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

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a concurrent fixed-interval (FI) FI schedule of food presentation on which, after pentobarbital administration, responses on one key were reinforced with food under an FI 60-s component and responses on the other key were reinforced under an FI 240-s component. After saline administration, the schedule contingencies on the two keys were reversed. After both pentobarbital and saline, pigeons responded more frequently on the key on which responses had been programmed to produce the reinforcer under the FI 60 component of the concurrent schedule. The schedule was changed to concurrent FI 150 FI 150 s for drug-substitution tests. In each bird, increasing doses of pentobarbital, ethanol, and chlordiazepoxide produced increases in the proportion of responses on the key on which responses had been reinforced under the FI 60 component after pentobarbital administration during training sessions. The proportion of responses on that key was slightly lower for ethanol than for chlordiazepoxide and pentobarbital. At a dose of pentobarbital higher than the training dose, responding decreased on the key that had been reinforced under the FI 60 component during training sessions. Phencyclidine produced less responding on the key programmed under the FI 60-s component than did pentobarbital. Methamphetamine produced responding primarily on the key on which responses had been reinforced under the FI 60-s component after saline administration.     

Drug discrimination using a conditioned taste-aversion paradigm in rhesus monkeys.

The development of drug discrimination was assessed in rhesus monkeys using the conditioned taste-aversion paradigm. Monkeys were initially trained to respond under a fixed-ratio 30-response schedule of food-pellet delivery to assess the rate-decreasing effects of alprazolam (0.03 to 3 mg/kg, i.m., 60 min presession). Alprazolam decreased responding at doses greater than 0.1 mg/kg. Discriminative stimulus effects of alprazolam were then assessed by giving 0.03 mg/kg before sessions in which 1.8 mEq/kg lithium chloride was given immediately after the session (alprazolam/lithium session). On intervening days, saline was given before and after the session (saline/saline session). Rates of responding decreased over successive alprazolam/lithium sessions and also during the saline/saline session that immediately followed an alprazolam/lithium session. During subsequent saline/saline sessions, rates of responding returned to levels near baseline rates within two to four sessions. The discriminative stimulus effects of alprazolam were then assessed by giving 0.1 mg/kg before sessions in which 1 mg/kg d-amphetamine was given immediately after the session (alprazolam/d-amphetamine session). Rates of responding decreased during subsequent alprazolam/d-amphetamine sessions in drug-experienced monkeys, but did not decrease during intervening saline/saline sessions. These findings demonstrate that drug stimuli associated with postsession drug injections can rapidly develop control over behavior and suggest that similar methods be explored in the assessment of drug discrimination.     

Repeated acquisition of response sequences: stimulus control and drugs.

Pigeons obtained food by making four responses on three keys in a specified sequence, e.g., left, right, center, right. Under the "tandem-learning" condition, all three keys were the same color throughout the response sequence, and the sequence was changed from session to session. After total errors per session (overall accuracy) and within-session error reduction (learning) had stabilized, the effects of varying doses phenobarbital and chlordiazepoxide were assessed. For comparison, the drug tests were also conducted under a "tandem-performance" condition, in which the response sequence was the same from session to session, and under corresponding "chain-learning" and "chain-performance" conditions, where different colored keylights were associated with the response sequence. Under all four baseline conditions, the largest dose of each drug impaired overall accuracy. Under the two learning conditions, the error rate decreased across trials within each session, but the degree of negative acceleration was less in the drug sessions than in the control sessions. In contrast, under the two performance conditions, the error rate was relatively constant across trials, but was higher in the drug sessions than in the control sessions. Of the four baselines, the chain-learning condition was the most sensitive to the drug effects.     

Distinct mechanisms underlying memory modulation after the first and the second session of two avoidance tasks

Rats were subjected to three consecutive sessions, one session per day, of either a step-down inhibitory avoidance task using a 60-Hz. 0.3-mA footshock, or a two-way active avoidance task using 20 presentations of a 5-s, 1-kHz tone and a 0.3-mA footshock. After either the first or the second training session animals received an intraperitoneal injection of ACTH (0.2 microgram/kg), epinephrine-HCl (5.0 micrograms/kg), or naloxone-HCl (0.8 mg/kg). All these treatments caused memory facilitation on both tasks when administered after the first training session. When administered after the second training session only ACTH and adrenaline were effective, on both tasks. As previous physiological and pharmacological reports point to the activation of the brain beta-endorphin system after the first, but not the second, session of a task, we propose that (a) memory facilitation by naloxone depends on the previous activation of the brain beta-endorphin system; and (b) memory facilitation due to ACTH or epinephrine does not depend on the opioid activity, so their effects are expressed after both the first and the second training sessions. It was also observed that the enhancement of performance in the second training session due to post-training facilitatory treatments carried over to the test session. These results suggest that some form of consolidation occurs both after the first and after the second training session.     

Diazepam-induced impairment of a go-no go successive discrimination

Diazepam (2.0 and 4.0 mg/kg, but not 1.0 mg/kg) administered in eight acquisition sessions significantly impaired the light-cued successive discrimination of male Sprague-Dawley rats. In two postdrug (vehicle) sessions, groups previously treated with the drug demonstrated good recovery in discrimination. An analysis of response components indicated that the impairment was due to the failure of drugged subjects to inhibit or withhold responses during the no go periods of the task. These findings are consistent with a "disinhibitory hypothesis" of drug impairment. The similarity of the present findings to those previously reported with chlordiazepoxide suggests that such effects are a generalized characteristic of the benzodiazepine class of drugs.     

Effects of increment size and reinforcer volume on progressive ratio performance

The progressive ratio schedule requires the subject to emit an increasing number of responses for each successive reinforcement. Eventually, the response requirement becomes so large that the subject fails to respond for a period of 15 min and thereby terminates the session. This point is arbitrarily defined as the “breaking point” of the subject's performance. The measure is quantified in terms of the number of responses in the final completed (i.e., reinforced) ratio run of the session. Previous work has shown that this measure varies as a function of several motivational variables and may thus be useful as an index of reinforcement strength. The present study is an extension of that work. The subjects were four rats. In the first experiment, the effects of the size of the increment by which each ratio run increased were studied. In two additional experiments, the volume of a liquid reinforcer was varied using both large and small ratio increments. The results indicate that the number of responses in the final completed ratio run increases as a function of the size of the ratio increment. However, the number of reinforcements obtained by the animals per session declines sharply. When large ratio increments are used, the number of responses in the final ratio increases as a function of the volume of the reinforcer, but when small increments are used, progressive satiation results in a decline in performance with the larger volumes of liquid.     

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.     

Immediate postsession feeding reduces operant responding in rats

Three experiments investigated the effects of immediate and delayed postsession feeding on progressive-ratio and variable-interval schedule performance in rats. During Experiments 1 and 2, immediate postsession feeding decreased the breakpoint, or largest completed ratio, under progressive-ratio schedules. Experiment 3 was conducted to extend the results of the first two experiments to responding maintained by variable-interval schedules with different session lengths (15 and 60 min). Response rates decreased in all 4 subjects when postsession feeding immediately followed a 15-min session and in 3 of 4 subjects when postsession feeding immediately followed a 60-min session. The implications of this research are twofold: (1) The functional context in which within-session reinforcers are embedded extends outside the experimental chamber, and (2) supplemental postsession feedings should be sufficiently delayed from the end of a session to avoid weakening operant behavior in the experimental sessions.     

Beta-endorphin enhancement of retrieval in a three-session paradigm

Rats were submitted to three consecutive sessions, one session per day, of step-down inhibitory avoidance task (60-Hz, 0.3-mA footshock) or of two-way active avoidance task (25 trials of a 5-s, 1-kHz tone and a 0.4-mA footshock). Animals received intraperitoneal (ip) injections of saline or beta-endorphin (2.0 micrograms/kg) before or after the second session and before the third session. beta-Endorphin given before either the second or the third session improved retention of both tasks, while its administration after the second session had no effect upon performance on both tasks. In Experiment 2, it was shown that rats receiving naloxone (0.2 mg/kg) ip after the first session did not exhibit the enhancement of retrieval by beta-endorphin administration before the second session, so a non-state-dependent improvement of retrieval by the opioid seems to be unlikely. In view of these results we can propose that the presession retrieval enhancing effect of beta-endorphin is due to an endogenous state dependency on the opioid that can be expressed either in the second or in the third session of aversive tasks.     

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.     

Prospective factors contribute little to within-session changes in responding

Five rats pressed levers for food delivered by a multiple variable interval 1-min variable interval 1-min schedule. In theunpredictable conditions, sessions were 20, 40, 60, 80, or 100 min long, determined randomly at the beginning of each session. In thepredictable conditions, each of these session durations was presented for 15 consecutive sessions. Rate of responding changed systematically within the session even when the end of the session was unpredictable. This implies that prospective factors related to anticipation of the end of the session are not necessary for producing withinsession changes in responding. Within-session patterns of responding were also similar for the predictable and unpredictable conditions. This suggests that prospective factors contributed little to the form of the within-session patterns under the present conditions.     

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.     

Drug discrimination in rats under concurrent variable-interval variable-interval schedules

Eight rats were trained to discriminate pentobarbital from saline under a concurrent variable-interval (VI) VI schedule, on which responses on the pentobarbital-biased lever after pentobarbital were reinforced under VI 20 s and responses on the saline-biased lever were reinforced under VI 80 s. After saline, the reinforcement contingencies programmed on the two levers were reversed. The rats made 62.3% of their responses on the pentobarbital-biased lever after pentobarbital and 72.2% on the saline-biased lever after saline, both of which are lower than predicted by the matching law. When the schedule was changed to concurrent VI 50 s VI 50 s for test sessions with saline and the training dose of pentobarbital, responding on the pentobarbital-biased lever after the training dose of pentobarbital and on the saline-biased lever after saline became nearly equal, even during the first 2 min of the session, suggesting that the presence or absence of the training drug was exerting minimal control over responding and making the determination of dose-effect relations of drugs difficult to interpret. When the pentobarbital dose-response curve was determined under the concurrent VI 50-s VI 50-s schedule, responding was fairly evenly distributed on both levers for most rats. Therefore, 6 additional rats were trained to respond under a concurrent VI 60-s VI 240-s schedule. Under this schedule, the rats made 62.6% of their responses on the pentobarbital-biased lever after pentobarbital and 73.5% of their responses on the saline-biased lever after saline, which also is lower than the percentages predicted by perfect matching. When the schedule was changed to a concurrent VI 150-s VI 150-s schedule for 5-min test sessions with additional drugs, the presence or absence of pentobarbital continued to control responding in most rats, and it was possible to generate graded dose-response curves for pentobarbital and other drugs using the data from these 5-min sessions. The dose-response curves generated under these conditions were similar to the dose-response curves generated using other reinforcement schedules and other species.     

Punished and Nonpunished Responding in A Multiple Schedule in Humans: A Brief Report

Four male subjects responded on a multiple schedule in which responding was maintained by a random interval 20-sec (RI20) schedule of point presentation. Responding was suppressed in alternating components by an added variable ratio 30 (VR30) schedule of point subtractions. Each component was accompanied by distinctive stimulus lights. Subjects were exposed to the multiple schedule from the initial session. Two subjects experienced four 50-min sessions daily (Experiment 1) and the other two subjects participated in one 50-min session daily (Experiment 2). Once responding in the punished components had stabilized, responding in the nonpunished components continued to increase across sessions. Nonpunished responding did not stabilize even after as many as 36 sessions. These results are discussed in the context of previous studies using animals which employed multiple schedules with punished and nonpunished response contingencies.

     

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.     

d-Serine facilitates the effects of extinction to reduce cocaine-primed reinstatement of drug-seeking behavior

Male Sprague Dawley rats were allowed to self-administer cocaine (0.5 mg/kg) during 90 min sessions for a period of 15 days. On day 16, rats were either held abstinent in their home cage environment or experienced an extinction session in which the active lever had no programmed consequences. Facilitating N-methyl-d-aspartate (NMDA) receptor activity with the coagonist d-serine (100 mg/kg i.p.) before or following the extinction session significantly reduced the subsequent cocaine-primed reinstatement of drug-seeking behavior tested on day 17. d-Serine significantly reduced drug-primed reinstatement only when combined with extinction, and its effectiveness when administered following the training session suggested that an enhancement of consolidation of extinction learning had occurred. In contrast, d-serine treatment did not reduce sucrose-primed reinstatement, indicating that the beneficial effects of this adjunct pharmacotherapy with extinction training were specific to an addictive substance (cocaine) and did not generalize to a natural reward (sucrose).     

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.     

Conditioned suppression by a stimulus associated with nalorphine in morphine-dependent monkeys

Three rhesus monkeys, physically dependent on morphine, were trained to press a lever for food on a fixed ratio of 10 responses. A tone, initially a neutral stimulus, was aperiodically presented every third or fourth session, 5 min before and after the intravenous injection of nalorphine, a morphine antagonist which produces an immediate withdrawal syndrome in morphine-dependent monkeys. After several sessions, conditioned suppression of food-lever response rate was observed. Conditioned bradycardia, emesis, and excessive salivation also occurred. In 40 to 45 sessions the conditioned suppression of food-lever response rate and the conditioned autonomic changes were extinguished by presenting pairings of a tone and saline injection. The monkeys were then reconditioned by presenting the tone aperiodically, every third or fourth session, 5 min before and after the intravenous injection of nalorphine. Results were similar to the initial conditioning sessions. Two rhesus monkeys not dependent on morphine were stabilized on a food schedule similar to that used for the first three monkeys. These monkeys showed no change in food-lever response rate during or after nalorphine injections.     

Post-reinforcement pauses and response rate of monkeys on a two-hand fixed-ratio schedule

Fixed-ratio behavior of monkeys was analyzed separately for two hands. While one hand responded on the fixed-ratio schedule the other performed a holding response and the function of the hands changed in alternate ratio runs. After performance was stable on the fixed ratio (70 responses, two monkeys; 100 responses, two monkeys, 120 responses, two monkeys) 90 sessions of further training equalized post-reinforcement pauses and the mean interresponse time of the two hands. Hand preference in reaching for food remained unchanged. Then, the fixed-ratio requirement was changed (a) in small sequential steps, (b) in two large steps, and, (c) within sessions alternating two runs at a high ratio with two runs at a low ratio. The mean duration of post-reinforcement pauses was correlated with a fixed ratio maintained throughout a session but single pauses were neither controlled by the immediately preceding nor by the following ratio run when a cue to its length was available. The mean interresponse time was insensitive to changes in fixed ratio. The fixed-ratio performance was generally similar to that of pigeons and rats.     

Long lasting increase in nociceptive threshold induced in mice by forced swimming: involvement of an endorphinergic mechanism

Mice submitted to forced swimming session(s) displayed a long lasting modification in their nociceptive threshold, assessed through their jump latency from a hot plate (55 degrees C). Thus two forced swimming sessions (6 min each, 8h apart), in water at 33 degrees C, increased by about 50% the jump latency when the hot plate test was performed 14 hours, 3 days or 6 days thereafter. The water temperature (16 degrees C vs 33 degrees C) had no critical influence in this respect. To be clearly effective (at 33 degrees C) the swimming session had to be performed twice (when performed only once it was irregularly effective); it apparently culminated for a 6 min duration, since its effectiveness was not significantly increased by extending the swimming time to 12 min or 18 min. Performing 2 forced swimming sessions (6 min each, 8h apart), 5 consecutive days, resulted in a suppression of the increase in jump latency in the hot plate test. The two forced swimming episodes-induced analgesia was prevented by the s.c. administration of diazepam (from 0.125 mg/kg) or morphine (from 5 mg/kg) or scopolamine (1 mg/kg) before each forced swimming episode. Morphine (7.5 mg/kg) was uneffective to prevent the induction of two forced swimming episodes-induced analgesia when it was administered immediately after each forced swimming session. Finally this analgesia was dose dependently reversed by naloxone (ID(50) = 0.14 mg/kg, s.c., 30 min before the hot plate test). It is hypothesized that the handling of mice immediately before the hot plate test induces the remembrance of the stress induced by previous forced swimming episodes, triggering a fear reaction which increases the nociceptive threshold.