Random interval schedule of reinforcement influences punishment resistance for cocaine in rats.

In an animal model of compulsive drug use, a subset of rats continues to self-administer cocaine despite footshock consequences and is considered punishment resistant. We recently found that punishment resistance is associated with habits that persist under conditions that typically encourage a transition to goal-directed control. Given that random ratio (RR) and random interval (RI) schedules of reinforcement influence whether responding is goal-directed or habitual, we investigated the influence of these schedules on punishment resistance for cocaine or food. Male and female Sprague Dawley rats were trained to self-administer either intravenous cocaine or food pellets on a seeking-taking chained schedule of reinforcement, with the seeking lever requiring completion of either an RR20 or RI60 schedule. Rats were then given four days of punishment testing with footshock administered at the completion of seeking on a random one-third of trials. For cocaine-trained rats, the RI60 schedule led to greater punishment resistance (i.e., more trials completed) than the RR20 schedule in males and females. For food-trained rats, the RI60 schedule led to greater punishment resistance (i.e., higher reward rates) than the RR20 schedule in female rats, although male rats showed punishment resistance on both RR20 and RI60 schedules. For both cocaine and food, we found that seeking responses were suppressed to a greater degree than reward rate with the RI60 schedule, whereas response rate and reward rate were equally suppressed with the RR20 schedule. This dissociation between punishment effects on reward rate and response rate with the RI60 schedule can be explained by the nonlinear relation between these variables on RI schedules, but it does not account for the enhanced resistance to punishment. Overall, the results show greater punishment resistance with the RI60 schedule as compared to the RR20 schedule, indicating that schedules of reinforcement are an influencing factor on resistance to negative consequences.

Resurgence mitigation across extended extinction following four and eight cycles of on/off alternative reinforcement.

Resurgence is an increase in an extinguished operant response resulting from a worsening of conditions (e.g., extinction) for a more recently reinforced alternative behavior. Previous research has shown that exposure to cycles of alternative reinforcement available versus unavailable (i.e., on/off alternative reinforcement) across sessions can reduce subsequent resurgence. Most previous assessments of the procedure have examined target operant responding during only single-session resurgence tests, and it remains unclear if exposure to relatively few cycles of on/off alternative reinforcement can maintain low rates of target behavior across extended exposure to extinction. This experiment with rats examined the effects of 4 or 8 cycles of on/off alternative reinforcement on subsequent resurgence during a 10-session extinction test. The results show that exposure to 4 cycles of on/off alternative reinforcement is as effective as 8 cycles in producing low rates of target behavior during treatment and across extended extinction. This result is consistent with extant theories of resurgence and suggests that on/off alternative reinforcement could have translational utility following relatively few cycles of exposure.

Punishment-induced resurgence.

The phenomenon of extinction-induced resurgence is well established, but there is comparatively little experimental evidence for punishment-induced resurgence. Punishment-induced resurgence can by tested by contingent shocks following the alternative response. The purpose of Experiment 1 was to test whether low-intensity shocks, that do not decrease rate of reinforcement, result in resurgence. Four rats served as subjects. Rats were exposed to three sequential conditions: (a) variable-interval (VI) 30-s food delivery for a lever press (target response); (b) VI 30-s food delivery for a nose poke (alternative response) and extinction of the lever press; (c) VI 30-s reinforcement for a nose poke with superimposed VI 60-s shock delivery. In the final condition, shocks increased gradually from 0.1 to 0.5 mA. Experiment 2 evaluated whether an abrupt introduction of a high-intensity shock would result in resurgence. Three rats served as subjects and were exposed to three sequential conditions: (a) VI 30-s food delivery for a lever press; (b) VI 30-s food delivery for a nose poke and extinction of the lever press; (c) continued VI 30-s reinforcement for a nose poke with superimposed VI 60-s 0.6 mA shock delivery. Resurgence was observed in all subjects, including in situations in which rate of responding, but not rate of reinforcement, decreased. The present study provides additional evidence for punishment-induced resurgence, but future studies are warranted to determine the extent to which punishment can produce resurgence with or without decreases in rates of reinforcement.

Comparison of synchronous reinforcement and accumulated reinforcement for increasing on-task behavior in preschoolers.

In synchronous-reinforcement schedules, the duration of behavior directly controls the duration of reinforcement on a moment-to-moment basis. We replicated and extended Diaz de Villegas et al. (2020) by comparing the effects of synchronous reinforcement with two accumulated-reinforcement schedules for increasing on-task behavior for seven preschoolers. One accumulated schedule was the same as the one used in Diaz de Villegas et al. and did not include tokens, whereas the other accumulated schedule included the delivery of tokens within session. Furthermore, we assessed preference for the three reinforcement schedules. The results showed that synchronous reinforcement was effective for increasing on-task behavior for all seven participants. Furthermore, it was most effective for increasing on-task behavior for three out of seven participants and preferred by all participants. For some participants, other schedules were also similarly effective. The results are discussed with respect to implications for application.

Assessing stimulus preference using response force in a conjugate preparation: A replication and extension.

The current study examined 98 participants' preferences for five pictorial stimuli. The researchers used a verbal multiple-stimulus-without-replacement (VMSWO) preference assessment with each participant to identify high-preference and low-preference pictorial stimuli. Next, participants viewed each pictorial stimulus in a randomized order on a computer while using a hand dynamometer that measured the amount of force they exerted to increase or maintain the visual clarity of each image. The results indicate that over 75% of participants' force response ranks corresponded with participants' VMSWO high-preference stimuli, VMSWO low-preference stimuli, or both. The results of the current study provide further evidence for the use of conjugate schedules in the assessment of stimulus preference with potential for use as a reinforcer assessment. Implications along with directions for future research and limitations of the findings are discussed.

Treatments for undefined log ratios in matching analyses.

A challenge in carrying out matching analyses is to deal with undefined log ratios. If any reinforcer or response rate equals zero, the logarithm of the ratio is undefined: data are unsuitable for analyses. There have been some tentative solutions, but they had not been thoroughly investigated. The purpose of this article is to assess the adequacy of five treatments: omit undefined ratios, use full information maximum likelihood, replace undefined ratios by the mean divided by 100, replace them by a constant 1/10, and add the constant .50 to ratios. Based on simulations, the treatments are compared on their estimations of variance accounted for, sensitivity, and bias. The results show that full information maximum likelihood and omiting undefined ratios had the best overall performance, with negligibly biased and more accurate estimates than mean divided by 100, constant 1/10, and constant .50. The study suggests that mean divided by 100, constant 1/10, and constant .50 should be avoided and recommends full information maximum likelihood to deal with undefined log ratios in matching analyses.

Effects of self- and experimenter-administered cocaine on subsequent ethanol drinking in rhesus monkeys.

BACKGROUND: One possible reason for the lack of FDA-approved pharmacotherapies to treat cocaine use disorder (CUD) is that, although cocaine is typically used in combination with alcohol, it is studied in isolation in preclinical studies. A better understanding of the cocaine-alcohol interactions that promote polysubstance use (PSU) will improve animal models of CUD and hasten pharmacotherapy development. We used a rhesus monkey model of cocaine-alcohol PSU to investigate one possible mechanism: that alcohol is used to mitigate negative effects associated with termination of cocaine use. METHODS: In 6 adult male rhesus monkeys, the relationship between self-administered cocaine intake and oral ethanol intake 2hours later was examined during self-administration of cocaine (0.0003-0.3mg/kg per injection, i.v.) under a fixed-ratio 30 schedule (FR30) or a progressive-ratio (PR) schedule. Next, ethanol consumption was measured 0-120minutes after experimenter-administered cocaine (0.3-1.7mg/kg, i.v.). RESULTS: Self-administered cocaine intake under both FR30 and PR schedules was unrelated to oral ethanol intakes 2hours later. When cocaine was administered non-contingently, cocaine decreased ethanol intake as well as intake of a non-alcoholic solution in monkeys who never consumed ethanol (n=4) in a time- and dose-dependent manner. CONCLUSIONS: Taken together, the results do not provide evidence for cocaine-induced increases in ethanol consumption. By extension, the results do not support the hypothesis that cocaine users drink alcohol to counteract negative effects that occur after terminating use. This finding implies either that such effects do not exist or that such effects exist but are unaffected by ethanol.

The active time model of concurrent choice.

The following paper describes a steady-state model of concurrent choice, termed the active time model (ATM). ATM is derived from maximization principles and is characterized by a semi-Markov process. The model proposes that the controlling stimulus in concurrent variable-interval (VI) VI schedules of reinforcement is the time interval since the most recent response, termed here "the active interresponse time" or simply "active time." In the model after a response is generated, it is categorized by a function that relates active times to switch/stay probabilities. In the paper the output of ATM is compared with predictions made by three other models of operant conditioning: melioration, a version of scalar expectancy theory (SET), and momentary maximization. Data sets considered include preferences in multiple-concurrent VI VI schedules, molecular choice patterns, correlations between switching and perseveration, and molar choice proportions. It is shown that ATM can account for all of these data sets, while the other models produce more limited fits. However, rather than argue that ATM is the singular model for concurrent VI VI choice, a consideration of its concept space leads to the conclusion that operant choice is multiply-determined, and that an adaptive viewpoint-one that considers experimental procedures both as selecting mechanisms for animal choice as well as tests of the controlling variables of that choice-is warranted.

Application of a terminal schedule probe method to inform schedule thinning with multiple schedules.

Multiple schedules are effective at decreasing challenging behavior and maintaining alternative behavior at acceptable levels. Currently, no conclusive guidance is available for empirically deriving multiple-schedule components (continuous reinforcement for alternative behavior and extinction for challenging behavior [discriminative stimulus] and extinction for both alternative and challenging behavior [delta stimulus]) during the schedule-thinning process. In the current investigation, we describe a terminal schedule probe method to determine delta stimulus starting points and strategies for subsequent schedule-thinning progressions to reach caregiver-informed terminal schedules. We review schedule-thinning outcomes for a clinical cohort using a consecutive controlled case series approach and report results for two groups: One group included applications of terminal probe thinning (n = 24), and the other involved traditional dense-to-lean thinning (n = 18). Outcomes suggest that the terminal schedule probe method produced effective treatments with less resurgence of challenging behavior and leaner, more feasible, multiple schedules.

Resurgence of destructive behavior following decreases in alternative reinforcement: A prospective analysis.

Basic and retrospective translational research has shown that the magnitude of resurgence is determined by the size of the decrease in alternative reinforcement, with larger decreases producing more resurgence. However, this finding has not been evaluated prospectively with a clinical population. In Experiment 1, five participants experienced a fixed progression of reinforcement schedule-thinning steps during treatment of their destructive behavior. Resurgence occurred infrequently across steps and participants, and when resurgence did occur, its clinical meaningfulness was often minimal. In Experiment 2, five new participants experienced these same schedule-thinning steps but in a counterbalanced order. Resurgence occurred most often and was generally largest with larger decreases in alternative reinforcement programmed earlier in the evaluation. Large decreases in alternative reinforcement may be more problematic clinically when they occur earlier in treatment. Whether larger transitions can be recommended in the clinic following the success of smaller ones will require additional research.

Examination of clinical variables affecting resurgence: A reanalysis of 46 applications.

Despite the efficacy of behavioral interventions, resurgence of challenging behavior (e.g., aggression, self-injury) following successful treatment can still occur. Applied work has focused on identifying treatment-related variables thought to affect the occurrence and magnitude of resurgence. The current study describes the relation between several variables (i.e., phase duration, response rates in baseline and treatment, obtained rates of reinforcement, downshift in reinforcement step size) and resurgence in a retrospective consecutive controlled case series of 46 treatment applications for challenging behavior conducted in an inpatient setting. Only the downshift in reinforcement (e.g., schedule-thinning) step size was correlated with the magnitude of resurgence. These results are consistent with recent findings suggesting that treatment duration and other factors have inconsistent effects on resurgence of challenging behavior.

Hyperbolae.

Hyperbolic relations between independent and dependent variables are ubiquitous in the experimental analysis of behavior, mentioned in over 150 articles in the Journal of the Experimental Analysis of Behavior. There are two principal forms of hyperbolae: The first describes the relation between response rate and reinforcement rate on variable-interval schedules of reinforcement; it rises asymptotically toward a maximum. The second describes the relation between the current equivalent value of an incentive and its delay or (im)probability; it falls from a maximum toward an asymptote of 0. Where do these come from? What do their parameters mean? How are they related? This article answers the first two questions and addresses the last.

Assessing negative reinforcement through simultaneous observing and committed concurrent progressive-ratio procedures: Preliminary investigations.

Efficient methods for assessing the relative aversiveness of stimuli are sparse and underresearched. Having access to efficient procedures that can identify aversive stimuli would benefit researchers and practitioners alike. Across three experiments, 13 participants helped to pilot, refine, and test two approaches to identifying negative reinforcers. The first experiment presented two conditions, one in which computerized button pressing started or stopped one of two recorded infant cries (or silence, when the control button was selected). Choices were presented either in a modified observing-response procedure (i.e., simultaneous observing) or in a modified progressive-ratio procedure (i.e., committed concurrent progressive ratio; CCPR). Results were favorable though not conclusive on their own. A second experiment, using more distinct stimuli (i.e., one likely aversive, one likely not aversive), replicated the first, and clearer results emerged. Finally, the third experiment tested the stimuli from the second experiment in a CCPR arrangement where sound was terminated contingent on responding and idiosyncratic negative reinforcement hierarchies emerged. The utility of these two procedures is discussed, and future work that addresses the limitations is outlined.

The generalization-across-dimensions model applied to conditional temporal discrimination.

Can simple choice conditional-discrimination choice be accounted for by recent quantitative models of combined stimulus and reinforcer control? In Experiment 1, two sets of five blackout durations, one using shorter intervals and one using longer intervals, conditionally signaled which subsequent choice response might provide food. In seven conditions, the distribution of blackout durations across the sets was varied. An updated version of the generalization-across-dimensions model nicely described the way that choice changed across durations. In Experiment 2, just two blackout durations acted as the conditional stimuli and the durations were varied over 10 conditions. The parameters of the model obtained in Experiment 1 failed adequately to predict choice in Experiment 2, but the model again fitted the data nicely. The failure to predict the Experiment 2 data from the Experiment 1 parameters occurred because in Experiment 1 differential control by reinforcer locations progressively decreased with blackout durations, whereas in Experiment 2 this control remained constant. These experiments extend the ability of the model to describe data from procedures based on concurrent schedules in which reinforcer ratios reverse at fixed times to those from conditional-discrimination procedures. Further research is needed to understand why control by reinforcer location differed between the two experiments.

Xylazine does not enhance fentanyl reinforcement in rats: A behavioral economic analysis.

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacodynamic and pharmacokinetic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer under both fixed-ratio and progressive-ratio drug self-administration procedures. Xylazine combined with fentanyl at three fixed dose-proportion mixtures did not significantly alter fentanyl reinforcement as measured using behavioral economic analyses. Xylazine produced a proportion-dependent decrease in the behavioral economic Q0 endpoint compared to fentanyl alone. However, xylazine did not significantly alter fentanyl self-administration at FR1. Fentanyl and xylazine co-administration did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. The premise for why illicitly manufacture fentanyl has been adulterated with xylazine remains to be determined.

Resurgence of ethanol seeking following voluntary abstinence produced by nondrug differential reinforcement of other behavior.

Resurgence refers to the relapse of a target behavior following the worsening of a source of alternative reinforcement that was made available during response elimination. Most laboratory analyses of resurgence have used a combination of extinction and alternative reinforcement to reduce target behavior. In contingency-management treatments for alcohol use disorder, however, alcohol use is not placed on extinction. Instead, participants voluntarily abstain from alcohol use to access nondrug alternative reinforcers. Inasmuch, additional laboratory research on resurgence following voluntary abstinence is warranted. The present experiment evaluated resurgence of rats' ethanol seeking following voluntary abstinence produced by differential reinforcement of other behavior (DRO). Lever pressing produced ethanol reinforcers during baseline phases. During DRO phases, lever pressing continued to produce ethanol and food reinforcers were delivered according to resetting DRO schedules. Ethanol and food reinforcers were suspended during resurgence test phases to evaluate resurgence following voluntary abstinence. Lever pressing was elevated during baseline phases and occurred at near-zero rates during DRO phases. During the resurgence test phases, lever pressing increased, despite that it no longer produced ethanol. The procedure introduced here may help researchers better understand the variables that affect voluntary abstinence from ethanol seeking and resurgence following voluntary abstinence.

A retrospective analysis of the relation between resurgence and renewal of behavior targeted for reduction.

Functional communication training (FCT) is an evidence-based treatment for behavior targeted for reduction that often combines extinction for target responses and arranges functionally equivalent reinforcement for alternative behavior. Long-term effectiveness of FCT can become compromised when transitioning from clinic to nonclinic contexts or thinning reinforcement schedules for appropriate behavior. Such increases in targeted behavior have been conceptualized as renewal and resurgence, respectively. The relation between resurgence and renewal has yet to be reported. Therefore, the present report retrospectively analyzed the relation between renewal and resurgence in data collected when implementing FCT with children diagnosed with developmental disabilities. We found no relation when evaluating all 34 individuals assessed for resurgence and renewal or a subset of individuals exhibiting both resurgence and renewal. These findings suggest that one form of relapse may not be predictive of another form of relapse.

Repeated Δ-9-Tetrahydrocannabinol administration dose dependently increases stablished schedule-induced drinking.

RATIONALE: Schedule-induced drinking (SID) reproduces an excessive and repetitive behavioural pattern that has led to propose this procedure as an animal model to study compulsive behaviours. Although it is known that cannabis can cause several adverse effects, in recent years there has been great interest in the medical application of cannabis derivatives for obsessive-compulsive related disorders. OBJECTIVES: The present study investigated the effects of repeated THC administration on rates of previously acquired SID, as well as the possible alteration of its temporal distribution along inter-food intervals. METHODS: Male Wistar rats acquired SID under a 30 min fixed-time 30-sec food delivery schedule (from 30 to 43 sessions to reach a stable level). Thereafter, 5 or 10 mg/kg daily i.p. injections of THC or vehicle were repeatedly administered for 7 days to evaluate the effects on SID. RESULTS: Repeated THC administration at a dose of 5 mg/kg resulted in an increase on licking. Surprisingly, no effects on SID were observed with the 10 mg/kg dose. However, magazine entries were reduced with both THC doses. THC also modified the temporal distributions of licking and magazine entries during inter-food intervals. CONCLUSIONS: The present results show that repeated THC administration may (i) increase induced licking at moderate doses, (ii) reduce magazine entries, and (iii) affect the temporal pattern of SID. These findings suggest that THC does not appear to be beneficial to reduce compulsive behaviour in this animal model, while another collateral effect of THC -such as a greater habitual-like behaviour- needs to be considered.

Intermittent nicotine access is as effective as continuous access in promoting nicotine seeking and taking in rats.

RATIONALE: Nicotine is a principal psychoactive agent in tobacco, contributing to tobacco's addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. OBJECTIVE: We determined how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. METHODS: Female and male rats had continuous (i.e., Long Access; LgA, 6 h/day) or intermittent (IntA; 12 min ON, 60 min OFF, for 6 h/day) access to intravenous nicotine (15 µg/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. RESULTS: Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. CONCLUSIONS: Intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.

Resurgence Following Higher or Lower Quality Alternative Reinforcement.

Resurgence is a temporary increase in a previously suppressed target behavior following a worsening in reinforcement conditions. Previous studies have examined how higher rates or magnitudes of alternative reinforcement affect suppression of the target behavior and subsequent resurgence. However, there has been no investigation of the effects of higher versus lower qualities of alternative reinforcement on resurgence. Using a three-phase resurgence preparation with rats, the present experiments examined the effects of an alternative reinforcer that was of higher (Experiment 1) or lower (Experiment 2) quality than the reinforcer that had previously maintained the target behavior. The results of both experiments showed greater reductions in target behavior with a higher quality alternative reinforcer and larger increases in target responding when a higher quality alternative reinforcer was removed. Along with prior findings with higher rates and magnitudes of alternative reinforcement, these findings suggest that variations in reinforcer dimensions that increase the efficacy of alternative reinforcement also tend to increase resurgence when alternative reinforcement is removed. The results are discussed in terms of the resurgence as choice in context model and in terms of potential clinical implications.