Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats.

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8mg/kg), cotinine (0.5-5.0mg/kg), anatabine (0.5-5.0mg/kg), and myosmine (5.0-20.0mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated.

Suboptimal choice in rats: Incentive salience attribution promotes maladaptive decision-making.

Stimuli that are more predictive of subsequent reward also function as better conditioned reinforcers. Moreover, stimuli attributed with incentive salience function as more robust conditioned reinforcers. Some theories have suggested that conditioned reinforcement plays an important role in promoting suboptimal choice behavior, like gambling. The present experiments examined how different stimuli, those attributed with incentive salience versus those without, can function in tandem with stimulus-reward predictive utility to promote maladaptive decision-making in rats. One group of rats had lights associated with goal-tracking as the reward-predictive stimuli and another had levers associated with sign-tracking as the reward-predictive stimuli. All rats were first trained on a choice procedure in which the expected value across both alternatives was equivalent but differed in their stimulus-reward predictive utility. Next, the expected value across both alternatives was systematically changed so that the alternative with greater stimulus-reward predictive utility was suboptimal in regard to primary reinforcement. The results demonstrate that in order to obtain suboptimal choice behavior, incentive salience alongside strong stimulus-reward predictive utility may be necessary; thus, maladaptive decision-making can be driven more by the value attributed to stimuli imbued with incentive salience that reliably predict a reward rather than the reward itself.

Naturalistic assessment of demand for cigarettes, snus, and nicotine gum.

RATIONALE: Behavioral economic measures of demand provide estimates of tobacco product abuse liability and may predict effects of policy-related price regulation on consumption of existing and emerging tobacco products. OBJECTIVE: In the present study, we examined demand for snus, a smokeless tobacco product, in comparison to both cigarettes and medicinal nicotine. We used both a naturalistic method in which participants purchased these products for use outside the laboratory, as well as laboratory-based self-administration procedures. METHODS: Cigarette smokers (N = 42) used an experimental income to purchase their usual brand of cigarettes and either snus or gum (only one product available per session) across a range of prices, while receiving all products they purchased from one randomly selected price. In a separate portion of the study, participants self-administered these products during laboratory-based, progressive ratio sessions. RESULT: Demand elasticity (sensitivity of purchasing to price) was significantly greater for snus than cigarettes. Elasticity for gum was intermediate between snus and cigarettes but was not significantly different than either. Demand intensity (purchasing unconstrained by price) was significantly lower for gum compared to cigarettes, with no significant difference observed between snus and cigarettes. Results of the laboratory-based, progressive ratio sessions were generally discordant with measures of demand elasticity, with significantly higher "breakpoints" for cigarettes compared to gum and no significant differences between other study products. Moreover, breakpoints and product purchasing were generally uncorrelated across tasks. CONCLUSIONS: Under naturalistic conditions, snus appears more sensitive to price manipulation than either cigarettes or nicotine gum in existing smokers.

Stuck in Time: Negative Income Shock Constricts the Temporal Window of Valuation Spanning the Future and the Past.

Insufficient resources are associated with negative consequences including decreased valuation of future reinforcers. To determine if these effects result from scarcity, we examined the consequences of acute, abrupt changes in resource availability on delay discounting-the subjective devaluation of rewards as delay to receipt increases. In the current study, 599 individuals recruited from Amazon Mechanical Turk read a narrative of a sudden change (positive, neutral, or negative) to one's hypothetical future income and completed a delay discounting task examining future and past monetary gains and losses. The effects of the explicit zero procedure, a framing manipulation, was also examined. Negative income shock significantly increased discounting rates for gains and loses occurring both in the future and the past. Positive income windfalls significantly decreased discounting to a lesser extent. The framing procedure significantly reduced discounting under all conditions. Negative income shocks may result in short-term choices.

Unstuck in time: episodic future thinking reduces delay discounting and cigarette smoking.

RATIONALE: Delay discounting, or the devaluation of delayed outcomes, appears to play an etiological role in tobacco and other substance-use disorders. OBJECTIVES: No human studies to our knowledge have been designed to examine whether experimental reductions in delay discounting produce concomitant reduction in drug use. METHODS: Using methods from prior studies on delay discounting and obesity, we examined the effects of episodic future thinking (EFT; a form of mental prospection) on delay discounting and cigarette self-administration in smokers. RESULTS: Consistent with prior data, EFT significantly reduced both delay discounting (Cohen's d effect size = 0.65) and the number of cigarette puffs earned in a cigarette self-administration task (d = 0.58). CONCLUSIONS: The effects of EFT on delay discounting generalize to smokers; EFT also reduces laboratory-based cigarette self-administration. Potential mechanisms of EFT's effects are discussed as well as implications of EFT for clinical treatment of substance-use disorders.

The relative value of two options for pigeons depends on their context.

It is well known that when humans are given a choice between two options, their preference is affected by the presence of a third. Generally, there is an increase in preference for the option closer to the third. We show that a shift in preference in the direction away from the third option can occur in animals. We gave pigeons a choice between A, reinforcement following 10 pecks and a 0.5-s delay, and B, reinforcement following 5 pecks and a 1.5-s delay. Once stable preferences were established, we introduced a third stimulus, less preferred than the other two: C, reinforcement following 20 pecks and a 0.5-s delay or D, reinforcement following 5 pecks and a 4.5-s delay. We found that pigeons presented with C showed an increased preference for B, whereas pigeons presented with D showed an increased preference for A. Our results were consistent with the similarity or attentional hypothesis, which suggests that the third option should interfere with the option more similar to it or would draw attention to the less preferred component of the third option and generalize to the option more similar to it. Possible accounts for the differences in outcomes are suggested.

Behavioral Economics of Cigarette Purchase Tasks: Within-Subject Comparison of Real, Potentially Real, and Hypothetical Cigarettes.

INTRODUCTION: Hypothetical rewards are commonly used in studies of laboratory-based tobacco demand. However, behavioral economic demand procedures require confirmation that the behavior elicited from real and hypothetical reward types are equivalent, and that results attained from these procedures are comparable to other accepted tasks, such as the hypothetical purchase task. METHODS: Nineteen smokers were asked to purchase 1 week's worth of cigarettes that they would consume over the following week either at one price that incrementally increased across four weekly sessions ("real" sessions) or four prices in a single session ("potentially real" session), one of which was randomly chosen to be actualized. At each session, participants also completed a hypothetical cigarette purchase task. After each week, participants reported the number of cigarettes they actually smoked. RESULTS: Demand was found to be equivalent under both the real and potentially real reward conditions but statistically different from the demand captured in the hypothetical purchase task. However, the amounts purchased at specific prices in the hypothetical purchase task were significantly correlated with the amount purchased at comparable prices in the other two tasks (except for the highest price examined in both tasks of $1.00 per cigarette). Number of cigarettes consumed that were obtained outside of the study was correlated with study cigarette price. CONCLUSIONS: Combined, these results suggest that purchasing behavior during potentially real sessions (1) was not functionally different from real sessions, (2) imposes fewer costs to the experimenter, and (3) has high levels of both internal and external validity.

The influence of multiple temporal memories in the peak-interval procedure.

Memories for when an event has occurred are used to anticipate future occurrences of the event, but what happens when the event is equally likely to occur at two different times? In this study, one group of rats was always reinforced at 21 s on the peak-interval procedure (21-only group), whereas another group of rats was reinforced at either 8 or 21 s, which varied daily (8-21 group). At the beginning of each session, the behavior of the 8-21 group largely lacked temporal control, but by the end of the session, temporal control was reestablished. When both groups were reinforced at 21 s, the patterns of responding were indistinguishable after subjects in the 8-21 group had experienced 13 reinforcement trials. Finally, the reinforcement times of previous sessions affected the 8-21 group, such that subjects were biased depending on the reinforcement time of the prior session. These results show that when the reinforcement time is initially ambiguous, rats respond in a way that combines their expectations of both possibilities; then they incrementally adjust their responding as they receive more information, but still information from prior sessions biases their initial expectation for the reinforcement time. Combined, these results imply that rats are sensitive to the age of encoded temporal memories in an environment in which the reinforcement time is variable. How these results inform the scalar expectancy theory, the currently accepted model of interval-timing behavior, is discussed.

Predictors of delay discounting among smokers: education level and a Utility Measure of Cigarette Reinforcement Efficacy are better predictors than demographics, smoking characteristics, executive functioning, impulsivity, or time perception.

Ninety-four smokers completed the delay discounting procedure for either hypothetical amounts of money, $10 (money) and $1000 (money) or hypothetical amounts of cigarettes ($10 and $1000 worth of cigarettes). We investigated how variables previously found to be related to rates of delay discounting accounted for the observed results. These variables included the following: demographic information, smoking characteristics, executive function abilities, impulsivity, time perception, and the Utility Measure of Cigarette Reinforcing Efficacy (UMCE). Education level and UMCE were each significantly correlated with 3 out of 4 of the discounting measures. Moreover, the largest effect sizes observed were between these two measures and the four discounting measures. All potential discounting predictors were also investigated using step-wise linear regression with Bayesian Information Criterion (BIC) analysis­these BIC models revealed that education level and UMCE accounted for large portions of the variance. We conclude that education level and UMCE were the most consistent predictors of discounting. This data is discussed within the framework of a widely accepted neuroeconomic model that suggests that two brain systems separately assess two separate facets of decision-making, and the interplay between these two systems determines self-control in smokers. We hypothesize that education level and UMCE may serve as surrogate measures of the functionality of these two systems and that discounting may be a sentinel measure of self-control.

Therapeutic Opportunities for Self-Control Repair in Addiction and Related Disorders: Change and the Limits of Change in Trans-Disease Processes.

Contemporary neuro-economic approaches hypothesize that self-control failure results from drugs annexing normal learning mechanisms that produce pathological reward processing and distort decision-making as a result from the dysregulation of two valuation systems. An emphasis on processes shared across different diseases and disorders is at odds with the contemporary approach that assumes unique disease etiologies and treatments. Studying trans-disease processes can identify mechanisms that operate in multiple disease states and ascertain if factors that influence processes in one disease state may be applicable to all disease states. In this paper we review the dual model of self-control failure, the Competing Neurobehavioral Decision Systems approach, the relationship of delay discounting to the relative control of these two systems, and evidence that the executive system can be strengthened. Future research that could result in more potent interventions for executive system improvement and potential constraints on the repair of self-control failure are discussed.

Prospective memory: a comparative perspective.

Prospective memory consists of forming a representation of a future action, temporarily storing that representation in memory, and retrieving it at a future time point. Here, we review the recent development of animal models of prospective memory. We review experiments using rats that focus on the development of time-based and event-based prospective memory. Next, we review a number of prospective-memory approaches that have been used with a variety of non-human primates. Finally, we review selected approaches from the human literature on prospective memory to identify targets for development of animal models of prospective memory. This article is part of a Special Issue entitled: "Tribute to Tom Zentall".

The behavioral- and neuro-economic process of temporal discounting: A candidate behavioral marker of addiction.

Addiction science would benefit from the identification of a behavioral marker. A behavioral marker could reflect the projected clinical course of the disorder, function as a surrogate measure of clinical outcome, and/or may be related to biological components that underlie the disorder. In this paper we review relevant literature, made possible with the early and sustained support by NIDA, to determine whether temporal discounting, a neurobehavioral process derived from behavioral economics and further explored through neuroeconomics, may function as a behavioral marker. Our review suggests that temporal discounting 1) identifies individuals who are drug-dependent, 2) identifies those at risk of developing drug dependence, 3) acts as a gauge of addiction severity, 4) correlates with all stages of addiction development, 5) changes with effective treatment, and 6) may be related to the biological and genetic processes that underlie addiction. Thus, initial evidence supports temporal discounting as a candidate behavioral marker. Additional studies will be required in several areas for a more conclusive determination. Confirmation that temporal discounting functions as a behavioral marker for addiction could lead to 1) a screen for new treatments, 2) personalization of prevention and treatment interventions, and 3) the extension of temporal discounting as a behavioral marker for other etiologically similar disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Event-based prospective memory in the rat.

People plan to act in the future when an appropriate event occurs, a capacity known as event-based prospective memory. Prospective memory involves forming a representation of a planned future action, subsequently inactivating the representation, and ultimately reactivating it at an appropriate point in the future. Recent studies suggest that monkeys, chimpanzees, and rats display elements of prospective memory, but it is uncertain if the full sequence (activation-inactivation-reactivation) that occurs in humans also occurs in nonhumans. Here, we asked if rats exhibit event-based prospective memory. Rats completed an ongoing temporal-discrimination task while waiting for a large meal. To promote the use of event-based prospective memory, we created an event (tone pulses) that provided information that the meal could be obtained soon. Event-based prospective memory was suggested by the dramatic decline in ongoing-task performance after the event, with excellent performance at other times. To document that the event initiated memory activation, we arranged for the event to occur at novel times. Finally, multiple, repeated presentations of the event on the same day demonstrate that rats inactivate and reactivate the memory representation in an on-demand, event-based fashion. Development of an animal model of prospective memory may be valuable to probe the biological underpinnings of memory disorders.

Prospective memory in the rat.

The content of prospective memory is comprised of representations of an action to perform in the future. When people form prospective memories, they temporarily put the memory representation in an inactive state while engaging in other activities, and then activate the representation in the future. Ultimately, successful activation of the memory representation yields an action at an appropriate, but temporally distant, time. A hallmark of prospective memory is that activation of the memory representation has a deleterious effect on current ongoing activity. Recent evidence suggests that scrub jays and non-human primates, but not other species, are capable of future planning. We hypothesized that prospective memory produces a selective deficit in performance at the time when rats access a memory representation but not when the memory representation is inactive. Rats were trained in a temporal bisection task (90 min/day). Immediately after the bisection task, half of the rats received an 8-g meal (meal group) and the other rats received no additional food (no-meal group). Sensitivity to time in the bisection task was reduced as the 90-min interval elapsed for the meal group but not for the no-meal group. This time-based prospective-memory effect was not based on response competition, an attentional limit, anticipatory contrast, or fatigue. Our results suggest that rats form prospective memories, which produces a negative side effect on ongoing activity.

Behavioral sensitivity of temporally modulated striatal neurons.

Recent investigations into the neural mechanisms that underlie temporal perception have revealed that the striatum is an important contributor to interval timing processes, and electrophysiological recording studies have shown that the firing rates of striatal neurons are modulated by the time in a trial at which an operant response is made. However, it remains unclear whether striatal firing rate modulations are related to the passage of time alone (i.e., whether temporal information is represented in an "abstract" manner independent of other attributes of biological importance), or whether this temporal information is embedded within striatal activity related to co-occurring contextual information, such as motor behaviors. This study evaluated these two hypotheses by recording from striatal neurons while rats performed a temporal production task. Rats were trained to respond at different nosepoke apertures for food reward under two simultaneously active reinforcement schedules: a variable-interval (VI-15 s) schedule and a fixed-interval (FI-15 s) schedule of reinforcement. Responding during a trial occurred in a sequential manner composing three phases; VI responding, FI responding, VI responding. The vast majority of task-sensitive striatal neurons (95%) varied their firing rates associated with equivalent behaviors (e.g., periods in which their snout was held within the nosepoke) across these behavioral phases, and 96% of cells varied their firing rates for the same behavior within a phase, thereby demonstrating their sensitivity to time. However, in a direct test of the abstract timing hypothesis, 91% of temporally modulated "hold" cells were further modulated by the overt motor behaviors associated with transitioning between nosepokes. As such, these data are inconsistent with the striatum representing time in an "abstract' manner, but support the hypothesis that temporal information is embedded within contextual and motor functions of the striatum.

A heterogeneous population code for elapsed time in rat medial agranular cortex.

The neural mechanisms underlying the temporal control of behavior are largely unknown. Here we recorded from medial agranular cortex neurons in rats while they freely behaved in a temporal production task, the peak-interval procedure. Due to variability in estimating the time of food availability, robust responding typically bracketed the expected duration, starting some time before and ending some time after the signaled delay. These response periods provided analytic "steady state" windows during which subjects actively indicated their temporal expectation of food availability. Remarkably, during these response periods, a variety of firing patterns were seen that could be broadly described as ramps, peaks, and dips, with different slopes, directions, and times at which maxima or minima occur. Regularized linear discriminant analysis indicated that these patterns provided sufficiently reliable information to discriminate the elapsed duration of responding within these response periods. Modeling this across neuron variability showed that the utilization of ramps, dips, and peaks, with different slopes and minimal/maximal rates at different times, led to a substantial improvement in temporal prediction errors, suggesting that heterogeneity in the neural representation of elapsed time may facilitate temporally controlled behavior.