Behavioral mechanisms of oxycodone's effects in female and male rats: Reinforcement delay and impulsive choice.

µ-Opioid agonists (e.g., morphine) typically increase impulsive choice, which has been interpreted as an opioid-induced increase in sensitivity to reinforcement delay. Relatively little research has been done with opioids other than morphine (e.g., oxycodone), or on sex differences in opioid effects, on impulsive choice. The present study investigated the effects of acute (0.1-1.0 mg/kg) and chronic (1.0 mg/kg twice/day) administration of oxycodone on choice controlled by reinforcement delay, a primary mechanism implicated in impulsive choice, in female and male rats. Rats responded under a concurrent-chains procedure designed to quantify the effects of reinforcement delay on choice within each session. For both sexes, choice was sensitive to delay under this procedure. Sensitivity to delay under baseline was slightly higher for males than females, suggesting more impulsive choice with males. When given acutely, intermediate and higher doses of oxycodone decreased sensitivity to delay; this effect was larger and more reliable in males than females. When given chronically, sex differences were also observed: tolerance developed to the sensitivity-decreasing effects in females, whereas sensitization developed in males. These data suggest that reinforcement delay may play an important role in sex differences in impulsive choice, as well as in the effects of acute and chronic administration of opioids in impulsive choice. However, drug-induced changes in impulsive choice could be related to at least two potential behavioral mechanisms: reinforcement delay and/or reinforcement magnitude. Effects of oxycodone on sensitivity to reinforcement magnitude remain to be fully characterized. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A method for studying reinforcement factors controlling impulsive choice for use in behavioral neuroscience.

Although procedures originating within the experimental analysis of behavior commonly are used in behavioral neuroscience to produce behavioral endpoints, they are used less often to analyze the behavioral processes involved, particularly at the level of individual organisms (see Soto, 2020). Concurrent-chains procedures have been used extensively to study choice and to quantify relations between various dimensions of reinforcement and preference. Unfortunately, parametric analysis of those relations using traditional steady-state, single-subject experimental designs can be time-consuming, often rendering these procedures impractical for use in behavioral neuroscience. The purpose of this paper is to describe how concurrent-chains procedures can be adapted to allow for parametric examination of effects of the reinforcement dimensions involved in impulsive choice (magnitude and delay) within experimental sessions in rats. Data are presented indicating that this procedure can produce relatively consistent within-session estimates of sensitivity to reinforcement in individual subjects, and that these estimates can be modified by neurobiological manipulation (drug administration). These data suggest that this type of procedure offers a promising approach to the study of neurobiological mechanisms of complex behavior in individual organisms, which could facilitate a more fruitful relationship between behavior analysis and behavioral neuroscience.

Effects of chlordiazepoxide on pausing during rich-to-lean transitions.

Extended pausing during discriminable transitions from rich-to-lean conditions can be viewed as escape (i.e., rich-to-lean transitions function aversively). Thus, an anxiolytic drug would be predicted to mitigate the aversiveness and decrease pausing. In the current experiment, pigeons' key pecking was maintained by a multiple fixed-ratio fixed-ratio schedule of rich (i.e., larger) or lean (i.e., smaller) reinforcers. Intermediate doses (3.0-10.0 mg/kg) of chlordiazepoxide differentially decreased median pauses during rich-to-lean transitions. Relatively small decreases in pauses occurred during lean-to-lean and rich-to-rich transitions. Effects of chlordiazepoxide on pausing occurred without appreciable effects on run rates. These findings suggest that signaled rich-to-lean transitions function aversively.

Effects of oxycodone on sensitivity to reinforcement magnitude: implications for effects of opioids on impulsive and risky choice.

Opioid addiction/dependence is associated with impulsive and risky behavior. Moreover, opioids can increase impulsive choice in preclinical studies with nonhumans. The objective of this study was to investigate a potential behavioral mechanism of opioids: a change in the impact of reinforcement magnitude on choice. Rats (n = 7) chose between smaller and larger reinforcers under a continuous-choice (concurrent-chains) procedure. The levers associated with the smaller and larger reinforcers alternated every five sessions. During baseline under this procedure, rats showed a reliable preference for the larger reinforcer. Effects of several doses (0.1-1.7 mg/kg, s.c.) of the prescription opioid, oxycodone, were examined on preference based upon reinforcement magnitude. Oxycodone dose-dependently decreased preference for the larger reinforcer (i.e. decreased sensitivity to reinforcement magnitude). The decrease in sensitivity to reinforcement magnitude was selective in that the intermediate doses did not affect, or had minimal impact on, other measures of performance (e.g. on general motivation to respond). These data suggest that a decrease in the sensitivity to reinforcement magnitude is a reliable outcome of µ-opioid administration, an effect that has important implications for the impact of these drugs on both impulsive and risky behavior.

Assessing functions of stimuli associated with rich-to-lean transitions using a choice procedure.

Under fixed-ratio schedules, transitions from more to less favorable conditions of reinforcement (rich-to-lean transitions) usually generate extended pausing. One possible explanation for this effect is that stimuli associated with rich-to-lean transitions are aversive and, thus, extended pausing functions as escape. The purpose of this study was to characterize further the aversive function of different transitions, and the stimuli associated with them, by allowing pigeons to choose to complete select ratios in the presence of either a mixed-schedule stimulus or a transition-specific multiple-schedule stimulus. The mixed schedule was preferred during transitions that signaled an upcoming lean reinforcer (rich-to-lean and lean-to-lean), whereas the multiple schedule was preferred during transitions that signaled an upcoming rich reinforcer (lean-to-rich and rich-to-rich). These findings support the notion that stimuli associated with rich-to-lean (and to some extent lean-to-lean) transitions can function aversively; whereas stimuli associated with other transitions (e.g., lean-to-rich and rich-to-rich) can function as conditioned reinforcers. When the opportunity to choose between schedule-correlated stimuli was available, however, choice latency was controlled exclusively by the multiple-schedule stimulus. That is, the opportunity to select the mixed schedule did not attenuate rich-to-lean pauses, suggesting that extended pausing may be more than simply escape.

Escape from rich-to-lean transitions: Stimulus change and timeout.

Extended pausing during discriminable transitions from rich-to-lean conditions can be viewed as escape (i.e., rich-to-lean transitions function aversively). In the current experiments, pigeons' key pecking was maintained by a multiple fixed-ratio fixed-ratio schedule of rich or lean reinforcers. Pigeons then were provided with another, explicit, mechanism of escape by changing the stimulus from the transition-specific stimulus used in the multiple schedule to a mixed-schedule stimulus (Experiment 1) or by producing a period of timeout in which the stimulus was turned off and the schedule was suspended (Experiment 2). Overall, escape was under joint control of past and upcoming reinforcer magnitudes, such that responses on the escape key were most likely during rich-to-lean transitions, and second-most likely during lean-to-lean transitions. Even though pigeons pecked the escape key, they paused before doing so, and the latency to begin the fixed ratio (i.e., the pause) remained extended during rich-to-lean transitions. These findings suggest that although the stimulus associated with rich-to-lean transitions functioned aversively, pausing is more than simply escape responding from the stimulus.

Effects of methylphenidate on sensitivity to reinforcement delay and to reinforcement amount in pigeons: Implications for impulsive choice.

Methylphenidate has been shown to decrease impulsive choice (increase choices of a larger more delayed reinforcer). The purpose of this study was to investigate 2 potential behavioral mechanisms of this effect: a drug-induced change in control by reinforcement delay (Experiment 1) and/or by reinforcement amount (Experiment 2). In Experiment 1, pigeons responded under a rapid-acquisition, concurrent-chains choice procedure involving delay to reinforcement; the option with the shorter delay varied unpredictably across sessions. The pigeons accurately tracked the shorter delay across sessions (i.e., a preference for the option with the shorter delay developed within each session). Methylphenidate selectively decreased sensitivity to reinforcement delay-it attenuated the acquisition of preference at doses that did not systematically affect bias or response rates. In Experiment 2, pigeons responded under a rapid-acquisition, concurrent-chains choice procedure involving reinforcement amount. The pigeons accurately tracked the option with the larger reinforcement amount across sessions. Methylphenidate selectively decreased sensitivity to reinforcement amount-it attenuated the acquisition of preference at doses that did not systematically affect bias or response rates. These data suggest that methylphenidate attenuates the degree to which the various reinforcement dimensions control choice, and that drug effects on impulsive choice depend upon the relative contributions of drug-induced changes in control of behavior by each relevant dimension. (PsycINFO Database Record

Limits to preference and the sensitivity of choice to rate and amount of food.

Studies of choice holding food-amount ratio constant while varying food-rate ratio within sessions showed that local changes in preference depend on relative amount of food. The present study investigated whether sensitivity of choice to food-rate ratio and sensitivity to food-amount ratio are independent of one another when food-rate ratios are varied across sessions and food-amount ratios are varied within sessions. Food deliveries for rats' presses on the left and right levers were scheduled according to three different food-rate ratios of 1:1, 9:1, and 1:9; each food-rate ratio lasted for 106 sessions and was arranged independently of seven food-amount ratios (7:1, 6:2, 5:3, 4:4, 3:5, 2:6, and 1:7 food pellets) occurring within sessions in random sequence. Each amount ratio lasted for 10 food deliveries and was separated from another by a 60-s blackout. Sensitivity to rate ratio was high (1.0) across food deliveries. Sensitivity to amount ratio was low when food rates were equal across alternatives, but was high when rate ratio and amount ratio opposed one another. When rate ratio and amount ratio went in the same direction, choice ratio reached an elevenfold limit which reduced sensitivity to approximately zero. We conclude that three factors affect sensitivity to amount: (1) the limit to preference, (2) the equal effect on preference of amounts greater than four pellets, and (3) the absence of differential effects of switches in amount in the equal-rates (1:1) condition. Taken together, these findings indicate that rate and amount only sometimes combine independently as additive variables to determine preference when amount ratios vary frequently within sessions.

Concurrent performance as bouts of behavior.

Log-survivor analyses of interresponse times suggest that the behavior of rats responding under single variable-interval schedules is organized into bouts (i.e., periods of engagement and disengagement). Attempts to generalize this analysis to the key pecking in pigeons, however, have failed to produce the characteristic broken-stick appearance typically obtained with rats. This failure may be due to a relatively low rate of reinforcement for engaging in alternative behavior experienced by pigeons. The present study tested this hypothesis by exposing four pigeons to concurrent schedules of reinforcement for key pecking, first without a changeover delay (COD) and then with a COD. In this arrangement, one of the concurrent options was treated as the target response and the rate of reinforcement for that option was manipulated across conditions. The other option provided explicit reinforcement for engaging in an alternative response (i.e., explicit reinforcement for disengaging from the target response). In the absence of a COD, log-survivor plots for three of the pigeons were approximately linear, thus providing no evidence that responding was organized into bouts. When a COD was present, plots were broken stick in appearance, indicating a bout structure had been generated in the pigeons' behavior. Both bout length and the rate of bout initiations were a function of differences in rate of reinforcement. These data suggest that behavior may become organized into bouts when contingencies create sufficiently long visits to both the target behavior and the extraneous behavior. Fits of a double-exponential model deviated systematically from the actual plots due to the presence of a plateau between the two limbs. An alternative, double-gamma, model was explored, and it provided a considerably better fit than did the double-exponential.

Preference pulses without reinforcers.

Preference pulses are thought to represent strong, short-term effects of reinforcers on preference in concurrent schedules. However, the general shape of preference pulses is substantially determined by the distributions of responses-per-visit (visit lengths) for the two choice alternatives. In several series of simulations, we varied the means and standard deviations of distributions describing visits to two concurrently available response alternatives, arranged "reinforcers" according to concurrent variable-interval schedules, and found a range of different preference pulses. Because characteristics of these distributions describe global aspects of behavior, and the simulations assumed no local effects of reinforcement, these preference pulses derive from the visit structure alone. This strongly questions whether preference pulses should continue to be interpreted as representing local effects of reinforcement. We suggest an alternative approach whereby local effects are assessed by subtracting the artifactual part, which derives from visit structure, from the observed preference pulses. This yields "residual" preference pulses. We illustrate this method in application to published data from mixed dependent concurrent schedules, revealing evidence that the delivery of reinforcers had modest lengthening effects on the duration of the current visit, a conclusion that is quantitatively consistent with early research on short-term effects of reinforcement.

Choice in a variable environment: effects of d-amphetamine on sensitivity to reinforcement.

Four pigeons responded under a 7-component mixed schedule in which each component arranged a different left:right reinforcer ratio (27:1, 9:1, 3:1, 1:1, 1:3, 1:9, 1:27). Components were unsignaled, and the order within each session was randomly determined. After extensive exposure to these contingencies, effects of a range of doses of d-amphetamine (0.3-5.6mg/kg) on estimates of sensitivity to reinforcement at several levels of analysis were assessed. Under non-drug conditions, the structure of choice was similar to that previously reported under this procedure. That is, responding adjusted within components to the reinforcer ratio in effect (i.e., sensitivity estimates were higher in the 2nd than in the 1st half of components), and individual reinforcers produced "preference pulses" (i.e., each food presentation produced an immediate, local, shift in preference toward the response that just produced food). Although there was a general tendency for d-amphetamine to reduce overall sensitivity to reinforcement, the size of this effect and its reliability varied across pigeons. Further analysis, however, revealed that intermediate d-amphetamine doses consistently reduced sensitivity immediately following reinforcer presentations; that is, these doses consistently attenuated preference pulses.

Development and maintenance of choice in a dynamic environment.

Four pigeons were exposed to a concurrent procedure similar to that used by Davison, Baum, and colleagues (e.g., Davison & Baum, 2000, 2006) in which seven components were arranged in a mixed schedule, and each programmed a different left∶right reinforcer ratio (1∶27, 1∶9, 1∶3, 1∶1, 3∶1, 9∶1, 27∶1). Components within each session were presented randomly, lasted for 10 reinforcers each, and were separated by 10-s blackouts. These conditions were in effect for 100 sessions. When data were aggregated over Sessions 16-50, the present results were similar to those reported by Davison, Baum, and colleagues: (a) preference adjusted rapidly (i.e., sensitivity to reinforcement increased) within components; (b) preference for a given alternative increased with successive reinforcers delivered via that alternative (continuations), but was substantially attenuated following a reinforcer on the other alternative (a discontinuation); and (c) food deliveries produced preference pulses (immediate, local, increases in preference for the just-reinforced alternative). The same analyses were conducted across 10-session blocks for Sessions 1-100. In general, the basic structure of choice revealed by analyses of data from Sessions 16-50 was preserved at a smaller level of aggregation (10 sessions), and it developed rapidly (within the first 10 sessions). Some characteristics of choice, however, changed systematically across sessions. For example, effects of successive reinforcers within a component tended to increase across sessions, as did the magnitude and length of the preference pulses. Thus, models of choice under these conditions may need to take into account variations in behavior allocation that are not captured completely when data are aggregated over large numbers of sessions.

Rapid acquisition of preference in concurrent schedules: effects of d-amphetamine on sensitivity to reinforcement amount.

In the present study, effects of d-amphetamine on sensitivity to reinforcement amount under concurrent schedules were examined using a rapid-acquisition procedure. Four pigeons key pecked under single concurrent variable-interval 30-s schedules of grain presentation. Two different reinforcer-amount ratios (7:1 and 1:7) changed across sessions according to a 31-step pseudo-random binary sequence (PRBS). After at least four times through the PRBS, response ratios generally tracked the session-to-session changes in amount ratios; estimates of sensitivity ranged from 0.26 to 0.31 across the four pigeons. Effects of a range of doses of d-amphetamine (0.3-5.6mg/kg) then were determined. For 3 of 4 pigeons, at least one dose, which did not dramatically alter overall response output or bias, decreased sensitivity to reinforcement amount. These results suggest that reducing sensitivity of responding to reinforcement amount may be one behavioral mechanism of stimulants, which may have implications for interpreting drug effects on self-control.

Effects of d-amphetamine on behavior maintained by signaled and unsignaled delays to reinforcement.

Four pigeons responded under a progressive-delay procedure. In a signaled-delay condition, a chained variable interval (VI) 30-s progressive time (PT) 4-s schedule was arranged; in an unsignaled-delay condition, a tandem VI 30-s PT 4-s schedule was arranged. Two pigeons experienced a signaled-unsignaled-signaled sequence; whereas, two pigeons experienced an unsignaled-signaled-unsignaled sequence. Effects of saline and d-amphetamine were determined under each condition. At intermediate doses (1.0 and 1.78m/kg) delay functions were shallower, area under the curve was increased, and, when possible, break points were increased compared to saline; these effects were not systematically related to signaling conditions. These effects on control by delay often were accompanied by decreased response rates at 0s. These results suggest that stimulus conditions associated with the delay may not play a crucial role in effects of d-amphetamine and other stimulants on behavior controlled by reinforcement delay.

Rapid acquisition of preference in concurrent chains: effects of d-amphetamine on sensitivity to reinforcement delay.

The purpose of this study was to examine effects of d-amphetamine on choice controlled by reinforcement delay. Eight pigeons responded under a concurrent-chains procedure in which one terminal-link schedule was always fixed-interval 8 s, and the other terminal-link schedule changed from session to session between fixed-interval 4 s and fixed-interval 16 s according to a 31-step pseudorandom binary sequence. After sufficient exposure to these contingencies (at least once through the pseudorandom binary sequence), the pigeons acquired a preference for the shorter reinforcement delay within each session. Estimates of the sensitivity to reinforcement immediacy were similar to those obtained in previous studies. For all pigeons, at least one dose of d-amphetamine attenuated preference and, hence, decreased estimates of sensitivity to reinforcement immediacy; in most cases, this effect occurred without a change in overall response rates. In many cases, the reduced sensitivity to reinforcement delay produced by d-amphetamine resulted primarily from a decrease in the asymptotic level of preference achieved within the session; in some cases, d-amphetamine produced complete indifference. These findings suggest that a reduction in the sensitivity to reinforcement delay may be an important behavioral mechanism of the effects of psychomotor stimulants.

Rapid acquisition of preference in concurrent schedules: effects of reinforcement amount.

Four pigeons were trained on concurrent variable-interval 30-s schedules. Relative reinforcer amounts arranged across the two alternatives were varied across sessions according to a pseudorandom binary sequence [cf., Hunter, I., Davison, M., 1985. Determination of a behavioral transfer function: white-noise analysis of session-to-session response-ratio dynamics on concurrent VI schedules. J. Exp. Anal. Behav. 43, 43-59]; the ratios (left/right) were either 1/7 or 7/1. Reinforcer amount was manipulated by varying the number of 1.2s hopper presentations. Sessions ended after 30 reinforcers (15 for each alternative). After approximately 30 sessions, response ratios for all pigeons began to track the changes in amount ratio (i.e., subjects' responding showed a moderate increase in sensitivity of responding to reinforcer amount). Characteristics of responding were similar to procedures in which reinforcer rate and immediacy have been manipulated, although sensitivity estimates for amount were lower than those previously obtained with rate and immediacy. This procedure may serve as a useful method for studying the effects of certain environmental manipulations (e.g., drug administration) on sensitivity to reinforcer amount.

Effects of methamphetamine on response rate: a microstructural analysis.

Key pecking in pigeons was maintained under a multiple random-interval (RI) 1-min, RI 4-min schedule of food presentation. Several doses (0.3-5.6 mg/kg) of methamphetamine were administered, and effects on overall response rates and on the microstructure of responding were characterized. In three of the four pigeons, methamphetamine dose-dependently decreased overall response rate in both components; in the fourth pigeon, intermediate doses increased response rates. Log-survivor analyses did not produce the clear "broken-stick" pattern previously reported with rats [Shull, R.L., Gaynor, S.T., Grimes, J.A., 2001. Response rate viewed as engagement bouts: effects of relative reinforcement and schedule type. J. Exp. Anal. Behav. 75, 247-274]. A fine-grained analysis of inter-response times (IRTs) revealed clear bands of responding around certain IRT durations. Methamphetamine tended to decrease the frequency of IRTs in the shorter bands and increase the frequency of IRTs across all bins greater than 2s. These results suggest that (a) survivor analyses may not extend to pigeon key pecking, (b) microstructural analyses can reveal order not evident with overall response rate, and (c) a detailed analysis of responding might prove more useful than summary measures in characterizing drug effects on behavior.

Morphine tolerance as a function of ratio schedule: response requirement or unit price?

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.