James B. Smith

Effects of chronically administered d-amphetamine on spaced responding maintained under multiple and single-component schedules

Key pressing by rats was maintained under spaced-responding and random-ratio schedules of food delivery, and rates of responding were reliably different for each schedule. When responding was maintained under a multiple schedule, appropriate doses of d-amphetamine (1.0 and 1.7 mg/kg) markedly increased low rates of spaced responding while markedly decreasing high rates of ratio responding. These drug-produced changes in response rate resulted in decreased food presentation during both schedule components. When 1.0 mg/kg d-amphetamine was given daily, tolerance developed to initially decreased ratio responding in six to nine sessions, but did not develop to initially increased spaced responding. However, when the ratio schedule was removed, tolerance developed very quickly to increases under the spaced-responding schedule, and associated food frequency returned to control levels. When the ratio schedule was reinstated, spaced responding was once again increased, and its associated frequency of food delivery was again decreased. The development of tolerance to the behavioral effects of d-amphetamine was influenced more by global changes in response consequences during entire experimental sessions than by local changes in response consequences in single components of those sessions. Whenever the concept of “response cost” is used, it should be understood in terms of total “cost.”

Situational specificity of tolerance to decreased operant responding by cocaine

Responding of rats was maintained in three different environmental situations each day. Interruption of a photobeam was maintained under a shock avoidance schedule in the first session, lever pressing was maintained under a 5-min fixed-interval (FI) schedule of food presentation in a second session, and nose-key pressing was maintained under a 30-response fixed-ratio (FR) schedule of food presentation in a third session. After receiving once-weekly injections of cocaine (3-17 mg/kg) prior to each of the sessions, animals received daily administration of 13 mg/kg after responding in the third daily session for four weeks, before responding in the third session for four weeks, before responding in the second daily session for four weeks, and then before responding in the first daily session for four weeks. Tolerance that developed in the environment that was coincident with the pharmacological actions of cocaine did not extend to operants in other environmental situations. Instead, tolerance to the behavioral effects of cocaine was specific to particular stimulus conditions associated with drug administration, indicating that the expression of tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.

Situational specificity of tolerance to decreased operant responding by morphine andl-nantradol

In one experiment, key pressing of rats was maintained under a fixed-ratio schedule of food presentation in a first daily session in one environmental situation, and interruption of a photobeam was maintained under a continuous shock avoidance schedule in a second daily session in another environmental situation. After receiving acute injections of the cannabinoidl-nantradol (0.01–0.3 mg/kg), rats received daily administration of a rate-decreasing dose of the drugafter the second session, thenbefore the second session, and thenbefore the first session. Tolerance that developed to decreased avoidance responding in the second daily session did not extend to decreased fixed-ratio responding in the first daily session, but was specific to circumstances coinciding with the pharmacological actions ofl-nantradol. In a second experiment, lever pressing of squirrel monkeys was maintained under an identical fixed-interval schedule of food delivery in two separate daily sessions in different experimental situations. After receiving once-weekly acute injections of morphine (0.3–3.0 mg/kg), monkeys received daily administration of a rate-decreasing dose of morphine in a counter-balanced orderbefore each session. Just as for experiment 1, tolerance that developed in the environment coinciding with the pharmacological actions of morphine did not immediately generalize to operants in the other environmental situation. Instead, tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.

Effects of fixed-ratio length on the development of tolerance to decreased responding by l-nantradol

Key pecking of pigeons was maintained under either a 100-response or a 300-response fixed-ratio schedule of food presentation, and animals received 0.03 mg/kg/day l-natradol prior to experimental sessions. Tolerance developed for initial rate decreases under fixed ratio 100 in 10–12 sessions, but tolerance did not develop under fixed ratio 300 for up to 30 sessions. When the fixed ratio was changed from 300 back to 100, tolerance developed in three to four sessions, and when the fixed ratio was changed from 100 back to 300, tolerance diminished in two to three sessions. The importance of fixed-ratio parameter for the observation of tolerance extends the generality of the influence of reinforcement processes on tolerance.

Changes in the rate-increasing effects of d-amphetamine and pentobarbital by response consequences

Keypecking in one group of pigeons was maintained under schedules in which food was presented only when a specified number of responses was followed by a 30-s pause without a response. d-Amphetamine and pentobarbital increased low rates of responding (and, thus, decreased food presentation) only after initial injections or when, during drug sessions, responses during the 30-s period did not reset the period. When responses during the pause-interval postponed food delivery, the rate-increasing effects of both drugs diminished over succeeding administrations. Thus, immediate effects of response consequences were as influential as the actual presence of a drug in determining the reproducibility of the behavioral effects of that drug. In a second experiment, keypecking in another group of pigeons was maintained under a 10-min fixed-interval schedule of food presentation but suppressed by a 100-response fixed-ratio schedule of shock delivery (punishment). d-Amphetamine and pentobarbital increased low rates of punished responding when shock delivery was eliminated during drug sessions. Pentobarbital, but not d-amphetamine, also increased punished responding when shock delivery was present. Rate-increasing effects of these drugs were determined by not only predrug patterns of responding but also effects of reinforcers and punishers that occurred during exposure to the drug.

Situational specificity of tolerance to effects of phencyclidine on responding of rats under fixed-ratio and spaced-responding schedules

Responding of rats (n=5) was maintained under DRL (lever) and Time-Delay (nose-key) schedules of food presentation in different experimental chambers during two separate daily sessions. Tolerance that developed to rate-decreasing effects of phencyclidine for nose-key pressing under the Time-Delay schedule did not extend to effects of phencyclidine on lever pressing under the DRL schedule. In a second experiment, both lever and nose-key pressing of rats were maintained under individual and multiple fixed-ratio schedules. One group of animals (n=5) experienced both the individual and the multiple schedules in the same experimental chamber and another group (n=5) experienced the individual and the multiple schedules in different experimental chambers. Tolerance that developed to behavioral effects of phencyclidine during the individual schedule did not extend to responding on even the same manipulandum under the multiple schedule in a different experimental chamber. In contrast, tolerance that developed to behavioral effects of phencyclidine during the individual schedule did extend to responding on even the different manipulandum under the multiple schedule in the same experimental chamber. Thus, tolerance that developed in the environment that was coincident with the pharmacologic actions of phencyclidine did not extend to similar operants in adifferent environmental condition, but did extend even to a different operant and schedule context in thesame environmental condition.

Effects of single and repeated daily injections of morphine, clonidine, and l-nantradol on avoidance responding of rats.

Interruption of a photobeam by rats was maintained under a continuous shock avoidance schedule, and moderate response rates were maintained at low shock frequencies. Responding decreased, and shock frequency increased, in a dose-dependent manner after acute injections of the narcotic morphine, the antihypertensive l-nantradol clonidine, and the cannabinoid l-nantradol. Clonidine and l-nantradol were about 100 times more potent than morphine for decreasing overall responding, and l-nantradol was about 3 times more potent than clonidine for decreasing escape responding. When drugs were given repeatedly prior to daily experimental sessions, tolerance developed to response rate decreases of morphine and l-nantradol within seven to ten sessions, but tolerance did not develop to rate decreases of clonidine for up to 30 sessions. Continued decreased responding by clonidine was antagonized by yohimbine, but not by prazosin or naltrexone. These results extend observations for the acute effects of l-nantradol and clonidine to operant responding under a schedule of continuous shock avoidance. Different potencies for drugs in the present and previous experiments suggest important effects of response topography on dose effects.

Behavioral influences on tolerance to the effects of morphine on schedule-controlled behavior.

Responding of pigeons was maintained under a multiple fixed interval, fixed ratio schedule of food delivery, and 10 mg/kg morphine was administered daily. Responding during both schedule components was initially decreased and measureable tolerance developed to this effect after four daily injections. However, the rate of tolerance development differed depending on whether or not presence of the drug conicided with performance during experimental sessions. Tolerance developed more rapidly when morphine was given before daily experimental sessions than when morphine was given daily but animals did not perform daily in experimental sessions. Tolerance to the rate-decreasing effects of morphine depended on relations between presence of the drug and exposure to experimental sessions.

Effects of shock intensity on observed tolerance to decreased avoidance responding by clonidine.

Interruption of a photobeam by rats was maintained under a Sidman avoidance schedule, and moderate response rates were maintained at low frequencies of electrical stimulation. After acute injections of clonidine, responding decreased, and frequency of electric stimulation increased, in a dose-dependent manner. At a lower intensity of electric stimulation, response-suppressive effects of clonidine did not diminish for up to 40 sessions with daily administration of clonidine. At a higher stimulus intensity, however, response-suppressive effects of clonidine diminished within 15 sessions, and stimulus frequency was at control level after 40 sessions with daily administration of clonidine. Behavioral consequences altered the effects of chronic clonidine so that tolerance was observed at a higher, but not a lower, intensity of electric stimulation.

Prevention by naltrexone of tolerance to the rate-decreasing effects of morphine on schedule-controlled responding in the pigeon.

Key-pecking in the pigeon was maintained under 10-min fixed-interval and 30-response fixed-ratio schedules of food presentation. Naltrexone alone (0.003–17 mg/kg) had no systematic effect on responding at any dose studied, and 10 and 17 mg/kg morphine practically eliminated responding. When naltrexone regularly preceded daily injections of morphine, tolerance was prevented for some dose combinations but not for others. If the daily dose of morphine was 17 mg/kg, tolerance was prevented by 1.0 mg/kg naltrexone but not by 0.3 mg/kg naltrexone. If the dose of naltrexone was 0.56 mg/kg, tolerance was prevented for 10 mg/kg morphine but not for 17 mg/kg morphine. Thus naltrexone prevented the development of tolerance to the rate-decreasing effects of morphine, although there were doses of naltrexone which completely antagonized the acute effects of morphine but which did not prevent tolerance development. The relative doses of naltrexone and morphine, not the absolute doses, determined whether or not development of tolerance was prevented. When combinations of naltrexone (0.3 or 1.0 mg/kg) and morphine (17 mg/kg) preceded experimental sessions by 6 h, the effects of the combination with 0.3 mg/kg naltrexone were more like those of 17 mg/kg morphine alone, whereas the effects of the combination with 1.0 mg/kg naltrexone were almost indistinguishable from those of saline. Differences in prevention of tolerance by doses of naltrexone that antagonized the acute effects of morphine were probably due to differences in duration of effect.