Ultrafast generation and control of an electron vortex beam via chiral plasmonic near fields.

Vortex-carrying matter waves, such as chiral electron beams, are of significant interest in both applied and fundamental science. Continuous-wave electron vortex beams are commonly prepared via passive phase masks imprinting a transverse phase modulation on the electron's wavefunction. Here, we show that femtosecond chiral plasmonic near fields enable the generation and dynamic control on the ultrafast timescale of an electron vortex beam. The vortex structure of the resulting electron wavepacket is probed in both real and reciprocal space using ultrafast transmission electron microscopy. This method offers a high degree of scalability to small length scales and a highly efficient manipulation of the electron vorticity with attosecond precision. Besides the direct implications in the investigation of nanoscale ultrafast processes in which chirality plays a major role, we further discuss the perspectives of using this technique to shape the wavefunction of charged composite particles, such as protons, and how it can be used to probe their internal structure.

Effects of an ethanol-paired conditioned stimulus on responding for ethanol suppressed by a conditioned-taste-aversion.

Ethanol-Paired Conditioned Stimuli (CS) can increase ethanol-responding either in extinction or occurring at low rates late in a session. To examine the generality of CS-induced increases in ethanol-responding, we examined whether a CS could increase responding suppressed by Conditioned-Taste-Aversion (CTA), which presumably suppresses responding by changing ethanol's valence from positive to negative. Rats were trained to respond for ethanol under a Random Interval (RI) schedule. We then removed the lever and paired Random-Time ethanol deliveries with illumination of a stimulus light (i.e., CS) for 10 sessions. Results were compared with a Truly Random Control group, in which the light and ethanol deliveries occurred independently. In a subsequent experiment, rats were treated similarly, except the light served as a discriminative stimulus, as the lever was extended and ethanol deliveries were available under a RI during light presentations. After this training, the lever was returned and rats again responded for ethanol. Subsequently, sessions were followed by LiCl administration. When responding reached low levels, LiCl administration stopped and the light was occasionally illuminated during the session. Responding during the light presentation was compared to responding during the period preceding light presentation. Responding partially recovered across 10 sessions and was greater during light presentations than in the period before it in all three groups. Increases were not reliably different between the groups, indicating that explanations for these increases such as CS-induced increases in motivation or approach toward the light are unlikely to be correct. The most likely explanation for these light-induced increases is that during sessions in which the light had been presented previously, LiCl had never been presented and thus, the light had come to signal that ethanol was safe to drink.

Shifts in stimulus control over opioid use with increasing periods of recovery.

BACKGROUND: Periods of engaging in an alternative behavior diminishes behavioral control by stimuli occasioning alcohol use. This increase in relapse resistance with increasing recovery suggests that changing stimulus control over substance use may be a mechanism responsible for decreased relapse rates with longer recovery. However, the generality of this phenomenon to other drugs of abuse, including opioid self-administration, remains unclear. This study tests the generality of these findings with etonitazene to determine whether the shift in attention represents a behavioral process that generalizes from conditions we previously reported. METHODS: Five adult male Lewis rats were trained to respond on levers under two stimulus conditions; high-cost food (food FR150 and etonitazene FR5) and low-cost food (both food and etonitazene FR 5). Next, only the high-cost food stimulus (occasioning etonitazene responding) was presented for 20 sessions (Use Phase) followed by 9 sessions in which only the low-cost food stimulus (occasioning food responding) was presented (Recovery Phase). During the Recovery Phase, testing occurred during the first component of sessions 0, 1, 2, 4, and 8 when rats were re-exposed to the high-cost food stimulus. The number of food responses prior to completing the etonitazene response requirement during this stimulus exposure was the primary measure. RESULTS: Food responses during stimulus re-exposure increased significantly as a function of recovery sessions completed with a slope [95 % CI] of 2.49 responses/recovery session [0.16, 4.81]. The average number of etonitazene deliveries per use session was 32 ± 6.6 or an average daily dose of 48.8 ± 10.1 µg/kg. During Recovery Phase, etonitazene deliveries decreased to 2.4 ± 1 or 3.6 ± 1.5 µg/kg. CONCLUSION: The decrease in stimulus control observed for ethanol self-administration appears to generalize to opioid self-administration, indicating this change in stimulus control may play a general role in recovery.

A Rapid Procedure to Assess Shifts in Discriminative Control Over Drinking During Recovery-Like Behavior.

BACKGROUND: Previously, we reported that recovery-like behavior decreases stimulus control over drinking, and this likely plays a role in the clinical observation that longer recovery increases relapse resistance. Those studies were conducted using a procedure that required repeated assessment, preventing a longitudinal analysis of the changes in stimulus control over time in each individual. Here we recapitulate those results and extend them to female rats using a more efficient procedure that allows repeated assessment of changes in stimulus control over drinking during recovery. METHODS: Under a multiple concurrent schedule, rats were trained to reliably respond predominately for ethanol (concurrent Ethanol FR5, Food FR150) in the presence of one stimulus and for food (concurrent Ethanol FR5, Food FR5) in the presence of another stimulus. Stimuli were either lights or tones, depending on the group. After that, a drinking phase in which only the stimulus occasioning ethanol responding was presented (10 or 20 sessions) followed by recovery-like sessions in which only the stimulus occasioning food responding was presented. During these sessions, rats were exposed to the ethanol stimulus under extinction during the first component on sessions 0, 1, 2, 4,8, and 16. The number of food responses during these stimulus exposures prior to the first 5 ethanol responses was the primary measure. RESULTS: Consistent with the earlier procedure, the number of food responses during ethanol tests increased as a function of the number of recovery sessions completed, regardless of whether the stimuli were visual or auditory. However, there were no significant effects of extended alcohol exposure or sex. CONCLUSIONS: A rapid procedure consistent with the earlier procedure and clinical evidence was developed in which stimulus control over drinking decreased following longer periods of recovery. Under conditions tested, stimulus type, length of drinking history and sex did not affect this relationship.

Ethanol-paired conditioned stimulus effects on concurrent reinforced responding for ethanol and food.

The influence of Pavlovian Conditioned Stimuli (CS) on ethanol self-administration and choice between ethanol and an alternative are potentially important. Ethanol-paired CS might increase ethanol self-administration, especially when it has been reduced during recovery, though the selectivity of these increases has been questioned. To date, one study examined the effects of an ethanol-paired CS on ethanol choice and found that the CS increased ethanol-responding more than food-responding when both were in extinction. However, it remains unclear whether ethanol-paired CS increase ethanol-choice that is not in extinction. Here, we examine the effects of an ethanol-paired CS on ethanol-choice when both food- and ethanol-responding are reinforced. Sixteen adult male Lewis rats were trained on a concurrent schedule to respond for ethanol on one lever and for food on the other lever. Ethanol was available under an FR 5 schedule, and food was available under an FR schedule that was adjusted for each rat to earn an equal number of food and ethanol deliveries. Then, 2-min light presentations were paired with an RT 25-sec schedule of ethanol delivery for 10 sessions in the absence of both levers. After this, subjects were placed back on the concurrent schedule for one session, then five sessions with the CS being present or absent on each trial of the concurrent schedule occurred. Rats learned to respond on one lever for ethanol and on the other for food and earned similar numbers of ethanol and food deliveries. During Pavlovian Conditioning, the number of head entries into the head-entry detector was higher in the presence of the CS than in its absence. In the test sessions, rats made more ethanol responses in the presence of the CS than in its absence. However, this effect was small and did not increase the amount of ethanol earned. Thus, ethanol-paired CS could increase ethanol-responding under a choice procedure but did not increase ethanol consumption meaningfully under the studied conditions.

Reduced alcohol use increases drink-refusal self-efficacy: Evidence from a contingency management study for DWI arrestees.

BACKGROUND: Several therapies and interventions to reduce drinking first target drink-refusal self-efficacy (DRSE) to influence drinking behavior. While higher self-efficacy scores are correlated with better outcomes, it is unclear that increased self-efficacy is the causative step leading to improved outcomes. Instead, this correlation may result from reduced drinking that increased self-efficacy. The current study sought to understand how changes in drinking behavior can influence DRSE. METHODS: Data were from 211 driving while intoxicated (DWI) arrestees participating in an 8-week contingency management (CM) study to reduce drinking. Some of participants were mandated by the courts to wear transdermal alcohol monitoring devices (Mandated group) and some were not mandated (Non Mandated group). All wore a transdermal alcohol monitor during the 8-week study and were randomized to CM or a Control condition stratified by the mandate group. Participants completed weekly assessments of DRSE. Group-based trajectory-modeling identified three drinking behavior trajectory groups. RESULTS: While there were no differences in baseline DRSE between the three trajectory groups, participants in the low- and moderate-frequency drinking behavior groups significantly increased DRSE across the study. CONCLUSION: The present study indicates that being able to maintain abstinence or reduce heavy drinking may increase DRSE.

Conditioned stimulus effects on paired or alternative reinforcement depend on presentation duration: Implications for conceptualizations of craving.

Conditioned stimuli (CS) associated with alcohol ingestion are thought to play a role in relapse by producing a craving that in turn increases motivation to drink which increases ethanol-seeking and disrupts other ongoing behavior. Alternatively, such CS may provide information indicating a likely increase in the density of the paired unconditioned stimulus and simultaneously elicit behavior that may be incompatible with other ongoing behavior, i.e., approach toward the CS. To explore these possibilities, rats were trained to respond for ethanol or food in two different components of the same session after which a light above the ethanol-lever was lighted twice during each component and each light presentation was followed by ethanol delivery. The duration of this CS was 10 s initially and then increased to 30 s, then to 100 s, and finally returned to 30 s. The change in responding for ethanol or food was compared to a matched period immediately preceding CS presentation. The CS presentation increased responding to ethanol, and this effect increases with longer CS presentations. In contrast, the CS presentation decreased responding to food, and this effect decreases with longer CS presentations. These results appear to support the informational account of CS action rather than simply a change in the motivation to seek and consume ethanol. This suggests that craving as it is commonly understood likely represents multiple behavioral processes, not simply increased desire for alcohol and that reports of craving likely reflect labeling based upon past experiences rather than a cause of future drug-taking.

The role of nicotine replacement therapy in early quitting success.

INTRODUCTION: Nicotine replacement therapy (NRT) is an effective but underutilized smoking cessation aid despite being available over the counter. This exploratory study examined whether voluntary early use of NRT predicted cessation in a self-initiated quit attempt better than other commonly studied variables. METHODS: Data were collected from 99 adult smokers desiring to quit smoking in the near future over a 10-day baseline period prior to the implementation of a contingency management intervention. NRT use was neither encouraged nor discouraged during the study. Initial abstinence, biochemically verified using a criterion of CO level <4 ppm, was conceptualized in 2 ways: (a) any day of baseline abstinence and (b) the sum of baseline days abstinent. We examined the predictive value of NRT use as well as demographics, self-efficacy, motivational readiness, and nicotine dependence. RESULTS: While greater self-efficacy was predictive of initial abstinence, NRT use was the most consistent predictor. The odds of abstaining at least 1 day during baseline were 16.8 times greater for those who used NRT on Day 1 than nonusers. Self-efficacy and "any baseline NRT use" contributed significant amounts of variance to the "sum of days abstinent," with the overall model explaining 29% of the variance (p < .001). The sum of baseline days of NRT use and use of NRT on Day 1 also predicted the "sum of days abstinent." DISCUSSION: Given NRT's effectiveness, but underutilization in real-world settings, the data support the need for interventions or strategies encouraging people to use NRT in their quit attempts.

Ethanol-paired stimuli can increase reinforced ethanol responding.

While ethanol-paired stimuli are frequently postulated to increase drinking motivation and thus increase ethanol responding and precipitate relapse, no study has demonstrated increases in ethanol-reinforced responding following presentation of an ethanol-paired stimulus that had not previously been part of a contingent relationship. Previous studies have shown that food-paired stimuli can increase food responding that is at low rates and increase food consumption in food-sated rats. In Experiment 1, we show that an ethanol-paired stimulus can increase ethanol responding that is at low levels late in the experimental session, presumably due to satiation. However, these increases may have resulted from either associative or non-associative mechanisms. In Experiment 2, we compared the effects of an ethanol-paired stimulus to those of the same stimulus in a Truly-Random-Control group. In a Truly-Random-Control, the stimulus and ethanol each are presented on independent random schedules, and thus any differences between the effects of the stimulus in the experimental and control groups is likely attributable to the association between the stimulus and ethanol. The stimulus increased ethanol-reinforced responding in both the experimental and control groups, but these increases were greater in the experimental than the control group. Thus, both stimulus-change and the pairing of the stimulus with ethanol may result in increases in ethanol-reinforced responding.

Cocaine receptors on dopamine transporters are related to self-administration of cocaine.

Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with their potencies in binding to a large number of other presynaptic and postsynaptic binding sites. Thus, the cocaine receptor related to substance abuse is proposed to be the one associated with dopamine uptake inhibition.

The relationship between self-efficacy and reductions in smoking in a contingency management procedure.

Social--cognitive and behavioral theories of change disagree on what the relevant controlling variables for initiating behavior change are. Correlations between baseline smoking cessation self-efficacy and the changes in breath carbon monoxide (CO) and the reduction in breath CO and increases in smoking cessation self-efficacy from baseline were obtained from a contingency management smoking cessation procedure. A test of the difference between the cross-lag correlations suggested a nonspurious causal relationship between smoking cessation self-efficacy and changes in breath CO. Path analyses showed that decreases in breath CO (reductions in smoking) predicted later increases in smoking cessation self-efficacy. Baseline self-reports of smoking cessation self-efficacy were not significantly correlated with subsequent changes in breath CO. Rather, significant correlations were found between reductions in breath CO and later increases in smoking cessation self-efficacy. These results suggest that self-efficacy may be a cognitive response to one's own behavior, and are inconsistent with a social--cognitive view of self-efficacy's role in behavior change. Implications for the development of smoking cessation programs and health-promoting behavior changes in general are discussed.

Examination of reinforcement magnitude on the pharmacological disruption of fixed-ratio performance.

Behavioral momentum theory proposes that operant behavior is the product of two separable processes: its rate of occurrence and its resistance to change. Generally speaking, operant situations providing more densely spaced or greater magnitudes of reinforcement should be more resistant to disruption. Attempts to disrupt ongoing behavior by manipulating the availability of food or deprivation level typically have supported the predictions of behavioral momentum. Tests with pharmacological disruptors, however, have yielded mixed results. Most investigations of pharmacological disruption of operant behavior have evaluated momentum across situations that differ in rate of reinforcement. The present experiment was an attempt to systematically replicate prior work, but under conditions of differing reinforcement magnitudes. Pigeons were trained to key peck on a multiple fixed-ratio 30 schedule of food presentation, where different components programmed 2-, 4-, or 8-s access to grain. Resistance to rate-decreasing effects of drugs was evaluated with several compounds drawn from distinct pharmacological classes: chlordiazepoxide, cocaine, clonidine, haloperidol, morphine, and ethanol were tested. Additionally, disruption by prefeeding and extinction was examined. Generally, resistance to change by drug administration was not modulated by reinforcement magnitude. Prefeeding and extinction tests, however, replicated previous work, indicating that our procedure was sensitive to more common disruptors. The results give additional support to the notion that pharmacological disruptors may not behave in the manner predicted by behavioral momentum theory.

Further psychometric analysis of the 20-item Partner Interaction Questionnaire in an adult sample of smokers.

The 20-item Partner Interaction Questionnaire (PIQ-20) is frequently used to assess social support for adults wanting to stop smoking. Given that social support may play a significant role in quitting success, there is a need to understand the structure and psychometric properties of assessment instruments designed to measure the construct of partner support. The current study examined the psychometric properties of the PIQ-20 when used to assess the frequency of partner behaviors. The study participants included 380 adult volunteers (M age = 41 years, SD = 12; 58% male). To assess internal consistency, we used both the traditional coefficient-alpha and the latent variable modeling composite reliability (coefficient-ρ) procedures. We conducted independent factor analytic methods to address issues of dimensionality and scoring of responses to the PIQ-20 items. Also, we used an item response theory modeling procedure to examine the specificity of scores on the items. Reliability estimates for the PIQ-20 subscale scores were adequate (values ≥.70). The bifactor analysis supported deriving a total score for each subscale. Item response theory modeling demonstrated that the discrimination (a-slope) parameter for each subscale item was significantly different from zero. The majority of items were associated strongly with their respective subscales. Twelve items were identified that could be adopted as a potential short form of the PIQ-20. The PIQ-20 or short form provides an opportunity for assessing positive and negative partner support simultaneously. There is empirical support for the dimensional structures and scoring of responses for both versions of the instrument. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of rat strain and method of inducing ethanol drinking on Pavlovian-Instrumental-Transfer with ethanol-paired conditioned stimuli.

Ethanol-paired conditioned stimuli (CSs) are widely thought to invigorate ethanol responding, and thus, precipitate relapse to drinking. However, preclinical studies investigating this issue using Pavlovian-Instrumental-Transfer (PIT) procedures have had mixed results, with some studies finding PIT while others did not. The studies failing to show PIT used Lewis rats and induced ethanol drinking using a post-prandial drinking procedure. The present experiments examined whether either of these two variables influenced the magnitude of PIT observed. In the first experiment, ethanol drinking in Lewis rats was induced using either sucrose fading or post-prandial drinking. In the second experiment, ethanol drinking was induced using post-prandial drinking in either Long-Evans Hooded or Lewis rats. In both experiments, rats were trained to respond for ethanol under a random interval schedule. Subsequently with the lever removed, 2-min light presentations were paired with ethanol deliveries. Finally, with the lever returned, the effect of light presentations on responding was tested while responding was in extinction. Light presentations similarly affected responding in Lewis rats regardless of the method of drinking induction. Likewise, light presentations similarly affected responding in both Lewis and Long-Evans Hooded rats. Neither ethanol induction method nor rat strain affected the magnitude of PIT observed, and thus, neither likely explains previous failures to observe PIT with ethanol-maintained behavior.

Author Correction: Attosecond coherent control of free-electron wave functions using semi-infinite light fields.

The authors became aware of a mistake in the original version of this Article. Specifically, an extra factor γ was incorrectly included in a number of mathematical equations and expressions. As a result of this, a number of changes have been made to both the PDF and the HTML versions of the Article. A full list of these changes is available online.

Holographic imaging of electromagnetic fields via electron-light quantum interference.

Holography relies on the interference between a known reference and a signal of interest to reconstruct both the amplitude and the phase of that signal. With electrons, the extension of holography to the ultrafast time domain remains a challenge, although it would yield the highest possible combined spatiotemporal resolution. Here, we show that holograms of local electromagnetic fields can be obtained with combined attosecond/nanometer resolution in an ultrafast transmission electron microscope (UEM). Unlike conventional holography, where signal and reference are spatially separated and then recombined to interfere, our method relies on electromagnetic fields to split an electron wave function in a quantum coherent superposition of different energy states. In the image plane, spatial modulation of the electron energy distribution reflects the phase relation between reference and signal fields. Beyond imaging applications, this approach allows implementing quantum measurements in parallel, providing an efficient and versatile tool for electron quantum optics.

Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Delta(9)-tetrahydrocannabinol in C57BL/6J mice.

RATIONALE: A variety of behavioral procedures have been developed to assess cannabinoid activity in mice; however, the feasibility of establishing Delta(9)-THC as a discriminative stimulus in mice has not been documented. OBJECTIVE: One goal was to establish Delta(9)-THC as a discriminative stimulus in mice; after having done so, another goal was to examine the in vivo mechanism of action of Delta(9)-THC with other cannabinoids and noncannabinoids. MATERIALS AND METHODS: C57BL/6J mice (n = 8) were trained to discriminate Delta(9)-THC (10 mg/kg i.p.) from vehicle while responding under a fixed ratio 30 schedule of food presentation. RESULTS: Mice satisfied the discrimination criteria in 18-98 (median = 67) sessions and the discriminative stimulus effects of Delta(9)-THC were dose-dependent (ED(50) = 2.6 mg/kg). CP 55940 and WIN 55212-2 dose-dependently increased Delta(9)-THC-appropriate responding to 100% (ED(50) = 0.032 and 0.45 mg/kg, respectively), whereas methanandamide and a variety of noncannabinoids (cocaine, ethanol, and ketamine) produced a maximum of 34% Delta(9)-THC-appropriate responding. The cannabinoid CB(1) antagonist SR 141716A (rimonabant) surmountably antagonized the discriminative effects of Delta(9)-THC, CP 55940, and WIN 55212-2; methanandamide did not significantly modify the Delta(9)-THC discriminative stimulus. CONCLUSIONS: The discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2 are mediated by the same (i.e., CB(1)) receptors, whereas the effects of methanandamide or a metabolite of methanandamide are mediated at least in part by non-CB(1) receptors. The discriminative stimulus effects of Delta(9)-THC in mice could be used to evaluate mechanisms of cannabinoid activity with approaches (e.g., inducible knockouts) currently unavailable in nonmurine species.

Acute tolerance to rate-decreasing effects of single doses of ethanol.

Acute tolerance occurs when behavioral impairment is greater at a given blood ethanol concentration (BAC) on the ascending versus descending limb of the BAC-time curve following administration of a single dose of ethanol, however studies utilizing learned behaviors have not been widely reported. We assessed acute tolerance to single doses of ethanol in five Lewis rats responding under a fixed-ratio (FR8) schedule of food presentation. Response rates for food during 1-min components (ending 2, 4, 11, 18, 33, and 57 min after ethanol administration) were determined, and BAC was measured immediately after each component using a rat breathalyzer. Ethanol (0.4, 0.6, 0.8, and 1.2 g/kg, i.p.) produced dose-related decreases in responding for food that tended to recover over time for all but the highest dose tested. Similarly, dose-related increases in BAC were also observed. Using either an analysis that expressed impairment per unit BAC on the ascending limb versus the descending limb (by assessing the area under the curve (AUC) for behavior and BAC on each limb), the slope of the function that relates the behavioral effect to BAC (each expressed as percent maximum effect), or a variant of the Mellanby method (hysteresis), acute tolerance was observed following a dose of 0.4 g/kg ethanol. Though behavior appeared to recover on the descending limb following higher doses (especially 0.6 and 0.8 g/kg), acute tolerance to these doses was not present.

Over-the-counter nicotine replacement therapy: can its impact on smoking cessation be enhanced?

Nicotine replacement therapies (NRTs) are efficacious smoking-cessation aids. However, only minimal increases in smoking cessation followed NRTs being made available over-the-counter (OTC), which presumably made these treatments more readily available. To better understand why the United States did not experience improvements in smoking cessation following the OTC availability of NRTs, it is useful to review factors that determine NRT's impact on smoking cessation and how these factors played out with the introduction of OTC NRT. The authors contend that for NRTs to have a greater impact on public health, increases are needed in the number of individuals making a quit attempt, the proportion using NRTs in a quit attempt, and the effectiveness of each quit attempt. Even small increases in the impact of OTC NRTs could yield significant benefits in terms of morbidity and mortality. The remainder of this article provides examples of interventions designed to target each of the aforementioned factors individually as well as examples of interventions that link increased cessation attempts, increased NRT reach, and increased NRT efficacy in order to synergistically enhance the impact of OTC NRTs.

Frustration stress (unexpected loss of alternative reinforcement) increases opioid self-administration in a model of recovery.

PURPOSE: Engaging in alternative activities in the context where opioid use had occurred can constrain opioid use and helps to maintain recovery. However, "frustration stress" that occurs when contingencies on these alternative activities unexpectedly change (e.g., job loss or divorce) is thought to threaten recovery by prompting a return to drug use. Yet it remains unclear whether frustration stress can result in a return to drug use, and if so, whether it returns to prior levels or to even greater levels. PROCEDURES: We examine the impact of unsignaled extinction of alternative reinforcement on opioid use. Rats were trained to respond for an etonitazene solution (5µg/ml, p.o.), then for food in alternating daily sessions. Subsequently, food and etonitazene were made concurrently available. Under concurrent availability conditions, rats were exposed to 1, 2, or 4 sessions of unsignaled food extinction, and effects on responding for etonitazene and food measured. FINDINGS: When etonitazene was the only reinforcer available, rats earned 58.3±20.3µg/kg/session (mean±S.E.M.). When food was available in alternating sessions, etonitazene earned was unchanged (65.3±19.2µg/kg/session). Concurrent food availability decreased etonitazene earned (13.5±4.5µg/kg/session). Unsignaled food extinction returned etonitazene earnedto levels similar to (60.5±18.4µg/kg/session), but not greater than, those observed previously when etonitazene alone was available. CONCLUSIONS: Unsignaled extinction of alternative behavior controlling opioid use can result in increased opioid use, but this use does not rise beyond previous levels observed when opioid use is unconstrained by alternative reinforced behavior.