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.     

Drug-behavior interaction history: modification of the effects of morphine on punished behavior.

Squirrel monkeys were trained to respond under a multiple fixed-interval, fixed-interval schedule in which the first response after 5 min terminated a visual stimulus in the presence of which electric shocks could occur. During one component of the schedule, correlated with one color of stimulus lights, every 30th response also produced electric shock; responding was suppressed during this component to approximately 10 to 12% of that occurring in the alternate component in which responding was not punished. In contrast to previous research, morphine (0.03 to 1.0 mg/kg) increased punished responding. Unpunished responding, however, was either not affected or decreased at doses of morphine that increased punished responding. Increases in rate of punished responding also occurred when the single-schedule punishment condition was studied alone in these animals. Subsequent experimentation, which systematically analyzed the development of the rate-enhancing effects of morphine on punished responding, involved the study of drug effects in additional monkeys trained initially under a single-schedule punishment condition. The effects of morphine on punished responding were studied before, after, and then during exposure to the multiple schedule that included a component in which responding was not punished. Increases in response rate with morphine did not occur until it was administered during exposure to the multiple schedule that included a component in which responding was not punished. As with the other monkeys, once the rate increases in punished responding occurred under the multiple schedule, these effects of morphine persisted, even when the multiple schedule was removed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Punishment of responding under schedules of stimulus-shock termination: effects of d-amphetamine and pentobarbital.

Responding maintained in squirrel monkeys under 5-min fixes-interval schedules of either food presentation or termination of a visual stimulus associated with electric-shock delivery was suppressed by presenting an electric shock for every thirtieth response (punishment). In monkeys responding under the schedule of food presentation, d-amphetamine sulfate only further decreased punished responding, and pentobarbital sodium markedly increased punished responding, as expected from previous reports. In monkeys responding under the schedule of stimulus-shock termination, however, the effects of the two drugs were opposite: d-amphetamine markedly increased punished responding, whereas pentobarbital only decreased responding. Thus, the effects of these drugs on punished responding were different depending on the type of event maintaining responding. These and previous results indicate that it may be misleading and inaccurate to speak of the effects of drugs on "punished responding" as though punishment were a unitary phenomenon. As with any behavior, the effects of drugs and other interventions on punished responding cannot be accurately characterized independently of the precise conditions under which the behavior occurs.     

Tolerance to and residual effects of cocaine in squirrel monkeys depend on reinforcement-schedule parameter.

Lever pressing by 4 squirrel monkeys was maintained under a three-component multiple fixed-ratio schedule of food presentation; components differed with respect to ratio size. For each monkey, acute administration of cocaine (0.03 to 1.3 mg/kg, i.m.) produced dose-dependent decreases in overall response rate in each component. During repeated daily administration of 1.0 mg/kg of cocaine, tolerance developed to the rate-decreasing effects under each of the ratio contingencies, but developed to a greater extent and was evident in earlier parts of sessions for performance under the smaller ratios. Response rates of 2 monkeys increased above nondrug control levels despite the putative reinforcer not being consumed during the session. When saline or a smaller dose of cocaine was substituted for 1.0 mg/kg, response rates often were suppressed below nondrug control-level responding. This suppressive effect was observed in each monkey and was more likely to be observed and/or to be of greater magnitude in large-ratio components for 3 of the 4 monkeys. When saline was administered chronically at the end of the chronic-drug phase, response rates remained suppressed in the large-ratio component for 2 of the monkeys. There was, therefore, a schedule-dependent dissociation between behavioral tolerance and the residual effects: Tolerance was greater when small ratios were arranged, whereas the residual effects were more pronounced when larger ratios were arranged.     

Tolerance to cocaine's rate-increasing effects upon repeated administration.

Four squirrel monkeys responded daily under a fixed-interval 5-min or 8-min schedule of food-pellet delivery. Cocaine (0.03 to 1.7 mg/kg) and saline were injected before occasional daily sessions (acute administration). Some doses of cocaine produced substantial overall increases in response rate for 3 of the subjects; effects were less substantial for the remaining subject, who exhibited modest increases in response rate early in the session and during the middle portion of the intervals. A dose that increased response rate when administered acutely was then administered before each session (chronic administration). Chronic administration resulted in a reduction in the increases in response rate seen under acute administration for all subjects.     

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.     

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.     

Synergistic effects of ethanol and cocaine on brain stimulation reward.

The effects of two widely abused drugs, ethanol and cocaine, were examined alone and in combination on intracranial reward processes. In agreement with previous research, higher doses of both cocaine and ethanol alone produced facilitation of behavior maintained by brain stimulation reward. Low intraperitoneal doses of ethanol and cocaine, which alone did not affect performance, were found to reduce stimulation reward threshold and modestly increase response rate. The enhancement of brain stimulation reward by the combination of ethanol and cocaine suggests that both drugs may produce their rewarding effects through common neuronal substrates and that they may potentiate the abuse of each other.     

Preference in rhesus monkeys given a choice between cocaine and d,l-cathinone

Previous experiments have shown that both cocaine and d,l-cathinone can function as positive reinforces when delivered intravenously to rhesus monkeys. However, the relative reinforcing efficacies of these compounds have not been established. In the present experiment, three rhesus monkeys were allowed to choose between saline and several doses of d,l-cathinone or cocaine as well as between several doses of both drugs in a discrete-trial choice procedure. Sufficient doses (.05 to .2 mg/kg/injection) of either drug maintained self-administration and the higher doses were reliably preferred to saline. Doses of d,l-cathinone that were preferred to saline were then compared to a range of cocaine doses in drug-drug choice. As the dose of d,l-cathinone that was available was increased, an increase in cocaine dose was necessary to maintain cocaine preference. Comparison of drug-drug choice data to dose combinations predicted to be chosen with equal frequency revealed that the reinforcing efficacy of d,l-cathinone was equivalent to that of cocaine.     

An inverse relationship between baseline fixed-interval response rate and the effects of a tandem response requirement.

Previous experiments examining the effects of adding a tandem fixed-ratio response requirement on fixed-interval schedule performance have reported inconsistent results. One variable that may account for such inconsistencies is the baseline response rate in the fixed-interval condition. This possibility was investigated in the present study. Rats were given histories with either interresponse times greater than 11 s or fixed-ratio 40 schedules of reinforcement, which engendered either relatively low or high rates of responding, respectively, in the subsequent fixed-interval condition. A tandem ratio response requirement (fixed-ratio 9) was then introduced. The effects of adding this tandem response requirement were inversely related to the baseline fixed-interval response rates; low rates of responding in the fixed-interval condition were markedly increased, whereas high rates of responding were relatively unaffected. This inverse relationship appears to be similar to the rate-dependent relations observed in behavioral pharmacology. These results may provide an explanation for the inconsistent findings reported in previous studies on tandem fixed-interval fixed-ratio schedules and suggest that principles of behavioral pharmacology research may be applicable to the study of the effects of nonpharmacological variables on schedule-controlled behavior.     

The effects of cocaine on behavior maintained by timeout from avoidance.

Rats were trained on concurrent schedules under which responses on one lever postponed shock (avoidance) and responses on the other lever produced brief (2-min) periods of signaled timeout from avoidance. For 6 rats, timeout from avoidance was programmed on a variable-interval 45-s schedule that generally resulted in rates that were lower than those on the avoidance lever. For another 6 rats, timeout was arranged on a variable-ratio 15 schedule that produced higher baseline rates. Cocaine (3 to 40 mg/kg) produced large, dose-dependent increases in behavior maintained by timeout in both groups of rats. Avoidance responding was also generally increased by cocaine, but the increases were of lesser magnitude. Increases in response rates were seen across a broad range of doses on behavior maintained by either interval or ratio schedules, an outcome that was unexpected on the basis of most studies of cocaine on food-maintained behavior. These results were similar to those of previous studies of the effects of amphetamine on behavior maintained by timeout from avoidance and suggest that stimulant drugs affect behavior maintained under a shock-postponement schedule differently than they affect behavior maintained by timeout from avoidance.     

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.     

Electric shock produced drinking in the squirrel monkey.

Squirrel monkeys were periodically exposed to brief electric tail shocks in a test environment containing a rubber hose, response lever, and a water spout. Shock delivery produced preshock lever pressing and postshock hose biting. Additionally, all subjects displayed licking responses following postshock biting-attack episodes. Further experiments showed that licking was: (1) influenced by hours of water deprivation; (2) drinking behavior; (3) the direct result of shock delivery; and (4) developed spontaneously in naive subjects with or without opportunities for hose biting or lever pressing. Removing the opportunity to attack increased postshock drinking. A noxious environmental stimulus that causes aggression can also produce drinking.     

Effects of cocaine on simple reaction times and sensory thresholds in baboons.

The effects of chronic, daily administration of cocaine on auditory and visual reaction times and thresholds were studied in baboons. Single intramuscular injections of cocaine hydrochloride (0.1 to 5.6 mg/kg) were given once daily for periods of 10 to 25 days, and were followed immediately by psychophysical tests designed to assess cocaine's effects on simple reaction times as on auditory and visual threshold functions. Consistent reductions in reaction times were frequently observed over the cocaine dose range of 0.32 to 1.0 mg/kg; at higher doses, either decreases or increases in reaction times were observed, depending upon the animal. Lowered reaction times generally occurred immediately following the 1st day's cocaine injection, and continued through all subsequent days during the dose administration period, suggesting little development of tolerance or sensitivity to these reaction-time effects. Reaction-time decreases showed a U-shaped dose-effect function. The greatest decreases in reaction times occurred from 0.32 to 1.0 mg/kg, and produced an average reaction-time decrease of 10 to 12%. Concurrently measured auditory and visual thresholds showed no systematic changes as a function of cocaine dose. Pausing was observed during performance of the psychophysical tasks, with the length of total session pause times being directly related to cocaine dose.     

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.     

Sequential effects of interval duration on fixed-interval performance

The bar pressing of rats was reinforced on a multiple fixed-interval schedule. The schedule intervals were 1 and 5 min long, and the sequence was such that intervals of either duration were equally likely to be followed by intervals of the same or of the other duration. Rates were higher during 1-min and after 5-min intervals. Best fit equations for cumulative responses during the 5-min intervals produced very similar exponents regardless of preceding duration. It was concluded that preceding duration may have affected the subjects' performances through direct effects on temporal discrimination.     

The role of verbal behavior in human learning: III. Instructional effects in children

Lever pressing of children from three age groups (2½ to 4, 5 to 6½, and 7½ to 9 years) could produce reinforcers according to a fixed-interval 40-s schedule: (1) Some were instructed to respond at a high rate, others at a low rate, and (2) they were subsequently taught to provide their own spoken self-instructions consonant with the earlier, experimenter-supplied instructions. All subjects who received high-rate instructions responded at a steady, high rate, which was maintained following self-instructional training. The effects of low-rate instructions were directly related to the age of the children. The two older groups produced low-rate patterns, with the oldest children responding at very low rates; effects were least noticeable in the youngest age group. Following self-instructional training, all three groups showed adult-like low-rate behavior and the oldest children showed an improved ability to estimate the interval length. The results provide further evidence of the importance of language as a determinant of human behavior.     

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.     

Effects of morphine, clonidine, and intensity change on electric-shock discrimination.

The effects of morphine, clonidine, and changes in stimulus intensity were examined in squirrel monkeys responding on one of two levers following brief presentations of one of two electric-shock intensities (0.1 and 0.5 mA). Responses were designated as correct or incorrect depending on which shock intensity had been presented and which lever was pressed. Morphine (0.42 to 1.80 mg/kg) and clonidine (0.075 to 0.18 mg/kg) decreased percentage correct responding. Morphine and clonidine also increased response latency and the number of shock presentations that were not followed by responses. Changes in shock intensity also decreased percentage correct responding but had no effect on response latency or on the number of shock presentations not followed by responses.