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.

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.

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.

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.

The role of stimulus combinations in the repeated assessment of resurgence.

The current study examined the role of stimulus combinations on the repeated assessment of resurgence. Using a within-session resurgence procedure, rats were exposed to different conditions, each with distinct stimulus combinations (AAA, ABA, ABB, ABC and AAB). Two arrangements of stimulus changes were compared: Experiment 1 involved changes in stimulus combinations every five sessions, while Experiment 2 implemented changes every session. Resurgence was observed in both experiments; however, Experiment 2 demonstrated more consistent and repeated resurgence when stimulus combinations changed every session. Notably, the ABA, ABB and ABC conditions showed the highest percentage of sessions in which resurgence was observed. Lastly, the current study extends the application of the within-session resurgence procedure to rats and auditory stimuli, providing a reliable method for assessing resurgence in single subjects under different variable conditions.

Assessment of the inbred C57BL/6 and outbred CD1 mouse strains using a progressive ratio schedule during development.

Inbred strains have a genetic similarity of at least 98.6% compared to their outbred counterparts. Several studies have shown that inbred C57BL/6 mice and outbred ICR (CD1) mice differ in locomotion, cognitive flexibility, and aggression. However, their performance in operant paradigms is not well understood. A progressive ratio (PR) schedule of reinforcement is a method of quantitative estimation of the incentive state of an animal for a reward by increasing response requirements for reinforcer delivery, which is relevant to assess the breakpoint (amount of response effort an animal is willing to invest for a single unit of reward). This study tested male and female C57BL/6 and CD1 mice with an open field to analyze locomotion. Then, we used conditioning chambers with a PR3 schedule for ten consecutive days (P30-P40). PR performance was measured with the breakpoint, and the mathematical principles of reinforcement (MPR) were used to estimate motivation, impulsivity, and motor skills to manipulate the operandum. We found that CD1 mice showed higher locomotor activity than C57BL/6 independently of sex. CD1 mice had a higher breakpoint. However, male CD1 mice gradually increased breakpoint until the last session. In the MPR model, CD1 mice showed decreased fixed paused parameter (impulsivity) than C57BL/6, independent of sex. Our data suggest that the higher breakpoint in CD1 strain may partially be related to impulsivity. Therefore, the MPR model can help identify factors that affect performances, such as motivation, impulsivity, and motor skills during a PR in adolescent CD1 and C57BL/6 mice. These findings are essential to characterize the differences in the behavioral performance between C57BL/6 and CD1 strains and their potential as animal models.

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.

An analysis of coordinated responding of pigeons.

Experimental analyses of coordinated responding (i.e., cooperation) have been derived from a procedure described by Skinner (1962) in which reinforcers were delivered to a pair of subjects (a dyad) if both responded within a short interval, thus satisfying a coordination contingency. Although it has been suggested that this contingency enhances rates of temporally coordinated responding, limitations of past experiments have raised questions concerning this conclusion. The present experiments addressed some of these limitations by holding the schedule of reinforcement (Experiment 1: fixed ratio 1; Experiment 2; variable interval 20 s) constant across phases and between dyad members and by varying, in different conditions, the number of response keys (one to three) across which coordination could occur. Greater percentages of coordinated responding occurred under the coordinated-reinforcement phases than under independent-reinforcement phases in most conditions. The one exception during the one-key condition of Experiment 1 appeared to be a consequence of variability introduced by the independent-reinforcement phase procedure. Furthermore, coordination percentages decreased with increasing response options under both schedules. These results confirm and extend the finding that coordination contingencies control higher rates of temporally coordinated responding than independent-reinforcement contingencies do.

A systematic review of enhanced resurgence paradigms.

Following successful treatment in which problem behavior is reduced, it may reemerge as a function of changes in contextual stimuli or the worsening of reinforcement conditions for an alternative response. Although understudied, preliminary research suggests that simultaneous changes in contextual stimuli and reinforcement conditions may represent particularly exigent treatment challenges that create the condition for additive or superadditive relapse. The purpose of the present review was to systematically examine the relapse literature involving simultaneous changes in contextual stimuli and reinforcement conditions in relapse tests and experimental preparations arranged to evaluate their effect on response recovery. We identified 16 empirical articles spanning 27 experiments. Although all experiments included at least one condition that experienced a change in contextual stimuli and worsening of alternative reinforcement conditions, only two experiments included the comparison conditions needed to precisely evaluate additive and superadditive relapse. Our findings establish the preclinical generality of relapse effects associated with simultaneous changes to reinforcement conditions and contextual stimuli across a range of subjects, schedule arrangements, response topographies, reinforcers, and types of contextual changes. We make several recommendations for future research based on our findings from this nascent and clinically relevant subdomain of the relapse literature.

Theoretical note: Quantity and concentration as co-determinants of the reinforcing value of sucrose: A re-analysis of some previously published data.

According to the Multiplicative Hyperbolic Model of reinforcer value (MHM), the overall value of a reinforcer may be defined by the multiplicative combination of a set of hyperbolic functions, each of which defines the impact of a particular feature of the reinforcer (e.g., quantity, immediacy of delivery). A previous experiment found that the relationship between the indifference volumes (qA(50)) of reinforcer A (a 0.4-M sucrose solution) and the fixed volume (qB) of reinforcer B (a 0.2-M sucrose solution: 32 - 256 µl) was consonant with this model. This paper describes a re-analysis of those data in an attempt to identify the nature of the effect of concentration on the two parameters of the size/value hyperbola (asymptote, ε, and sensitivity, Q). Comparison of two versions of the model in which (i) both parameters were free to vary as a function of qB and (ii) only ε was free to vary, showed that the latter model provided a satisfactory account of the data and that the inclusion of Q as an additional free parameter was not justified. Implications for the development of MHM are discussed.

Comparing extinction and contrast effects for operant wheel running and lever pressing on a multiple schedule.

Extinction and positive contrast effects were assessed on a multiple schedule with lever pressing as the operant in one component and wheel running as the operant in the other component. FR 15 schedules produced 15% sucrose reinforcement in each component. Contrast for both operants was generated by placing responding in the alternate component on extinction. Results showed that extinction decreased and contrast increased both lever-pressing and wheel-running rates. However, the magnitude of the changes was greater for lever pressing. Extinction increased and contrast decreased postreinforcement pause (PRP) duration for lever pressing, but for wheel running, extinction decreased PRP duration while contrast did not change PRP duration. Finally, outcomes for lever pressing decreased with extinction and increased with contrast, but for wheel running, outcomes did not change with extinction and increased with contrast. These differences in contrast and extinction effects were explained by an automatic reinforcement effect generated by wheel-running, but not lever pressing. These findings provide further support for an automatic reinforcement effect generated by wheel running.

Time, uncertainty, and suboptimal choice.

Under certain conditions, pigeons prefer information about whether food will be forthcoming at the end of an interval to a higher chance of obtaining the food. In the typical protocol, choosing one option (Informative) is followed by one of two 10-s long terminal-link stimuli: SG always ending in food or SR never ending in food, with SG occurring only 20% of the trials. The other option (Non-informative) is also followed by one of two 10-s long terminal-link stimuli: SB or SY, both ending in food 50% of the trials. Although the Informative option yields food with a lower probability than the Non-informative (0.2 vs. 0.5), pigeons prefer it. To determine whether such preference occurs because SG and SR disambiguate the trial outcome immediately upon choice, we delayed the moment the disambiguation took place in two experiments. In Experiment 1, when the Informative option was chosen, SG always ensued for t seconds of the terminal-link, and then the standard contingencies followed. Experiment 2 was similar, except that SR always ensued for t seconds. Across conditions, t varied from 0 to 10 s. In both experiments, preference for the Informative option decreased with t, but the effect was stronger in Experiment 1. We discuss the implication of these findings for functional and mechanistic models of suboptimal choice.

The effects of gonadal hormones on heroin Self-Administration in male gonadectomized rats.

RATIONALE: Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. OBJECTIVES: The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. METHODS: Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75 mg, sc), estradiol (0.0005 or 0.005 mg, sc), progesterone, (0.0125 or 0.125 mg, sc), or their vehicles. After 14 days of chronic treatment, a dose-effect curve was determined for heroin (0.0003-0.03 mg/kg/infusion) over the course of one week. RESULTS: Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125 mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. CONCLUSIONS: These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder.

Response-dependent point loss and response force as disrupting operations on behavioral resistance to change in humans.

Behavioral momentum theory (BMT) provides a theoretical and methodological framework for understanding how differentially maintained operant responding resists disruption. A common way to test operant resistance involves contingencies with suppressive effects, such as extinction or prefeeding. Other contingencies with known suppressive effects, such as response-cost procedures arranged as point-loss or increases in response force, remain untested as disruptive events within the BMT framework. In the present set of three experiments, responding of humans was maintained by point accumulation programmed according to a multiple variable-interval (VI) VI schedule with different reinforcement rates in either of two components. Subsequently, subtracting a point following each response (Experiment 1) or increasing the force required for the response to be registered (Experiments 2 and 3 decreased response rates, but responding was less disrupted in the component associated with the higher reinforcement rate. The point-loss contingency and increased response force similarly affected response rates by suppressing responding and human persistence, replicating previous findings with humans and nonhuman animals when other types of disruptive events (e.g., extinction and prefeeding) were investigated. The present findings moreover extend the generality of the effects of reinforcement rate on persistence, and thus BMT, extending the analysis of resistance to two well-known manipulations used to reduce responding in the experimental analysis of behavior.

Acquisition of cocaine reinforcement using fixed-ratio and concurrent choice schedules in socially housed female and male monkeys.

RATIONALE: Previous studies in socially housed monkeys examining acquisition of cocaine self-administration under fixed-ratio (FR) schedules of reinforcement found that subordinate males and dominant females were more vulnerable than their counterparts. OBJECTIVES: The present studies extended these findings in two ways: (1) to replicate the earlier study, in which female monkeys were studied after a relatively short period of social housing (~ 3 months) using cocaine-naïve female monkeys (n = 9; 4 dominant and 5 subordinate) living in well-established social groups (~ 18 months); and (2) in male monkeys (n = 3/social rank), we studied cocaine acquisition under a concurrent schedule, with an alternative, non-drug reinforcer available. RESULTS: In contrast to earlier findings, subordinate female monkeys acquired cocaine reinforcement (i.e., > saline reinforcement) at significantly lower cocaine doses compared with dominant monkeys. In the socially housed males, no dominant monkey acquired a cocaine preference (i.e., > 80% cocaine choice) over food, while two of three subordinate monkeys acquired cocaine reinforcement. In monkeys that did not acquire, the conditions were changed to an FR schedule with only cocaine available and after acquisition, returned to the concurrent schedule. In all monkeys, high doses of cocaine were chosen over food reinforcement. CONCLUSIONS: The behavioral data in females suggests that duration of social enrichment and stress can differentially impact vulnerability to cocaine reinforcement. The findings in socially housed male monkeys, using concurrent food vs. cocaine choice schedules of reinforcement, confirmed earlier social-rank differences using an FR schedule and showed that vulnerability could be modified by exposure to cocaine.

Effect of instructions on the microstructure of human schedule performance.

Three experiments examined the effect of instructions on human free-operant performance on random ratio (RR) and random interval (RI) schedules. Both rates of responding, and the microstructure of behavior, were explored to determine whether bout-initiation and within-bout responding may be controlled by different processes. The results demonstrated that responding in acquisition (Experiments 1 and 2) and extinction (Experiment 3) was impacted in line with given instructions. During acquisition, rates were higher on RR compared to RI for accurate and minimal instructions. During extinction, rates decreased when there were minimal instructions. However, instructions had a greater impact on within-bout responding, than they did on bout-initiation responding. Overall rates of responding, and within-bout rates, varied in line with the nature of the instructions, but bout-initiation responding did not (Experiments 1 and 2). Resistance to extinction was increased by instructions in terms of overall responding and within-bout rates, but not in terms of bout-initiation rates (Experiment 3). These data are consistent with the hypothesis that bout-initiation responding may be less impacted by instructions than within-bout responding, speculatively, the former is stimulus-driven, automatic/habitual, and less accessible to conscious processing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The sequencing of trials during partial reinforcement affects subsequent extinction.

If a conditioned stimulus or response has been inconsistently ("partially") reinforced, conditioned responding will take longer to extinguish than if responding had been established by consistent ("continuous") reinforcement. This partial reinforcement extinction effect (PREE) is one of the best-known phenomena in associative learning but defies ready explanation by associative models which assume that a partial reinforcement schedule will produce weaker conditioning that should be less resistant to extinction. The most popular explanation of the PREE is that, during partial reinforcement, animals learn that recent nonreinforced (N) trials are associated with subsequent reinforcement (R), and therefore the presence of N trials during extinction serves to promote generalization of conditioning to extinction. According to sequential theory (Capaldi, 1966), animals can encode whole sequences (runs) of N trials and associate their memory of the sequence with subsequent R. The length of these N sequences during conditioning affects how long the animal will continue to respond during extinction. The present experiment used Pavlovian magazine approach conditioning with rats to test two predictions of this theory. Consistent with sequential theory, the PREE was sensitive to the length of the N sequence: conditioning with long sequences (runs of 3-5 N trials) produced a stronger PREE than conditioning with short sequences (runs of 1 or 2) even when the total number of N and R trials was held constant. Surprisingly, there was no PREE among rats trained with the short sequences. Moreover, contrary to the theory's prediction, interrupting the long N sequences with reinforced trials of a different conditioned stimulus did not affect the subsequent PREE. I conclude that uncertainty about reinforcement, rather than the memory of N sequences per se, is a key factor in the development of the PREE. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The multiple-stimulus-without-replacement preference assessment tool and its predictive validity.

This study demonstrates the use of two web-based programs, one to identify video preferences and the other to assess their reinforcing effects. We used the Multiple-Stimulus-Without-Replacement Preference Assessment Tool (MSWO PAT) to identify the video preference hierarchies of seven participants, ages 4-11 years old. We then used a customized reinforcer assessment program that arranged a concurrent-chains preparation with programmed conjugate schedules of reinforcement. Button presses emitted by participants modulated the quality (volume and opacity) of selected videos on a moment-to-moment basis, allowing us to identify the reinforcing effects of the videos in little time. The results showed that the preference assessment had predictive value for five of seven participants. We discuss the MSWO PAT, parameters that may affect the identification of preferences and the use of conjugate schedules to identify reinforcers.

Multiple schedules of conjugate reinforcement and extinction: A translational model for assessing automatically reinforced behavior.

This study evaluated the extent to which a conjugate reinforcement schedule (CONJ) involving a contingency between pedaling a stationary bike and viewing a preferred movie could serve as a translational preparation for the analysis of automatically reinforced behavior. In part, researchers examined whether providing participants with either an accurate or an inaccurate rule about the extinction (EXT) component of a multiple schedule (MULT) contributed to the development of control by the MULT (CONJ EXT) schedule. Results show schedule control emerged for four of five participants who received the accurate rule and none of the five participants who received the inaccurate rule. In addition, participants who received accurate rules typically increased pedaling during CONJ components that followed two consecutive EXT components, suggesting that they experienced deprivation for audio and visual stimulation generated by pedaling. These preliminary findings suggest that researchers could use this translational preparation to identify matched interventions for some automatically reinforced behavior.