Active and passive waiting in impulsive choice: Effects of fixed-interval and fixed-time delays.

Behavioral interventions to improve self-control, preference for a larger-later (LL) reward over a smaller-sooner (SS) reward, involve experience with delayed rewards. Whether they involve timing processes remains controversial. In rats, there have been inconsistent results on whether timing processes may be involved in intervention-induced improvements in self-control. Interventions that improved self-control with corresponding timing improvements used fixed-interval (FI) delays, whereas interventions that failed to find corresponding timing improvements used fixed-time (FT) delays. The FI schedule includes a response contingency (active waiting), whereas the FT schedule delivers reward automatically (passive waiting). The present study compared the effects of FI and FT schedules in interventions and impulsive choice tasks to evaluate effects on self-control and timing behavior. The impulsive choice task evaluated preference for an SS option (one pellet after 10-, 15-, 20-, 25-, and 30-s delays) versus an LL option (two pellets after a 30-s delay). The intervention task included forced-choice SS (one pellet after 10 s) and LL (two pellets after 30 s) sessions under FI or FT schedules. FI schedules produced greater sensitivity to SS delay in the impulsive choice task. Both FI and FT interventions increased LL choices. Following choice testing, temporal bisection and peak interval tasks revealed better timing precision for rats with an FI delay experience. Overall, the FI choice contingency was associated with improved temporal attention and timing precision.

Exercise recovers weight gain, but not increased impulsive choice, caused by a high-fat diet.

A high-fat diet has negative effects on physical, neurological, and behavioral outcomes. One consistent finding is that a diet high in fat increases impulsive choice behavior-behavior that is linked to a wide range of other negative health behaviors. While the mechanism for this increase in impulsive choice is not well understood, exercise, with its well-known and many benefits, may serve as an effective and accessible way to combat increased impulsive choice associated with a high-fat diet. The goal of this work was to test this possibility. Rats were divided into four groups in a two-by-two factorial design: exercise and control diet, sedentary and control diet, exercise and high-fat diet, sedentary and high-fat diet. Rats in the exercise groups engaged in 30-min of forced, moderate intensity wheel-running exercise five days per week. Rats in the high-fat diet groups ate a diet high in fat. Impulsive choice was measured using a delay discounting task. Exercise prevented weight gain associated with the high-fat diet. Exercise also preserved relative motivation for food reinforcement. However, exercise did not prevent increases in impulsive choice observed for rats that consumed a high-fat diet relative to the rats that consumed the control diet. This work rules out several possible mechanisms by which a high-fat diet may increase impulsive choice behavior. It makes clear that exercise alone may not stave off increases in impulsive choice caused by a high-fat diet. Future work is necessary to uncover the underlying mechanism for this effect and discover interventions, perhaps ones that combine both physically and cognitively demanding activities, to improve health and behavior as it relates to decision making processes.

Laboratory method to induce state boredom increases impulsive choice in people who use cocaine and controls.

Background: Impulsive choice is associated with both cocaine use and relapse. Little is known about the influence of transient states on impulsive choice in people who use cocaine (PWUC).Objective: This study investigated the direct effects of induced boredom on impulsive choice (i.e., temporal discounting) in PWUC relative to well-matched community controls.Methods: Forty-one PWUC (≥1× cocaine use in past 3 months; 7 females) and 38 demographically matched controls (5 females) underwent two experimental conditions in counterbalanced order. Temporal discounting was assessed immediately after a standardized boredom induction task (peg-turning) and a self-selected video watched for the same duration (non-boredom). Subjective mood state and perceived task characteristics were assessed at baseline, during experimental manipulations, and after the choice task.Results: PWUC and controls were well matched on sex, age, and socioeconomic status. Groups were also similar in reported use of drugs other than cocaine, except for recent cigarette and alcohol use (PWUC > controls). As expected, peg-turning increased boredom in the sample overall, with higher boredom reported during peg-turning than the video (p < .001, η2p = .20). Participants overall exhibited greater impulsive choice after boredom than non-boredom (p = .028, η2p = .07), with no preferential effects in PWUC (p > .05, BF01 = 2.9).Conclusion: Experimentally induced boredom increased state impulsivity irrespective of cocaine use status - in PWUC and carefully matched controls - suggesting a broad link between boredom and impulsive choice. This is the first study to show that transient boredom directly increases impulsive choice. Data support a viable laboratory method to further parse the effects of boredom on impulsive choice.

Effects of the estrous cycle on impulsive choice and interval timing in female rats.

Research in humans and animals shows differences in impulsive choice, which is a failure to wait for larger, delayed rewards, when comparing males and females. It is possible that fluctuations in sex hormones (estradiol and progesterone) across the reproductive cycle contribute to sex differences in impulsive choice. The current study delivered an impulsive choice task with peak interval trials to female rats while estrous cycles, the rodent reproductive cycle, were tracked over the course of the task. Female rats were more sensitive to changes in delay in the proestrus phase of the estrous cycle and made more larger-later choices when in estrus, particularly when the delay to the smaller reward was short. Estradiol increases dramatically during proestrus while progesterone peaks during estrus, suggesting that estradiol and progesterone may affect impulsive choice through mechanisms such as delay discounting, delay aversion, and/or timing processes. Analyses of timing of the choice task delays showed inconsistent effects of the estrous cycle across delays, suggesting that reward-timing interactions may have complicated how hormone fluctuations affected interval timing. Further research is needed to determine the mechanism underlying increased larger-later choices during the estrus phase, increased delay sensitivity during the proestrus phase, and variability in interval timing across delays and estrous cycle stages.

Mechanisms of impulsive choice: Experiments to explore and models to map the empirical terrain.

Impulsive choice is preference for a smaller-sooner (SS) outcome over a larger-later (LL) outcome when LL choices result in greater reinforcement maximization. Delay discounting is a model of impulsive choice that describes the decaying value of a reinforcer over time, with impulsive choice evident when the empirical choice-delay function is steep. Steep discounting is correlated with multiple diseases and disorders. Thus, understanding the processes underlying impulsive choice is a popular topic for investigation. Experimental research has explored the conditions that moderate impulsive choice, and quantitative models of impulsive choice have been developed that elegantly represent the underlying processes. This review spotlights experimental research in impulsive choice covering human and nonhuman animals across the domains of learning, motivation, and cognition. Contemporary models of delay discounting designed to explain the underlying mechanisms of impulsive choice are discussed. These models focus on potential candidate mechanisms, which include perception, delay and/or reinforcer sensitivity, reinforcement maximization, motivation, and cognitive systems. Although the models collectively explain multiple mechanistic phenomena, there are several cognitive processes, such as attention and working memory, that are overlooked. Future research and model development should focus on bridging the gap between quantitative models and empirical phenomena.

Wheel running leads to sex-specific effects on Western diet-associated glucose homeostasis and brain insulin signaling without altering food-related impulsive choice.

OBJECTIVES: There is a clear association between obesity and impulsivity. While exercise can suppress weight gain and decrease impulsive choice (IC), the relationship between impulsivity, the consumption of palatable, energy dense diets, and exercise is unclear. We examined IC before and after Western diet (WD) exposure in rats of both sexes and whether exercise would rescue any diet-mediated increases in IC. Our hypotheses were twofold: first, increased impulsivity would be associated with higher WD preference in a positive feedback loop and second, increased WD consumption would impair both peripheral and central insulin signaling, both of which exercise would attenuate. METHODS: Following baseline assessment of IC through a delay discounting task, rats were divided into naïve, sedentary (Sed), or wheel running (WR) groups for a 5-week WR and two-diet choice period after which rats underwent an oral glucose (OGTT) and insulin tolerance test (ITT) in addition to a re-test of IC. Insulin induced Akt-GSK3ß signaling in the brain was examined using western blot. RESULTS: All Sed rats preferred the WD diet, and all WR rats initially avoided the WD but subsequently reversed their avoidance to preference with females reversing earlier than males. Exercise suppressed weight gain and adiposity to a greater extent in males than females. Only WR males showed improved glucose clearance during OGTT, but both male and female WR rats had a faster recovery of hypoglycemia during ITT. Furthermore, WR rescued WD-induced deficits in hypothalamic Akt-GSK3ß signaling in males but not females. In the prefrontal cortex, however, WD and WR both reduced Akt-GSK3ß signaling in males but not females. There were no sex differences in IC at baseline, and all rats made more impulsive choices during the re-test independent of diet, sex, or exercise. DISCUSSION: The results suggest that while exercise may have a greater efficacy at attenuating diet-mediated metabolic dysregulation in males, it has some beneficial effects for females and highlights the need to develop sex-specific interventions for restoring energy balance.

Reducing impulsive choice VII: effects of duration of delay-exposure training.

Impulsive choice is related to substance use disorders, obesity, and other behaviors that negatively impact human health. Reducing impulsive choice may prove beneficial in ameliorating these maladaptive behaviors. Preclinical research in rats indicates that one reliable method for producing large and lasting reductions in impulsive choice is delay-exposure (DE) training. In all six of the prior DE-training experiments, rats were given extensive experience (~ 120 training sessions) with a delayed reinforcement contingency. The present experiment evaluated if similar large and lasting reductions in impulsive choice could be achieved with less training. The duration of DE training between groups of male Wistar rats was 0 sessions (training ended after a lever-pressing acquisition criterion was met), 30, 60, or 120 sessions. Comparison groups were given the same durations of training with immediate reinforcement. A post-training assessment of impulsive choice was completed using an increasing-delay procedure. For rats assigned to the 60-session condition, impulsive choice was reassessed at a 120-day follow-up. DE training reduced impulsive choice but, contrary to expectation, reductions in impulsive choice did not increase with DE-training duration (no significant training-duration by group interaction). Importantly, 60 sessions of DE training produced reductions in impulsive choice that were comparable to prior published findings and this effect remained significant at the 120-day follow-up. Procedural elements that may be responsible for the DE-training effect, and how they could be improved in future experiments, are discussed.

The paradoxical performance by different species on the ephemeral reward task.

The ephemeral reward task consists of giving an animal a choice between two distinctive stimuli, A and B (e.g., black and white), on each of which is placed a bit of food. If the animal chooses the food on A, it gets that reinforcer, but the other stimulus, B, is removed, and the trial is over. If it chooses the food on B, however, it gets that food and the stimulus A remains, so it can have that food as well. Thus, choice of stimulus B gives the animal two reinforcers rather than one. Wrasse (cleaner fish) easily learn to choose optimally, whereas surprisingly, most non-human primates do not. Parrots, however, appear to learn this task as easily as the fish. To test the hypothesis that animals that choose with their mouth can learn it, we tested pigeons and found that they show no evidence of optimal learning with this task (with either the manual presentation of the stimuli or the operant presentation of the stimuli). Similarly, rats show no evidence of optimal learning. However, if a 20-s delay (fixed-interval schedule) is inserted between stimulus choice and reinforcement, both pigeons and rats learn to perform optimally. The ephemeral reward task appears to promote impulsive choice in several species, but with this task (and others), inserting a delay between choice and reinforcement promotes more careful choice, leading to optimal performance.

The relationship between dietary fat intake, impulsive choice, and metabolic health.

Unhealthful foods are convenient, ubiquitous, and inexpensive. Overconsumption of unhealthful foods can result in disease states such as obesity and Type 2 diabetes. In addition to the physiological consequences of unhealthful foods, research in rats has shown that diets high in processed fat and sugar induce impulsive choice behavior. Research in humans has demonstrated a link between metabolic health and impulsive choice, but most investigations have not included diet. We investigated how dietary fat intake interacts with body fat percentage, fasting glucose, insulin response, and systemic inflammation levels to predict impulsive choices in humans. Participants were split into either Control (<35% calories from fat) or High-Fat (≥40% calories from fat) groups based on self-reported dietary intake, completed an impulsive choice task, and underwent testing to determine their body fat, glucose, insulin response, and inflammation levels. High-fat diets were not predictive of impulsive choices, but added sugar was predictive. Body fat percentage was associated with impulsive choices only in the group who reported consuming high-fat diets. In addition, fasting glucose was associated with impulsive choices in the control group. Therefore, metabolic health and dietary fat intake interacted to predict impulsive choices. These findings indicate that knowledge of dietary patterns coupled with metabolic health markers may help us better understand impulsive choices, thereby improving our ability to target individuals who could benefit from interventions to reduce impulsive choice behavior, with the goal of promoting more self-controlled food choices.

Dietary effects on the determinants of food choice: Impulsive choice, discrimination, incentive motivation, preference, and liking in male rats.

The current study sought to understand how long-term exposure to diets high in saturated fat and refined sugar affected impulsive choice behavior, discrimination abilities, incentive motivation, food preferences, and liking of fat and sugar in male rats. The results showed that 8 weeks of dietary exposure impaired impulsive choice behavior; rats exposed to diets high in processed fat or sugar were more sensitive to changes in delay, a marker of impulsivity. For the high-fat group, these deficits in impulsive choice may stem from poor time discrimination, as their performance was impaired on a temporal discrimination task. The high-fat group also showed reduced magnitude sensitivity in the impulsive choice task, and they earned fewer rewards during lever press training indicating potentially reduced incentive motivation. The high-fat group also developed a preference for high-fat foods compared to the chow and high-sugar group who both preferred sugar. In contrast, dietary exposure did not alter the liking of fat or sugar as measured by a taste reactivity task. Together, the results suggest that the alterations in impulsive choice, time discrimination, incentive motivation, and food preferences induced by consumption of a high-fat diet could make individuals vulnerable to overeating, and thus obesity.

Females in the forefront: time-based intervention effects on impulsive choice and interval timing in female rats.

Impulsive choice has been implicated in substance abuse, gambling, obesity, and other maladaptive behaviors. Deficits in interval timing may increase impulsive choices, and therefore, could serve as an avenue through which suboptimal impulsive choices can be moderated. Temporal interventions have successfully attenuated impulsive choices in male rats, but the efficacy of a temporal intervention has yet to be assessed in female rats. As such, this experiment examined timing and choice behavior in female rats, and evaluated the ability of a temporal intervention to mitigate impulsive choice behavior. The temporal intervention administered in this study was successful in reducing impulsive choices compared to a control group. Results of a temporal bisection task indicated that the temporal intervention increased long responses at the shorter durations. Further, results from the peak trials within the choice task combined with the progressive interval task suggest that the intervention increased sensitivity to delay and enhanced timing confidence. Overall, these results indicate that a temporal intervention can be a successful avenue for reducing impulsive choice behavior in female rats, and could contribute to the development of behavioral interventions to prevent impulsive choice and maladaptive behaviors that can be applied to both sexes.

Pair Housing Alters Delay Discounting in Lewis and Fischer 344 Rats.

Impulsive choice underlies several psychological disorders and can be assessed in laboratory rats using delay-discounting tasks, in which choice is for either one food pellet immediately or three food pellets after a delay. Choice for the smaller, immediate reinforcer is considered the impulsive choice. Lewis (LEW) and Fischer 344 (F344) rats differ in the number of impulsive choices made during this task when singly housed, with LEW choosing the impulsive option more often. Due to increasing recommendations to provide environmental enrichment as a component of animal-husbandry practices, a systematic replication of two previous studies was conducted using pair-housed LEW and F344. Delay discounting was assessed with pair-housed LEW and F344 and compared to previous data from singly housed LEW and F344 collected from the same laboratory. Results showed that differences in impulsive choice between the two strains were attenuated with pair housing. The main result driving this change appears to be an increase in impulsive choice in pair-housed F344 relative to singly housed F344.

Dissociated neural substrates underlying impulsive choice and impulsive action.

There is a growing consensus that impulsivity is a multifaceted construct that comprises several components such as impulsive choice and impulsive action. Although impulsive choice and impulsive action have been shown to be the common characteristics of some impulsivity-related psychiatric disorders, surprisingly few studies have directly compared their neural correlates and addressed the question whether they involve common or distinct neural correlates. We addressed this important empirical gap using an individual differences approach that could characterize the functional relevance of neural networks in behaviors. A large sample (n=227) of college students was tested with the delay discounting and stop-signal tasks, and their performances were correlated with the neuroanatomical (gray matter volume, GMV) and functional (resting-state functional connectivity, RSFC) measures, using multivariate pattern analysis (MVPA) and 10-fold cross-validation. Behavioral results showed no significant correlation between impulsive choice measured by discounting rate (k) and impulsive action measured by stop signal reaction time (SSRT). The GMVs in the right frontal pole (FP) and left middle frontal gyrus (MFG) were predictive of k, but not SSRT. In contrast, the GMVs in the right inferior frontal gyrus (IFG), supplementary motor area (SMA), and anterior cingulate cortex (ACC) could predict individuals' SSRT, but not k. RSFC analysis using the FP and right IFG as seed regions revealed two distinct networks that correspond well to the "waiting" and "stopping" systems, respectively. Furthermore, the RSFC between the FP and ventromedial prefrontal cortex (VMPFC) was predictive of k, whereas the RSFC between the IFG and pre-SMA was predictive of SSRT. These results demonstrate clearly neural dissociations between impulsive choice and impulsive action, provide new insights into the nature of impulsivity, and have implications for impulsivity-related disorders.

Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults.

Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24-34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.

Impulsive choice predicts anxiety-like behavior, but not alcohol or sucrose consumption, in male Long-Evans rats.

BACKGROUND: Prior human research indicates robust, positive relations between impulsive choice (i.e., preference for smaller, immediate over larger, delayed rewards) and alcohol use disorders. However, varied findings in the nonhuman literature reveal a relatively ambiguous relation between impulsive choice and alcohol consumption in rodents. In addition, few rodent studies have investigated potential relations between impulsive choice and common covariates of alcohol consumption (e.g., avidity for sweet substances or anxiety-like behavior). METHODS: Ninety-two male Long-Evans rats completed an impulsive-choice task. From this larger sample, extreme high- and low-impulsive groups (n = 30 each) were retained for further testing. In separate tests, subsequent open-field behavior and consumption of oral alcohol (12% w/v) and isocaloric sucrose were examined. Impulsive choice was then retested to examine whether behavior remained stable over the course of the experiment. RESULTS: No significant relations emerged between impulsive choice and either alcohol or sucrose consumption. However, impulsive choice predicted greater anxiety-like behavior (avoidance of the center field, defecation) in the open-field test. In turn, greater anxiety predicted lower alcohol and sucrose consumption. Finally, choice remained generally stable across the experiment, although high-impulsive rats tended toward less impulsive choice in the retest. CONCLUSIONS: Although impulsive choice and alcohol consumption appear to share some variance with anxiety-like behavior, the present data offer no support for a relation between impulsive choice and alcohol consumption in Long-Evans rats. Together with mixed rodent data from prior reports, these findings attenuate cross-species comparisons to human relations between impulsive choice and alcohol use disorders.

Aberrant glutamatergic systems underlying impulsive behaviors: Insights from clinical and preclinical research.

Impulsivity is a broad construct that often refers to one of several distinct behaviors and can be measured with self-report questionnaires and behavioral paradigms. Several psychiatric conditions are characterized by one or more forms of impulsive behavior, most notably the impulsive/hyperactive subtype of attention-deficit/hyperactivity disorder (ADHD), mood disorders, and substance use disorders. Monoaminergic neurotransmitters are known to mediate impulsive behaviors and are implicated in various psychiatric conditions. However, growing evidence suggests that glutamate, the major excitatory neurotransmitter of the mammalian brain, regulates important functions that become dysregulated in conditions like ADHD. The purpose of the current review is to discuss clinical and preclinical evidence linking glutamate to separate aspects of impulsivity, specifically motor impulsivity, impulsive choice, and affective impulsivity. Hyperactive glutamatergic activity in the corticostriatal and the cerebro-cerebellar pathways are major determinants of motor impulsivity. Conversely, hypoactive glutamatergic activity in frontal cortical areas and hippocampus and hyperactive glutamatergic activity in anterior cingulate cortex and nucleus accumbens mediate impulsive choice. Affective impulsivity is controlled by similar glutamatergic dysfunction observed for motor impulsivity, except a hyperactive limbic system is also involved. Loss of glutamate homeostasis in prefrontal and nucleus accumbens may contribute to motor impulsivity/affective impulsivity and impulsive choice, respectively. These results are important as they can lead to novel treatments for those with a condition characterized by increased impulsivity that are resistant to conventional treatments.

Abbreviated Fixed-Interval Interventions Promote Self-Control in Rats.

Impulsive choice, defined as choices of a smaller-sooner reward over a larger-later reward, can be reduced by time-based interventions that expose rats to delayed rewards. These interventions improve temporal processing concurrent with reducing impulsive choice. Exposure to delayed reinforcement has produced improvements in self-control after 30 sessions of intervention exposure (Renda et al., 2021). Experiment 1 of the present study used a pre-/post-test design to investigate a range of intervention exposures (6, 15, 30, and 45 sessions), including shorter exposures that have not previously been examined. Peak-interval timing was also assessed to determine whether different intervention exposures would improve temporal processing. All intervention exposures, including the abbreviated intervention, reduced impulsive choice, and improved temporal processing. Experiment 2 showed that the 6-session intervention improved self-control relative to a no-delay control, further strengthening the proposal that an abbreviated intervention may be sufficient to reduce impulsive choice. Moreover, improvements in peak-interval timing were observed in groups receiving a pre-intervention impulsive choice assessment, suggesting that exposure to the impulsive choice task may improve temporal processing.

A systematic review and meta-analysis of test-retest reliability and stability of delay and probability discounting.

In this meta-analysis, we describe a benchmark value of delay and probability discounting reliability and stability that might be used to (a) evaluate the meaningfulness of clinically achieved changes in discounting and (b) support the role of discounting as a valid and enduring measure of intertemporal choice. We examined test-retest reliability, stability effect sizes (dz; Cohen, 1992), and relevant moderators across 30 publications comprising 39 independent samples and 262 measures of discounting, identified via a systematic review of PsychInfo, PubMed, and Google Scholar databases. We calculated omnibus effect-size estimates and evaluated the role of proposed moderators using a robust variance estimation meta-regression method. The meta-regression output reflected modest test-retest reliability, r = .670, p < .001, 95% CI [.618, .716]. Discounting was most reliable when measured in the context of temporal constraints, in adult respondents, when using money as a medium, and when reassessed within 1 month. Testing also suggested acceptable stability via nonsignificant and small changes in effect magnitude over time, dz = 0.048, p = .31, 95% CI [-0.051, 0.146]. Clinicians and researchers seeking to measure discounting can consider the contexts when reliability is maximized for specific cases.

Self-Control Training: A Scoping Review.

We conducted a scoping review of the behavior analytic self-control training (SCT) literature. To identify included articles, we searched key terms in six databases for articles published between 1988 and 2021. We included empirical articles that used a behavioral approach to self-control training with human participants for whom increasing self-control choice was a clinically significant goal and measured self-control and impulsive choice as dependent variables. Twenty-five experiments from 24 articles with a total of 79 participants were included in the review. This review aims to summarize the characteristics of SCT procedures and outcomes, provide recommendations for future research directions, and offer practical suggestions to clinicians incorporating SCT into practice. We examined similarities across studies regarding the independent variables manipulated in SCT, dependent variables measured, metrics of successful interventions, and assessment of generalization and maintenance of self-control choice. Twenty-one experiments arranged concurrent self-control- and impulsive-choice options with positive reinforcement, and four experiments arranged self-control training with negative-reinforcement contingencies. Variations of SCT included progressively increasing delays, intervening activities, signaled delays, antecedent rules, and commitment responses. Providing an intervening activity during the delay was largely successful at increasing self-control choice. Maintenance and generalization of increased self-control choice were assessed in two and three experiments, respectively. Future research should focus on improving the generality of SCT procedures in clinical settings by increasing terminal delays, fading out intervening activities, including probabilistic outcomes, and combining appetitive and aversive outcomes. Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-023-00885-y.

Behavioral and neuronal extracellular vesicle biomarkers associated with nicotine's enhancement of the reinforcing strength of cocaine in female and male monkeys.

While the majority of people with cocaine use disorders (CUD) also co-use tobacco/nicotine, most preclinical cocaine research does not include nicotine. The present study examined nicotine and cocaine co-use under several conditions of intravenous drug self-administration in monkeys, as well as potential peripheral biomarkers associated with co-use. In Experiment 1, male rhesus monkeys (N = 3) self-administered cocaine (0.001-0.1 mg/kg/injection) alone and with nicotine (0.01-0.03 mg/kg/injection) under a progressive-ratio schedule of reinforcement. When nicotine was added to cocaine, there was a significant leftward/upward shift in the number of injections received. In Experiment 2, socially housed female and male cynomolgus monkeys (N = 14) self-administered cocaine under a concurrent drug-vs-food choice schedule of reinforcement. Adding nicotine to the cocaine solution shifted the cocaine dose-response curves to the left, with more robust shifts noted in the female animals. There was no evidence of social rank differences. To assess reinforcing strength, delays were added to the presentation of drug; the co-use of nicotine and cocaine required significantly longer delays to decrease drug choice, compared with cocaine alone. Blood samples obtained post-session were used to analyze concentrations of neuronally derived small extracellular vesicles (NDE); significant differences in NDE profile were observed for kappa-opioid receptors when nicotine and cocaine were co-used compared with each drug alone and controls. These results suggest that drug interactions involving the co-use of nicotine and cocaine are not simply changing potency, but rather resulting in changes in reinforcing strength that should be utilized to better understand the neuropharmacology of CUD and the evaluation of potential treatments.