Schedule Of Reinforcement Research Articles

Time to choose: impact of intertrial interval on selecting between methamphetamine and food reinforcement in male and female rats.

A central component of substance use disorder is the maladaptive choice of the drug over natural reinforcers. Compared to other drugs of abuse, methamphetamine (METH) choice has received limited study. We sought to characterize the role of intertrial interval on METH choice behavior. We examined the choice of METH versus food, across multiple METH doses (0.05-0.2mg/kg/infusion), between male and female rats, employing a fixed ratio (FR1) reinforcement schedule with intertrial intervals (ITIs) of 20 and 600s. Rats learned to lever-press for either the METH or the food reinforcer during separate, alternating training sessions. Rats then underwent choice testing, where both levers were presented for 25 discreet trials per session. Lastly, under a progressive ratio (PR) schedule, breakpoints for METH and food were assessed during separate, alternating sessions. METH choice was substantially higher when using the 20s versus 600s ITI. When the 20s ITI was used, choice was dose- but not sex-dependent. When using the 600s ITI, choice was influenced by dose and sex, with female rats in the higher dose group choosing METH more than other groups. PR breakpoints were higher for METH than for food, and this effect was more pronounced among female rats. METH choice was positively correlated with the ratio of METH/food breakpoints. Reinforcement schedule parameters, namely ITI, during discrete choice testing can markedly influence METH choice behavior; thus, this should be carefully considered during experiment design and selected based on overarching study aims.

Long- vs short-access cocaine alters behavioral inhibition for cocaine in male rats

Impulsivity and behavioral inhibition are measures commonly associated with substance misuse, particularly cocaine use disorder. However, patterns of impulsive behaviors have been shown to differ based on cocaine use history and level of cocaine dependence. Extended cocaine access, which more closely models neural and behavioral changes that take place during the development of problematic cocaine use, has been shown to decrease behavioral inhibition in comparison to limited cocaine access. However, previous preclinical studies investigating these relationships have been mostly correlational and only utilize non-drug rewards. This study aims to utilize a differential rates of low reinforcement (DRL) schedule to investigate the impact of extended access to cocaine on behavioral inhibition toward a cocaine reinforcer. Male Sprague Dawley rats first self-administered intravenous cocaine infusions on a DRL schedule of reinforcement before being split into two groups: one given 6-h extended cocaine access (LgA) and one given 1-h short cocaine access (ShA) for 10 daily sessions. Following a washout period, the rats were placed back on DRL cocaine self-administration sessions. Results revealed that LgA rats showed impaired performance on the behavioral inhibition measure during the DRL self-administration sessions compared to baseline DRL performance and compared to ShA post-access behavioral inhibition measures. These results indicate that extended cocaine access impairs an organism's behavioral inhibition toward future cocaine use, indicating that those individuals with a history of heavy cocaine use will have impaired behavioral inhibition toward future cocaine use.

Punishment and dynamic choice: Assessment of the direct-suppression model.

The effects of punishment rate on response allocation were investigated using a choice procedure where relative reinforcement rates changed rapidly within session. Predictions from a modified version of the direct-suppression model were tested in two separate experiments. In both experiments, sessions were composed of seven unsignaled components, each programming a different reinforcement ratio. In Experiment 1, equal punishment rates were superimposed on the schedule of reinforcement for both responses and absolute punishment rates increased across blocks of sessions. Punishment increased preference for the richer schedule of reinforcement, but the degree of the preference shift was not a function of absolute punishment rates. In Experiment 2, unequal punishment rates were superimposed on the schedules of reinforcement for both responses and relative punishment rates changed across blocks of sessions. Response allocation shifted away from the richer punishment schedule creating a bias toward the option associated with less frequent punishment. The results from both experiments challengedthe predictions of the direct-suppression model. Furthermore, fits of the generalized matching law to the data indicated that superimposition of equal or unequal punishment schedules on responses maintained by unequal reinforcement schedules differentially affect the values of sensitivity and bias.

Variable schedules of reinforcement do not reliably distinguish habit from goal-directed behavior.

Contemporary analyses of neurophysiological mechanisms of associative learning suggest that instrumental behavior can be controlled by separable action and habit processes. An increasingly broad range of human psychiatric and neurological disorders are now associated with maladaptive habit formation. The question of how the brain controls transitions into habit is thus relevant. Widely used training procedures that might differentially generate goal-directed actions or habits are variable schedules of reinforcement. Random interval schedules are known to generate habitual behavior compared with random ratio schedules Here, we report attempt to identify the behavioral characteristics of the bifurcation point of habitual and goal-directed behavior. We compared the time courses of learning in random ratio and random interval schedules with more common for neurophysiological researches parameters. Behavioral differences between schedules emerge early in learning. However, in outcome devaluation test we found that training in the random ratio schedule, but not in the random interval schedule, led to results interpreted as habitual behavior. This result is the opposite of what we expected based on previous research. We assume that the most commonly used variable schedules of reinforcement cannot serve as a reliable tool for analyzing neural mechanisms of habitual and goal-directed behavior.

After a Hand Was Lent: Sporadically Experiencing Multisensory Interference During the Rubber Hand Illusion Does Not Shield Against Disembodiment.

Observations from multisensory body illusions indicate that the body representation can be adapted to changing task demands, e.g., it can be expanded to integrate external objects based on current sensorimotor experience (embodiment). While the mechanisms that promote embodiment have been studied extensively in earlier work, the opposite phenomenon of, removing an embodied entity from the body representation (i.e., disembodiment) has received little attention yet. The current study addressed this phenomenon and drew inspiration from the partial reinforcement extinction effect in instrumental learning which suggests that behavior is more resistant to extinction when reinforcement is delivered irregularly. In analogy to this, we investigated whether experiencing occasional visuo-motor mismatches during the induction phase of the moving rubber hand illusion (intermittent condition) would result in slower disembodiment as compared to a regular induction phase where motor and visual signals always match (continuous condition). However, we did not find an effect of reinforcement schedule on disembodiment. Keeping a recently embodied entity in the body schema, therefore, requires constant updating through correlated perceptual and motor signals.

Delayed Dynamic Model Scheduled Reinforcement Learning with Time-Varying Delays for Robotic Control

Delayed Dynamic Model Scheduled Reinforcement Learning with Time-Varying Delays for Robotic Control

PeerPub: A Device for Concurrent Operant Oral Self-Administration by Multiple Rats.

The social environment has long been recognized to play an important role in substance use, which is often modeled in rodents using operant conditioning. However, most operant chambers only accommodate one rodent at a time. We present PeerPub-a unique social operant chamber. PeerPub employs touch sensors to track the licking behavior on drinking spouts. When the number of licks meets a set reinforcement schedule, it dispenses a drop of solution with a fixed volume as a reward at the tip of the spout. A radio frequency identification (RFID) chip implanted in each rat's skull identifies it throughout the experiment. The system is managed by a Raspberry Pi computer. We evaluated PeerPub using Sprague Dawley rats in daily 1 h sessions, where supersac (a glucose and saccharin solution) was provided under a fixed-ratio five schedule. We discovered that male rats consumed more supersac in dual rat conditions compared with single rat conditions. These findings illustrate PeerPub's effectiveness in modeling the interaction between motivated behavior and social context. We expect devices like PeerPub will help highlight the role of social environments in substance use disorder phenotypes. All computer code, 3D design, and build instructions for PeerPub can be found at http://github.com/nijie321/PeerPub.

Evaluating the effect of lag schedule of reinforcement and progressive-time delay in increasing varied augmented requesting.

Request training can produce highly repetitive requests unless the setting is organized to encourage request diversity, particularly for individuals who depend on speech-generating devices (SGDs). Previous studies have shown that request training utilizing a lag schedule and progressive-time delay led to an increase in variability among children diagnosed with autism spectrum disorder (ASD). The impact of lag schedules on augmented requesting remains to be seen. Hence, the present research aimed to examine the effect of a lag schedule of reinforcement in conjunction with progressive-time delay on enhancing the frequency of variant augmented requests in three children with ASD. Additionally, the study assessed the participants' ability to apply the acquired skills to different situations (such as preferred objects and daily routines) and sustain the desired behavior. The initial findings indicated that the intervention effectively boosted varied augmented requests, mainly when using a thinner schedule of reinforcements. The paper concludes by discussing the clinical significance, constraints, and potential paths for future investigation.

Reversal of the motivational effects of tetrabenazine by NMDA receptor blockade.

Apathy is a syndrome of decreased goal-directed activity, one of the main features of different brain disorders. Despite its high prevalence and life-threatening potential, there are currently very few options for its pharmacological treatment, which may be related to the lack of valid animal models. The vesicular monoamine transporter 2 inhibitor tetrabenazine (TBZ) was used in this study to model apathy-related behavior in pathologies linked to a depletion of dopamine. The atypical dopamine transporter inhibitor CE-123 and the NMDA receptor antagonist MK-801 were evaluated for their effects on goal-directed activity in intact and TBZ-treated rats to compare dopamine and non-dopamine approaches. To assess goal-directed behavior, the progressive ratio 3 (PR3) operant schedule of food reinforcement was conducted in adult male rats. To assess the motivational changes underlying the schedule, a model analysis based on the mathematical principles of reinforcement was applied. Treatment with TBZ (0.3 mg/kg) induced a decrease in response rate as the number of required responses increased. This effect was not accompanied by a decrease in the incentive value of the reinforcer or locomotor disturbances, suggesting that decreased tolerance to high effort demands was the underlying mechanism of the decrease in goal-directed activity. Treatment with MK-801 increased operant activity in both TBZ-treated and pharmacologically naïve rats. Our results support the previously proposed view that the TBZ-treated rats can be a model of apathy-related behavior in pathologies linked to a depletion of dopamine and suggest that NMDA receptors are a potential therapeutic target for the development of novel approaches to the treatment of apathy in both dopamine-depleted and dopamine-intact states.

Divergent changes in social stress-induced motivation in male and female mice.

Exposure to stressors has been shown to dysregulate motivated behaviors in a bidirectional manner over time. The relationship between stress and motivation is relevant to psychological disorders, including depression, binge eating, and substance abuse; however, this relationship is not well characterized, especially in females, despite their increased risk of these disorders. Social defeat stress is a common model to study stress-induced motivation changes, however, historically this model excluded females due to lack of female-to-female aggression and unreliable male-to-female aggression. Additionally, changes in motivation are often assessed well after stress exposure ends, potentially missing or occluding changes to motivation during stress. Recently, the chronic non-discriminatory social defeat stress (CNSDS) model has demonstrated social defeat of male and female C57BL/6J mice by exposing both mice to an aggressive male CD-1 mouse simultaneously. Here we use this model to directly compare changes in the motivated behavior of male and female mice during and following chronic stress. We hypothesized that motivated behavioral responses would be dysregulated during stress and that the effects would worsen as the stress exposure continued. To monitor motivated behavior, mice had access to a Feeding Experimental Device.3 (FED3), a home cage device for operant responding. Operant responding was monitored prior to, during, and after stress by measuring nose pokes for sucrose pellets on a modified progressive ratio schedule of reinforcement. Our results demonstrated divergent behavioral outcomes between males and female mice in response to stress; where male mice increased motivated behavior during stress only, whereas female mice exhibited a decrease in motivation during and after stress. This study highlights the need to investigate the effects of stress-induced motivation over time, as well as the increased need to understand differences in the stress response in females.

Multidimensional Analysis of Pigeons’ Behavior under Ratio and Interval Schedules Using a Video Tracking System: A Pilot Study

AbstractIn studies on reinforcement schedules, the target behavior (which is the operant behavior to be measured) is defined as an act on an operandum, and its occurrence is measured discretely on a time axis. These studies have provided significant findings on the functional relationship between the environment and behavior in terms of the temporal dimension of behavior. However, the effects of reinforcement schedules on the spatial dimensions of the target behavior and other behaviors have not been fully investigated. This study measured the positions of multiple body parts of pigeons under fixed-ratio, fixed-interval, variable-ratio, and variable-interval schedules using a video-tracking system. The results showed that the movement pattern of pigeons varied more in the fixed-ratio schedule than in the other schedules and that the speed of movement differed between the schedules. These findings demonstrate the potential of multidimensional analyses using video tracking systems. Further refinements in measurement and analytical methodologies are required.

Exploring the Utility of Curvilinear Feedback Systems for Improving Muscle Strength via Surface Electromyography

Our knees play a crucial role in our everyday lives and mobility; however, their constant usage leads to life-changing injuries such as osteoarthritis and ligament tears. Recent advancements in knee-related interventions have focused on enhancing the recovery process, with a particular emphasis on the Vastus Medialis Oblique (VMO), a quadricep muscle pivotal for knee stability. The strengthening of this muscle can be beneficial for those recovering from knee-related injuries. Utilizing surface electromyography (sEMG) to measure muscle contractions, behavior analysts can provide feedback and establish contingencies for promoting stronger VMO contractions. While previous studies have worked with discrete schedules of reinforcement, this study utilizes conjugate schedules that mirror real-world contingencies. We compare two types of curvilinear relations in the conjugate schedule, influencing the relation between muscle response and feedback. In one condition, a negatively accelerating relation was created, where low to moderate muscle contractions produced the greatest amount of reinforcement. The other arrangement featured a positively accelerating relation, where highly intense contractions would be reinforced the most. Results showed that all eight participants had their strongest contractions under the positively accelerating relation. Six of them also demonstrated higher average amplitudes within that same condition, providing valuable insight into the efficacy of curvilinear relations in shaping VMO contractions.

The role of uncertain reward in voluntary task-switching as revealed by pupillometry and gaze.

Cognitive flexibility, the brain's ability to adjust to changes in the environment, is a critical component of executive functioning. Previous literature shows a robust relationship between reward dynamics and flexibility: flexibility is highest when reward changes, while flexibility decreases when reward remains stable. The purpose of this study was to examine the role of uncertain reward in a voluntary task switching paradigm on behavior, pupillometry, and eye gaze. We used pupil dilation as a neuropsychological correlate of arousal and accumulated fixations on a region (i.e. dwell time) to measure oculomotor attention capture. Results during the cue phase showed that pupil dilation under a deterministic, but not a stochastic reinforcement schedule tracked arousal from the magnitude of reward. In addition, dwell time was increased for the eventual choice and dwell-time was reduced under high reward. Taken together, results show that arousal and attentional capture by reward depends to some extent on reward certainty. Turning to reward outcome, pupil dilation was highest (and average dwell time was lowest) following Error feedback compared to correct rewarded feedback. Overall results show that uncertain reward cues may alter pupil-linked arousal and attention as compared to certain reward, highlighting the role of uncertainty as an important modulator affecting attention and reward processing in environments that demand cognitive flexibility.

Design and Structural Analysis of a G+20 Multi-Storey Commercial Complex Using STAAD.Pro

This project encompasses the layout, design, analysis, planning, and estimation of a G+20 commercial building located in Hyderabad, developed on a plot measuring 21.33 m × 10.67 m. The layout and drafting were executed using AutoCAD, providing precise structural drawings that also served as input for structural analysis and design in STAAD Pro. The analysis identified critical forces acting on various structural members and generated reinforcement schedules. Concrete take-offs and reinforcement weights were determined using STAAD Pro, streamlining cost estimation and material planning. The foundation was designed as an isolated footing based on soil conditions, with design values computed in STAAD Foundation. This approach integrated drafting, design, and analysis, ensuring accurate and efficient structural planning. Keywords: G+20 commercial building, AutoCAD, STAAD Pro, structural analysis, foundation design, cost estimation, isolated footing, Hyderabad.

Contrasting the reinforcing effects of the novel dopamine transport inhibitors JJC8-088 and JJC8-091 in monkeys: Potential translation to medication assisted treatment

Despite considerable efforts, there remains no Food and Drug Administration-approved medications for cocaine use disorder. One strategy to mitigate cocaine craving and relapse is to elevate dopamine. The dopamine transport inhibitor and releaser d-amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogs reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as “cocaine-like” in rats, and JJC8-091, characterized as “atypical” and not SA by rats. The present study evaluated the reinforcing effects of both compounds in monkeys under several conditions. For experiment 1, 4 male cocaine-experienced rhesus monkeys self-administered cocaine (0.001–0.3 mg/kg per injection), JJC8-088 (0.001–0.3 mg/kg per injection), and JJC8-091 (0.1–3.0 mg/kg per injection) under a progressive-ratio schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For experiment 2, 1 male and 2 female drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all 3 monkeys. In experiment 3, monkeys from experiment 2 responded under a concurrent drug versus food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that although JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. Significance StatementJJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration (SA) in rats and in nonhuman primates. This study found that both compounds maintained SA in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the SA session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may have lower abuse liability than cocaine and may be a viable candidate for cocaine use disorder because, in the human population, alternatives to drug use are often available.

Integrating habit science and learning theory to promote maintenance of behavior change: does adding text messages to a habit-based sleep health intervention (HABITs) improve outcomes for eveningness chronotype young adults? Study protocol for a randomized controlled trial

BackgroundEveningness chronotype—the tendency for later sleep and wake times—arises from a confluence of psychosocial, behavioral, and biological factors. With the onset and progression of puberty, many young people develop an eveningness chronotype, which remains prevalent through the transition into adulthood. Eveningness has been associated with increased risk for poorer health. While eveningness is modifiable, maintaining the necessary behavior changes can be challenging. The science on habits demonstrates that habit formation is a key mechanism for maintaining behavior change over time. Learning theory offers schedules of reinforcement that also hold promise for enhancing the maintenance of behavior change. The present study will evaluate the Habit-based Sleep Health Intervention (HABITs)—which combines the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) with the science of habits—and a text message intervention informed by learning theory to attempt to sustainably modify the contributors to eveningness among young adults (18–30 years of age).MethodsParticipants (N = 160) will be randomly allocated to HABITs and HABITs + Texts. Both interventions include HABITs which involves three 50-min sessions followed by six 30-min sessions. Alongside the latter six sessions, HABITs + Texts will concurrently receive the text message intervention. Aims 1–3 will compare HABITs + Texts to HABITs on improvements in the outcomes of (1) utilization of sleep health behaviors and habit formation, (2) sleep and circadian functioning, and (3) functioning in five health-relevant domains, in the short (post-treatment) and longer (6-month and 12-month follow-up) term. Exploratory analysis will (1) compare HABITs and HABITs + Texts on (a) if sleep health behavior habit formation mediates the effects of intervention on improvement in outcomes and (b) if intervention effects are moderated by select variables, and (2) to evaluate if HABITs (regardless of the text message intervention) is associated with an improvement in outcomes in the short and longer term.DiscussionThis study has the potential to advance knowledge on (1) the value of leveraging the science of habits and learning theory in behavior change interventions, (2) the use of a low-cost and efficient intervention for habit formation and maintenance, (3) interventions that address eveningness chronotype, and (4) processes related to behavior change during emerging adulthood.Trial registrationClinicaltrials.gov NCT05167695. Registered on December 22, 2021.

Contingency management for monosubstance use disorders: Systematic review and assessment of predicted versus obtained effects.

Contingency management (CM) is notably successful as a substance use disorder treatment and is most effective when targeting monosubstance use. Evidence suggests the effects of CM exceed predictions based on the value of the incentives delivered for monosubstance abstinence. In this systematic review, we examine common variations of CM interventions applied to a single substance to determine what factors may contribute to the larger effect. Our results show that CM produced moderate to large effect sizes when single drugs were targeted, with stable effects over time. We also found that interventions targeting cocaine abstinence overwhelmingly outperformed their predicted effect, whereas interventions for smoking cessation did not. Thus, incentives alone may not account for the success of CM, at least when applied to stimulant use disorder. We propose other potential sources of the effect including social reinforcement and the specific parameters of the reinforcement schedule.

Caregiver-Implemented Interventions to Improve Daily Living Skills for Individuals With Developmental Disabilities: A Systematic Review.

Many individuals with intellectual and developmental disabilities (DD) encounter difficulties in performing daily living skills, which limits their self-sufficiency and autonomy. Caregivers, such as parents, are often the individuals who interact with individuals with DD the most during daily living skills routines. Therefore, it is critical to teach caregivers to implement daily living skills interventions with their children. A systematic review of the literature related to caregiver-implemented daily living skills interventions yielded 38 articles. Of those, 20 articles, with 21 experiments, were rated as high quality based on What Works Clearinghouse design standards. Behavior skill training was the most common strategy used to teach caregivers to implement interventions. Common daily living skills interventions included prompting, reinforcement, and task analysis. The most common form of prompting was verbal prompting, and the most common schedule of reinforcement was a continuous schedule of reinforcement. Of the 21 high-quality experiments, 86% demonstrated caregiver-implemented interventions yielded improvements in daily living skills. Several studies demonstrated generalization and maintenance of daily living skills. Implications for research and practice are discussed.

Delineating anticipatory arousal from reward consumption: evaluating fixed-intervals in cocaine seeking-taking response chains.

Anticipation is a critical antecedent to drug use, in which the prospect of imminent drug availability can potently motivate instrumental actions directed to procure it. Models that capture the behavioral dynamics that precede drug access may allow for the dissociation of key neural mechanisms underlying appetitive or consummatory processes in drug self-administration. We aimed to isolate measurements attributed to the procurement and consumption of a reward by defining distinct actions for each using a chain-schedule of reinforcement. Male Long-Evans rats were trained to self-administer cocaine or saccharin under a chained schedule of reinforcement (FI-FR) in order to dissociate appetitive ('seeking') from consummatory ('taking') behaviors. Completion of a fixed-interval (5min) was followed by 5min of continuously reinforced responding (FR1) on another lever. The FI-FR chain procedure appears to provide sensitive and dissociable dimensions of cocaine self-administration within a single experimental session. Importantly, we demonstrate that responding during the FI (i.e., seeking) link tracks with the incentive value of anticipated reward access - whereby response rates corresponded to expected reward magnitude, degree of reward-specific satiety, and general motivational state. The FI component is a sensitive and reliable index of motivational changes induced by either the extrinsic incentive value of reinforcement (i.e., anticipated dose) or intrinsic motive states (i.e., satiety or deprivation). This procedure provides a valuable tool for interrogating the neural dynamics of drug-seeking and -taking behavior, in isolation.

Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

BackgroundAlthough countless studies have aimed to identify and test novel therapeutics for stimulant misuse, there are still no FDA-approved pharmacotherapies for stimulant use disorders. One potential treatment target is the dopamine D3 receptor (D3R) and studies in rodents have suggested that the novel D3R partial agonist (±)VK4–40 may be effective at decreasing cocaine self-administration. However, no previous studies have examined the efficacy of (±)VK4–40 in reducing cocaine self-administration in nonhuman primates nor the generality of effects by examining self-administration of other stimulants using a within-subjects design. MethodsExperiment 1 examined how acute treatment with (±)VK4–40 (1.7–3.0mg/kg, i.v.) influenced cocaine and d-amphetamine self-administration in three rhesus monkeys responding under a progressive-ratio (PR) schedule of reinforcement. In Experiment 2, the reinforcing effects of (±)VK4–40 were evaluated under a PR schedule and compared to cocaine and d-amphetamine. ResultsWhen given as a pretreatment, (±)VK4–40 significantly reduced the reinforcing strength of d-amphetamine but not cocaine. In general, the effects of (±)VK4–40 on d-amphetamine responding were parallel downward shifts in the self-administration dose-response curve. When (±)VK4–40 was substituted for cocaine, it functioned as a reinforcer in 2 of 3 monkeys. However, the reinforcing strength of (±)VK4–40 was significantly lower than cocaine and d-amphetamine, suggesting lower potential for misuse. ConclusionsOverall, these findings support further exploration of D3R partial agonists, including (±)VK4–40, for treatment of d-amphetamine misuse or potentially in combination with d-amphetamine for treatment of cocaine use disorder.