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

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

Are responses in avoidance procedures "safety" signals?

Dinsmoor's (2001) position has the advantage of parsimony in that it relies on well-established principles rather than a separate process--shock-frequency reduction--to account for avoidance. Other advantages are that it blends well with what is known about the effectiveness of momentary contiguities in the study of positive reinforcement and that it might provide an account of why different response forms seem to condition at different rates. Despite these advantages, the view needs elaboration about the temporal characteristics of response-associated stimuli, the functions that "warning'' stimuli may have, and especially about how ''safety" is established.

Measuring reinforcer efficacy: does relative persistence do it? Comment on Meisch (2000)

R. A. Meisch (2000a) offers a new way to scale the effectiveness of reinforcers. Specifically, he uses as a measure the ratio of output under a relatively large fixed-ratio schedule to the output under a smaller fixed-ratio schedule. With such metrics, it is usually the case that as reinforcer magnitude is increased, the measured ratio increases. The method, however, violates a foundation of all measurement, comparison against a fixed standard. Some of the data provided in this article illustrate the problem of selecting what will serve as the "baseline" for comparison (i.e., what will serve as the denominator of the measure). Depending on the selection of baseline, one can find effects of a particular experimental operation ranging from none to substantial.

A comparison of fixed and variable doses of cocaine in producing and augmenting tolerance to its effects on schedule-controlled behavior.

Twelve pigeons were trained to peck a key under a fixed-ratio 20-response schedule of food presentation. Acute effects of cocaine (03-10.0 mg/kg), determined by administering the drug once per week, revealed dose-dependent decreases in frequency of key pecking. The pigeons were then divided into six pairs, matched with respect to acute dose-response curves. One of each pair received one of five different doses before each daily session (variable-dosing condition) and the other received a fixed dose equal to the arithmetic average of the doses experienced by its pair mate (fixed-dosing condition). Following 50 days of exposure, subjects in the variable-dosing condition were then switched to the fixed-dosing condition. Dose-response functions were then determined in both groups by substituting doses for the fixed daily dose, once per week. Rate-decreasing effects were attenuated similarly in both groups of subjects, both at the end of the variable-dosing regimen and during subsequent fixed dosing. Next, an attempt was made to increase the degree of tolerance. Specifically, pigeons in the variable-dosing condition were exposed repeatedly to a range of doses in which the largest dose was 1/8 to 1/4 log unit larger than in the original variable-dosing phase. Pigeons in the fixed-dosing group were exposed daily to the largest dose that did not eliminate key pecking by the end of the initial repeated-dosing regimen. Dose effects were determined after at least 35 days of exposure. If the dose-response function had shifted to the right, the largest dose for the variable-dosing subjects was increased by 1/8 to 1/4 log unit and the smallest dose in the sequence was eliminated, and another period of variable dosing commenced. For the fixed-dosing subjects, if the curve had shifted to the right, the fixed dose was increased by 1/8 to 1/4 log unit and the process repeated. Only very modest shifts of the dose-response function to the right were observed, and in several cases curves shifted left after exposure to larger doses. Overall the results suggest that a variable-dosing regimen holds promise as a technique for investigating the development of tolerance to the effects of cocaine, and that the magnitude of tolerance cannot be increased to any great degree by increasing the dose or doses repeatedly experienced. Additionally, it appears that experience with relatively large doses of cocaine may limit the degree to which tolerance can be developed, or decrease the magnitude of tolerance previously observed.

Attenuation of cocaine-induced response-rate increases during repeated administration despite increases in rate of reinforcement.

Repeated administration of cocaine often results in tolerance to its effects on operant behavior. The tolerance is often associated with an initial drug effect that results in loss of reinforcement. Cocaine can also produce effects that result in a gain of reinforcement, and it is not known if tolerance will be observed in such a circumstance. The present experiments investigated whether tolerance would develop when cocaine was administered repeatedly to subjects who experienced an increase in the frequency of reinforcement when cocaine was administered acutely. Pigeons were trained to peck a response key under fixed-ratio schedules of food presentation. The ratio value for each pigeon was chosen such that performance indicated that the ratio was relatively large, and produced "ratio strain.". Cocaine was administered acutely (once per week), and then subsequently a dose was chosen and administered before each session. Once performance under the daily drug regimen was stable, other doses occasionally were substituted for the usual daily dose. Acute administration of cocaine (0.3-10.0 mg/kg) revealed substantial increases of 100% or more in response rate, and therefore equivalent increases in rate of food presentation, at some doses. That finding permitted examination of the role of drug-induced increases in rate of reinforcement during repeated administration of a response-rate-increasing dose. Repeated, daily administration of a rate-increasing dose resulted in attenuation of the effects of that dose, and subsequent administration of other doses that previously had increased response rates revealed that these doses, too, had lost their ability to increase rates. That is, "tolerance" developed to the rate-increasing effects, even though the rate increases were associated with more frequent access to food. These findings suggest that "reinforcement gain" may not be sufficient to prevent tolerance from developing to effects of cocaine on operant behavior.

Statistical inference in behavior analysis: Some things significance testing does and does not do.

Significance testing plays a prominent role in behavioral science, but its value is frequently overestimated. It does not estimate the reliability of a finding, it does not yield a probability that results are due to chance, nor does it usually answer an important question. In behavioral science it can limit the reasons for doing experiments, reduce scientific responsibility, and emphasize population parameters at the expense of behavior. It can, and usually does, lead to a poor approach to theory testing, and it can also, in behavior-analytic experiments, discount reliability of data. At best, statistical significance is an ancillary aspect of a set of data, and therefore should play a relatively minor role in advancing a science of behavior.

Response suppression during cumulative dosing: a role for Pavlovian conditioning.

Key pecking by pigeons was maintained by a fixed-ratio 15 or a fixed-interval 15 s schedule of food presentation. Sessions consisted of six blocks that included a 4 min blackout then 2 min of schedule time or six food presentations. Cumulative dose-response curves were assessed by injecting saline at the start of the second block and increasing cocaine doses at the onset of subsequent blocks. Repeated cumulative dosing often shifted dose-response curves to the left, and these effects appeared to be due to the reliable correlation between smaller and larger doses administered early and later in the session. When saline was substituted for the larger doses later in the session, dose-response curves initially remained shifted to the left, and continued substitution eventually resulted in curves shifting to the right. Cumulative dosing was compared with two noncumulative dosing procedures: (a) pre-session dosing and (b) one cocaine injection at the block in which the same cumulative dose would be tested, with saline injections at the other blocks (except the first). Noncumulative dosing tended to produce more reliable (repeatable) results than did cumulative dosing, and at least one interpretation is the possibility of conditioning factors that may be present in cumulative-dosing but not in noncumulative-dosing procedures.

Effects of variable-interval value and amount of training on stimulus generalization.

In Experiment 1 pigeons pecked a key that was illuminated with a 501-nm light and obtained food by doing so according to a variable-interval (VI) schedule of reinforcement, the mean value of which differed across groups: either 30 s, 120 s, or 240 s. The pigeons in all three groups were trained for 10 50-min sessions. Generalization testing was conducted in extinction with different wavelengths of light. Absolute and relative generalization gradients were similar in shape for the three groups. Experiment 2 was a systematic replication of Experiment 1 using line orientation as the stimulus dimension and a mean VI value of either 30 s or 240 s. Again, gradients of generalization were similar for the two groups. In Experiment 3 pigeons pecked a key that was illuminated with a 501-nm light and obtained food reinforcers according to either a VI 30-s or a 240-s schedule. Training continued until response rates stabilized (> 30 sessions). For subjects trained with the 30-s schedule, generalization gradients were virtually identical regardless of whether training was for 10 sessions (Experiment 1) or until response rates stabilized. For subjects trained with the VI 240-s schedule, absolute generalization gradients for subjects trained to stability were displaced upward relative to gradients for subjects trained for only 10 sessions (Experiment 1), and relative generalization gradients were slightly flatter. These results indicate that the shape of a generalization gradient does not necessarily depend on the rate of reinforcement during 10-session single-stimulus training but that the effects of prolonged training on stimulus generalization may be schedule dependent.

Effects of step size and break-point criterion on progressive-ratio performance.

Key pecking by pigeons was maintained by arithmetic progressive-ratio schedules of food delivery. Successive conditions arranged different step sizes, and each condition remained in effect until behavior appeared stable. Each session continued until a period of time passed in which no key pecks were recorded (the break-point criterion); both a 5-min and a 15-min criterion were tested across a range of step sizes. Average breaking points (i.e, the largest ratio completed) were relatively unaffected by step-size magnitude, whereas the average number of ratios completed and average response rates generally declined across increasing step sizes. Within sessions, preratio pauses were relatively short and fairly constant in duration as the ratio increased; pause durations increased rapidly near the end of a session. The relation between the average number of completed ratios and step size was described well by a power function [y = b(xa), in which y represents the average number of completed ratios, x represents the step size, and a and b are fitted parameters]. Increasing the break-point criterion from 5 to 15 min resulted in increased values of b, whereas parameter a was relatively unaffected and was close to -1 (consistent with the lack of effect of step size on breaking point). This function also provided an excellent description of data drawn from previous reports.

Key pecking during extinction after intermittent or continuous reinforcement as a function of the number of reinforcers delivered during training.

Key pecking by 7 pigeons was established and maintained on a multiple variable-ratio variable-ratio (VR) schedule of food presentation. The schedule in one of the components was then changed to fixed-ratio (FR) 1 for a predetermined number of reinforcers. Both components were then changed to extinction (i.e., multiple extinction, extinction). This sequence was repeated a different number of times for each pigeon to determine the relation between the number of reinforcers delivered during each component of the multiple VR FR 1 schedule and the number of responses during extinction. For most pigeons, there were fewer responses during extinction in the presence of a stimulus recently correlated with FR 1, regardless of the number of reinforcers received. The ratio of the total responses in extinction in the former VR component to the total responses in the former FR 1 component increased as the number of reinforcers delivered during each component of the multiple schedule increased. Within-subject replications of the partial-reinforcement extinction effect generally occurred, and there were no overall reductions in the number of responses in extinction with repeated exposures to extinction.

Relations between dose magnitude, subject sensitivity, and the development of tolerance to cocaine-induced behavioral disruptions in pigeons.

Keypecking by 12 pigeons, maintained by a fixed-ratio 30 schedule of food presentation, was decreased in rate by acute pre-session injections of cocaine in a dose-dependent manner, with larger doses producing more disruption. A constant dose of cocaine was then injected prior to every session for 40 days. Some subjects received a relatively small dose, some received a medium-sized dose, and others received a large dose. Subsequently, dose-effects were reassessed via once-weekly probe injections, with every other session continuing to be preceded by injection of the daily dose of cocaine. Then a different dose of cocaine was administered daily for 40 more days, after which the dose-effect function was redetermined in like manner. In general, tolerance to cocaine-induced response-rate reductions was most likely to develop when (a) the repeatedly-administered dose of cocaine was relatively small (even without acute effect on keypecking) and (b) the subject's keypecking was disrupted by smaller doses of cocaine in the initial dose-effect assessment. Tolerance was generally observed as a shift in the dose-effect function that, in several cases, could be eliminated by increasing the magnitude of the daily administered dose. In addition, every subject's rate of keypecking following saline injections was lowered after daily exposure to cocaine. These results (a) are partially consistent with the reinforcement-loss account of tolerance to cocaine-induced behavioral disruptions, and (b) support previous observations of withdrawal symptoms following cessation of extended exposure to cocaine.

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

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

Cocaine and food deprivation: effects on food-reinforced fixed-ratio performance in pigeons.

Key pecking by 6 pigeons was maintained by a fixed-ratio 30 schedule of food presentation while body weights were 80% of free-feeding weights. Acute administration of cocaine (0.3 to 13.0 mg/kg, i.m.) dose-dependently decreased response rates. Dose-effect curves were shifted to the right when 3 of the 6 pigeons were maintained at 70% of free-feeding weights and were shifted to the left when the other 3 pigeons were maintained at 90% of free-feeding weights. Then a dose of cocaine that initially decreased response rates by more than 95% of control rates was administered before each daily session. Comparable degrees of tolerance to these rate-decreasing effects developed in the two groups. The rate at which responding recovered was relatively rapid for pigeons in the 70% free-feeding-weight group and was slower for 2 of the 3 pigeons in the 90% free-feeding-weight group. When body weights were then increased from 70% to 80% or were decreased from 90% to 80% of free-feeding weight, performance was disrupted initially only for pigeons whose weight went from 70% to 80% of free feeding. In the present experiment the degree of deprivation may have indirectly influenced the degree of tolerance that developed to cocaine's response rate-decreasing effects because it directly influenced the dose chosen to be administered chronically. The degree of deprivation appeared to have a more direct influence on the rate at which tolerance developed.

Persistence of tolerance to effects of cocaine on schedule-controlled behavior in pigeons.

Keypecking by seven pigeons, maintained by a fixed-ratio 30 schedule of food presentation, was decreased in rate by acute pre-session administration of cocaine. In Part 1 (four pigeons), tolerance to the rate-suppressing effects of cocaine developed during daily administration conditions. Tolerance persisted (1) when daily cocaine injections were replaced by conditions in which cocaine was administered every other day, then every fourth day, then every eighth day, then every 16th day, with all intervening sessions preceded by saline injections and (2) when daily cocaine administration was replaced abruptly by a condition in which cocaine injections were spaced 16 days apart, with all intervening sessions preceded by saline. In Part 2 (three pigeons), tolerance developed during intermittent administration conditions (e.g. cocaine injected every eighth day) for two subjects, and during daily administration for the third subject. As in Part 1, tolerance persisted when cocaine was administered only once every 16 days. These results are consistent with an interpretation of tolerance based upon operant compensatory reactions to drug-induced behavioral disruptions and suggest that a simple associationist model of tolerance to cocaine-induced response-rate suppression may be inadequate. The data also have practical implications regarding tolerance development during intermittent administration conditions similar to conventional acute dose-effect determination procedures.

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.

Key pecking of pigeons under variable-interval schedules of briefly signaled delayed reinforcement: effects of variable-interval value.

Key pecking of 4 pigeons was maintained under a multiple variable-interval 20-s variable-interval 120-s schedule of food reinforcement. When rates of key pecking were stable, a 5-s unsignaled, nonresetting delay to reinforcement separated the first peck after an interval elapsed from reinforcement in both components. Rates of pecking decreased substantially in both components. When rates were stable, the situation was changed such that the peck that began the 5-s delay also changed the color of the keylight for 0.5 s (i.e., the delay was briefly signaled). Rates increased to near-immediate reinforcement levels. In subsequent conditions, delays of 10 and 20 s, still briefly signaled, were tested. Although rates of key pecking during the component with the variable-interval 120-s schedule did not change appreciably across conditions, rates during the variable-interval 20-s component decreased greatly in 1 pigeon at the 10-s delay and decreased in all pigeons at the 20-s delay. In a control condition, the variable-interval 20-s schedule with 20-s delays was changed to a variable-interval 35-s schedule with 5-s delays, thus equating nominal rates of reinforcement. Rates of pecking increased to baseline levels. Rates of pecking, then, depended on the value of the briefly signaled delay relative to the programmed interfood times, rather than on the absolute delay value. These results are discussed in terms of similar findings in the literature on conditioned reinforcement, delayed matching to sample, and classical conditioning.

Changes due to food deprivation in the effects of cocaine on the responding of pigeons.

The responding of eight pigeons was maintained under a fixed-ratio 30 schedule of food reinforcement. While the pigeons were maintained at 80% of their free-feeding body weights the effects of presession injection of a range of cocaine doses (1.0 or 3.0mg/kg to 10.0 or 17.0mg/kg) were determined. The weights of one group of pigeons were then increased to between 90 and 100% of their free-feeding weights, while the other group's weights were reduced to 70% of their free-feeding weights. The effects of cocaine were determined again. Following this, pigeons' weights were adjusted to the percentage of free-feeding weight to which they had not yet been exposed, and the effects of cocaine determined a third time. Cocaine produced dose-dependent decreases in response rates. Decreases were observed at smaller cocaine doses when pigeons were relatively food-satiated (i.e. 90-100% of free-feeding weight); larger doses were required to decrease responding when pigeons were maintained at 70% free-feeding weight. If increased resistance to the behaviorally suppressive effects of cocaine when food deprivation levels are increased occurs also when cocaine is self-administered, this could help account for increases in amounts of cocaine-reinforced behavior under conditions of food deprivation.