saline) of their reinforcers for responding under the FI 100-s component of the concurrent schedule. These birds made an average of 70% of their responses on both the pentobarbital-biased key after the training dose of pentobarbital and the saline-biased key after saline. After responding stabilized under the concurrent FI 40-s FI 80-s schedule, pigeons earned an average of 67% of their reinforcers for responding under the FI 40 component after both saline and the training dose of pentobarbital. These birds made an average of 75% of their responses on the pentobarbital-biased key after the training dose of pentobarbital, but only 55% of their responses on the saline-biased key after saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, ethanol, phencyclidine, or methamphetamine, the dose-response curves were similar under these two concurrent schedules. Pentobarbital, chlordiazepoxide, and ethanol produced dose-dependent increases in responding on the pentobarbital-biased key as the doses increased. For some birds, at the highest doses of these drugs, the dose-response curve turned over. Increasing doses of phencyclidine produced increased responding on the pentobarbital-biased key in some, but not all, birds. After methamphetamine, responding was largely confined to the saline-biased key. These data show that pigeons can perform drug discriminations under concurrent schedules in which the reinforcement frequency under the schedule components differs only by a factor of two, and that when other drugs are substituted for the training drugs they produce dose-response curves similar to the curves produced by these drugs under other concurrent interval schedules.     

Drug discrimination under a concurrent fixed-ratio fixed-ratio schedule.

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-ratio 10 fixed-ratio 40 schedule of food presentation, in which the fixed-ratio component with the lower response requirement was programmed to reinforce responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized, pigeons averaged 98% of their responses on the pentobarbital-biased key during training sessions preceded by pentobarbital, and they averaged 90% of their responses on the saline-biased key during training sessions preceded by saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, or ethanol, pigeons switched from responding on the saline-biased key at low doses to responding on the pentobarbital-biased key at higher doses (the dose-response curve was quantal). High doses of phencyclidine produced responding on both keys, whereas pigeons responded almost exclusively on the saline-biased key after all doses of methamphetamine. These and previous experiments using concurrent reinforcement schedules to study drug discrimination illustrate that the schedule of reinforcement is an important determinant of the shape of dose-effect curves in drug-discrimination experiments.     

A pharmacological examination of the resistance-to-change hypothesis of response strength.

The effects of d-amphetamine sulfate, sodium pentobarbital, haloperidol, and cholecystokinin-octapeptide were examined within the context of Nevin's (1974, 1979) resistance-to-change hypothesis of response strength. In three experiments, rats' responding was reinforced by delivery of food under chained random-interval 30-s random-interval 30-s, multiple fixed-interval 30-s fixed-interval 120-s, or multiple random-interval 30-s random-interval 120-s schedules. Each rat received several doses of each drug and changes in response rate were measured. The resistance-to-change hypothesis predicts greater disruption of response rate relative to baseline in the initial component of the chained schedule and in the 120-s component of the multiple schedules. In the chained schedule cholecystokinin-octapeptide produced greater reductions in response rate relative to baseline in the initial component. However, no differences between components were observed with haloperidol or sodium pentobarbital, and high doses of d-amphetamine reduced response rate in the terminal component relatively more than in the initial component. In the multiple schedules either no differences were observed between components or response rate was reduced more relative to baseline in the 30-s component. The data fail to support the notion that drugs may be viewed within the same context as other response disruptors such as extinction, satiation, and the presentation of alternative reinforcement.     

Drug discrimination under concurrent variable-ratio variable-ratio schedules

Pigeons were trained to discriminate 5 mg/kg pentobarbital from saline under concurrent variable-ratio (VR) VR schedules, in which responses on the pentobarbital-biased lever were reinforced under the VR schedule with the smaller response requirements when pentobarbital was given before the session, and responses on the saline-biased key were reinforced under the VR schedule with the larger response requirements. When saline was administered before the session, the reinforcement contingencies associated with the two response keys were reversed. When responding stabilized under concurrent VR 20 VR 30, concurrent VR 10 VR 40, or concurrent VR 5 VR 50 schedules, pigeons responded almost exclusively on the key on which fewer responses were required to produce the reinforcer. When other doses of pentobarbital and other drugs were substituted for the training dose, low doses of all drugs produced responding on the saline-biased key. Higher doses of pentobarbital and chlordiazepoxide produced responding only on the pentobarbital-biased key, whereas higher doses of ethanol and phencyclidine produced responding only on this key less often. d-Amphetamine produced responding primarily on the saline-biased key. When drugs generalized to pentobarbital, the shape of the generalization curve under concurrent VR VR schedules was more often graded than quantal in shape. Thus, drug discrimination can be established under concurrent VR VR schedules, but the shapes of drug-discrimination dose-response curves under concurrent VR VR schedules more closely resemble those seen under interval schedules than those seen under fixed-ratio schedules. Graded dose-response curves under concurrent VR VR schedules may relate to probability matching and difficulty in discriminating differences in reinforcement frequency.     

Barbiturates and Human Physical Aggression

The effects of barbiturates on aggressive behavior were investigated in two studies. In both studies, subjects were given the opportunity to administer electric shocks to an opponent within the context of a competitive reaction time task. In Study 1, 30 subjects received increasing provocation from an opponent following their ingestion of one of three doses of secobarbital. Aggressive behavior was not found to increase as a function of drug dosage. In Study 2, 30 subjects ingested a placebo or one of two doses of pentobarbital. Once again, the barbiturate did not influence aggressive responding. The findings suggest that barbiturates, in moderate, clinically appropriate doses do not facilitate aggressive responding.     

Effects of amphetamine-CNS depressant combinations and of other CNS stimulants in four-choice drug discriminations

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine-pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs at these doses, and saline (methamphetamine-morphine group). After 10 to 13 months of training, the pigeons averaged more than 90% of their responses on the appropriate key during training sessions. In subsequent testing, dose-response curves were determined for the individual drugs, for a wide range of dose combinations of the training drugs, and for two drugs to which the pigeons had not been exposed previously (pseudoephedrine and nicotine). After low test doses of the training drugs, pigeons responded on the saline key. As the dose increased, responding on the key associated with that drug during training sessions increased. When training drugs were combined at doses that were not discriminable when given alone, responding occurred on the saline key. When a discriminable dose of one training drug was combined with a nondiscriminable dose of the other training drug, responding occurred on the key associated with the discriminable dose. When both drugs were given at discriminable doses, responding almost always occurred on the drug-combination key. The response-rate decreasing effects of pentobarbital and amphetamine were mutually antagonized when the drugs were combined, but the rate-decreasing effects of morphine and methamphetamine were not. After low doses of pseudoephedrine and nicotine, pigeons in both groups responded on the saline key. After higher doses of pseudoephedrine and nicotine, responding in the amphetamine-pentobarbital group occurred primarily on the amphetamine key. In the methamphetamine-morphine group, higher doses of pseudoephedrine and especially nicotine engendered more responding on the combination key than had occurred in the other group. The four-choice procedure can reveal subtle effects in the discrimination of individual drugs and drug combinations that are not apparent with procedures offering fewer response alternatives.     

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.     

d-Amphetamine-chlorpromazine antagonism in a food reinforced operant

Dose effect curves for d-amphetamine and chlorpromazine were obtained with rats on a milk reinforced FR 10 schedule. A dose of d-amphetamine (2.5 mg/kg, i.p.) which completely suppressed all responding for 60 min was administered simultaneously (concomitant with the pretreatment times) with various doses of chlorpromazine. The d-amphetamine-induced cessation of responding was removed by several of the doses of chlorpromazine with maximal antagonism occurring at a dose of 1.5 mg/kg i.p. This dose of chlorpromazine, when administered independently, produced no observable side effects and showed no effect on the FR 10 schedule. One animal appeared to develop tolerance to the repeated dosages of d-amphetamine.     

Cooperative responding in rats maintained by fixed‐ and variable‐ratio schedules

The present study investigated the effects of fixed‐ratio (FR) and variable‐ratio (VR) reinforcement schedules on patterns of cooperative responding in pairs of rats. Experiment 1 arranged FR 1, FR 10, and VR 10 schedules to establish cooperative responding (water delivery depended on the joint responding of two rats). Cooperative response rates and proportions were higher under intermittent schedules than under continuous reinforcement. The FR 10 schedule generated a break‐and‐run pattern, whereas the VR 10 schedule generated a relatively high and constant rate pattern. Experiment 2 evaluated the effects of parametric manipulations of FR and VR schedules on cooperative responding. Rates and proportions of cooperative responding generally increased between ratio sizes of 1 and 5 but showed no consistent trend as the ratio increased from 5 to 10. Experiment 3 contrasted cooperative responding between an FR6 schedule and a yoked control schedule. Coordinated behavior occurred at a higher rate under the former schedule. The present study showed that external consequences and the schedules under which the delivery of these consequences are based, select patterns of coordinated behavior.     

Pentobarbital and d-amphetamine effects on concurrent performances.

The effects of pentobarbital and d-amphetamine were studied in pigeons responding under several concurrent fixed-ratio variable-interval and concurrent fixed-ratio fixed-interval schedules of food presentation. Drug effects were compared with different fixed ratios, fixed and variable intervals, changeover delays, and with the schedules operating singly. Doses of d-amphetamine that increased or did not affect responding under the interval schedules decreased responding under the fixed-ratio schedule, whereas doses of pentobarbital that increased responding under the fixed-ratio schedule decreased or eliminated responding under the interval schedules. These effects depended both on the schedule of food delivery and the parameters of schedules arranged concurrently. Pentobarbital increased responding under the fixed-ratio schedule with 4-minute and 10-minute interval schedules arranged concurrently, but not with 1.5-minute schedules. d-Amphetamine decreased concurrent ratio and interval responding with the 1.5-minute interval schedules, but either increased or did not affect responding with the longer intervals. Changes in the parameter of one schedule altered responding controlled by that schedule and also other concurrent performances. As a consequence, the effects of drugs on each behavior were altered.     

Selective antagonism of the error-increasing effect of morphine by naloxone 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. Errors produced a brief timeout but did not reset the chain. When either morphine or naloxone was administered alone, the overall response rate decreased with increasing doses. The rate-decreasing effect was accompanied by an increase in percent errors with morphine but not with naloxone. Both effects of morphine were antagonized by doses of naloxone that were ineffective when given alone. The antagonism was selective in that naloxone (3 mg/kg) completely blocked the error-increasing effect but not the rate-decreasing effect of the higher doses of morphine. The view that naloxone is a specific narcotic antagonist was supported by the finding that naloxone failed to antagonize the rate-decreasing and error-increasing effects of d-amphetamine, pentobarbital, and phencyclidine.