A review of research on cigarette smoking in Preventive Medicine in recognition of the journal's 50th anniversary.

This report reviews the literature on cigarette smoking published in Preventive Medicine over the past 50 years. The goal is twofold. First, to acknowledge the 50th anniversary of Preventive Medicine and its role in disseminating research on cigarette smoking by providing an abridged summary of smoking research published in the journal from inception through June 23, 2022. Second, to review experimental reports to identify contributions to innovations in tobacco control and regulatory efforts to reduce cigarette smoking. We searched PubMed using the search terms cigarette/cigarettes, tobacco products, smoking, smoking cessation, Preventive Medicine. Titles and abstracts were reviewed in duplicate, excluding reports not addressing cigarette smoking. Included reports were categorized by study type (original study, commentary, review). Experimental articles were assessed for impact using iCite, a National Institutes of Health web application that provides bibliometric information for articles in defined topic areas. The review identified 1181 articles on cigarette smoking: 1018 original studies (86.2%), 107 literature reviews (9.1%), and 56 commentaries (4.7%); 166 of the 1018 original studies (16%) were experimental reports. In the iCite analysis these 166 experimental articles received 6366 total citations, a mean (standard error) citation rate/article of 38.35 (±3.21) and mean relative citation ratio of 1.85 (±0.17) which is at the 73rd percentile for NIH-funded field- and time-normalized reports. Overall, this review demonstrates an ongoing and impactful contribution of Preventive Medicine to efforts to reduce cigarette smoking, the most preventable cause of premature death.

Relating individual differences in the reinforcing value of smoking and dependence severity to nicotine exposure levels in vulnerable populations.

Cigarette smoking is overrepresented in populations with psychiatric conditions and socioeconomic disadvantage. Greater understanding of the role of reinforcement and nicotine dependence in smoking among vulnerable populations may facilitate development of better targeted interventions to reduce smoking. Prior research demonstrated that individual differences in the reinforcing value of smoking and nicotine-dependence severity predicted total nicotine-exposure in vulnerable populations. The present study uses multivariate regression to address two aims: (1) Quantify the degree to which the reinforcing value of smoking, assessed using the Cigarette Purchase Task (CPT), and dependence severity assessed using the Fagerström Test of Nicotine Dependence and Brief Wisconsin Inventory of Smoking Dependence Motives (B-WISDM) each account for individual differences in cotinine-plus-3'-hydroxycotinine (COT+3HC) levels. (2) Explore whether there is overlap in the variance accounted for by the CTP, FTND, and B-WISDM. Participants were 628 adults with co-morbid psychiatric conditions or socioeconomic disadvantage who smoked daily. The CPT, FTND, and B-WISDM models accounted for 23.76%, 32.45%, and 29.61% of the variance in COT+3HC levels, respectively. Adding CPT to the FTND model failed to increase the variance accounted for and adding it to the B-WISDM model did so by only 1.2% demonstrating considerable overlap in the variance in nicotine exposure levels accounted for by these three instruments. These results provide new knowledge on the relationship between individual differences in the reinforcing value of smoking and nicotine-exposure levels and suggest differences in reinforcing value may underpin a considerable portion of the variance in nicotine exposure accounted for by dependence severity.

Using an experimental tobacco marketplace to pilot test the substitutability of JUUL e-cigarettes and other alternative nicotine and tobacco products for conventional cigarettes among vulnerable populations.

The Experimental Tobacco Marketplace (ETM) is an online research marketplace where increasing the cost of cigarettes is used to investigate the substitutability of other fixed-price tobacco products such as electronic nicotine delivery systems (ENDS). The ETM is useful for modeling effects of potential policy changes on use of various concurrently available products. To our knowledge, the ETM has not been used to investigate substitutability of newer generation e-cigarettes or populations at increased risk for smoking, heavy smoking, nicotine dependence, and smoking-attributable adverse effects. In the current pilot study, participants were 30 adult daily smokers with socioeconomic disadvantage or comorbid psychiatric conditions (substance-use disorder or mental illness). In each session, cigarette prices increased ($0.12, $0.25, $0.50, $1.00. and $2.00 per cigarette) while prices for alternative products remained fixed. Across three ETM sessions, either all products, all products except little cigars and cigarillos (LCCs), or all products except ENDS (JUUL e-cigarettes) were available. Linear regression was performed on individual participant data using log-transformed cigarette price to determine demand and substitution. Cigarette demand decreased as price increased across sessions (significantly non-zero slopes, ps ≤ 0.0001). When all products were available, ENDS substitution increased as cigarette price increased (significantly non-zero slope, p = .016). When LCCs were unavailable, ENDS again were a significant substitute (p = .008). When ENDS were unavailable, LCCs did not substitute (ps ≥ 0.48). In all sessions, participants rarely purchased other products (e.g., snus). Overall, ENDS were the most robust substitute for cigarettes, further underscoring the potential importance of ENDS availability on the impact of tobacco regulatory policies.

The effects of large, small, and thinning magnitudes of alternative reinforcement on resurgence.

Resurgence refers to an increase of a previously reinforced target behavior following the worsening of conditions for a more recently reinforced alternative behavior. There is evidence to suggest that alternative reinforcers of greater magnitude are more effective at reducing target responding but may also result in more resurgence when removed. Similar effects have been observed with high rates of alternative reinforcement. However, in clinical settings, reinforcement rate thinning is used to reduce the likelihood of resurgence associated with higher rates of alternative reinforcement. Given the clinical importance of alternative reinforcer magnitude, it is necessary to evaluate how reinforcer magnitude thinning may impact resurgence as well. Following Phase 1 in which target responding was reinforced, rats earned either large (six pellets), small (one pellet), or thinned (reduced from six pellets to one across sessions) magnitude reinforcement for alternative responding during target-response extinction in Phase 2. Then, alternative responding was placed on extinction for all groups in Phase 3. Target responding was comparably elevated at the end of Phase 2 for groups Small and Thin compared to group Large. In Phase 3, resurgence was evident only in group Large but target responding remained relatively elevated in groups Small and Thin. These results provide additional evidence of the important interplay between conditions of alternative reinforcement and the persistence and resurgence of target responding.

Resurgence of alcohol seeking following abstinence induced by punishment in male and female rats.

To better approximate the human condition, animal models of relapse to drug and alcohol seeking have increasingly employed negative consequences to generate abstinence. Here we report the first demonstration of relapse to punishment-suppressed alcohol seeking induced by loss of non-drug reward (i.e., resurgence). We also report the first examination of potential sex differences in any form of relapse to alcohol seeking following suppression by punishment. Male and female rats first pressed a lever for 20 % oral alcohol. Next, lever pressing for one group continued to produce alcohol, but also produced occasional footshock. For another group, lever pressing similarly produced alcohol and occasional footshock, and a nose-poke response produced alternative non-drug reward (i.e., food). Males showed similar suppression of alcohol seeking by punishment alone and punishment + alternative non-drug reward, whereas females showed less suppression by punishment alone. Finally, when alternative reinforcement and punishment were suspended, resurgence occurred for both sexes in the group that previously had access to non-drug reward. Exposure to and then removal of punishment alone did not produce relapse for males, but it did for females. These results suggest that loss of alternative non-drug reward can generate relapse to alcohol seeking following abstinence induced by negative consequences. Future research should further examine the role of potential sex differences in sensitivity to punishment and how such differences may contribute to relapse more broadly.

Examination of alternative-response discrimination training and resurgence in rats.

Resurgence is an increase in a previously reinforced behavior following a worsening of conditions for a more recently reinforced behavior. Discrimination training is incorporated into treatment for problem behavior to prevent treatment adherence failures that may result in resurgence. There is evidence that resurgence may be reduced when a stimulus that signals alternative-response extinction is present compared with absent; however, the generality of this effect is unknown given the limited testing conditions. The goal of the present experiments was to further examine the effects of such stimuli in a reverse-translational evaluation using rats. Target responding was reinforced in baseline and then placed on extinction in the following discrimination-training phase. An alternative response was differentially reinforced in a two-component multiple schedule where one stimulus (i.e., SD) signaled alternative-response reinforcement and the other (i.e., SΔ) signaled extinction. Experiment 1 assessed resurgence in both the SΔ and SD when alternative reinforcement was removed. Experiment 2 evaluated resurgence under conditions that better approximated those used in the clinic in which the alternative-response SΔ was present or absent. The SΔ failed to suppress target responding during resurgence testing in both experiments. These findings suggest that the conditions under which an alternative-response SΔ will successfully mitigate resurgence may be limited and require further research.

Resurgence and downshifts in alternative reinforcement rate.

Resurgence refers to an increase in a previously suppressed target behavior with a relative worsening of conditions for a more recently reinforced alternative behavior. This experiment examined the relation between resurgence and the magnitude of a reduction in the rate of reinforcement for the alternative behavior. Groups of both male and female rats initially pressed a target lever for food on a variable-interval (VI) 30-s schedule. In a second phase, responding to the target lever was extinguished for all groups and pressing an alternative lever was reinforced on a VI 10-s schedule. Next, the rate of reinforcement for alternative behavior was reduced differentially across groups by arranging extinction, VI 80-s, VI 40-s, VI 20-s, or continued VI 10-s reinforcement. Target responding increased as an exponential function of the magnitude of the reduction in alternative reinforcement rates. With the exception that males appeared to show higher rates of target responding in baseline and higher rates of alternative responding in other phases, the overall pattern of responding across phases was not meaningfully different between sexes. The pattern of both target and alternative response rates across sessions and phases was well described quantitatively by the Resurgence as Choice in Context model.

Re-exposure to reinforcement in context a during treatment in context b reduces ABC renewal.

Previous work from our laboratory showed that intermittently re-exposing rats to reinforcement for lever pressing in a training (A) context, while eliminating lever pressing in a second (B) context, increased ABA renewal of lever pressing relative to rats that experienced only Context B during response elimination. In the current study, we replicated these procedures while assessing renewal in the presence of a novel context (i.e., ABC renewal). Unlike the findings described above, renewal was reduced in the group that experienced re-exposure to Context A during lever-press elimination relative to rats that experienced only Context B. These findings suggest that alternating between contexts associated with reinforcement and extinction during treatment reduces the probability that organisms will respond in novel contexts. These outcomes may be the result of discrimination and/or generalization processes. Moreover, this training procedure may offer a potential mitigation strategy for ABC renewal.

Resurgence as Choice in Context: Treatment duration and on/off alternative reinforcement.

Resurgence as Choice (RaC) is a quantitative theory suggesting that an increase in an extinguished target behavior with subsequent extinction of an alternative behavior (i.e., resurgence) is governed by the same processes as choice more generally. We present data from an experiment with rats examining a range of treatment durations with alternative reinforcement plus extinction and demonstrate that increases in treatment duration produce small but reliable decreases in resurgence. Although RaC predicted the relation between target responding and treatment duration, the model failed in other respects. First, contrary to predictions, the present experiment also replicated previous findings that exposure to cycling on/off alternative reinforcement reduces resurgence. Second, RaC did a poor job simultaneously accounting for target and alternative behaviors across conditions. We present a revised model incorporating a role for more local signaling effects of reinforcer deliveries or their absence on response allocation. Such signaling effects are suggested to impact response allocation above and beyond the values of the target and alternative behaviors as longer-term repositories of experience. The new model provides an excellent account of the data and can be viewed as an integration of RaC and a quantitative approximation of some aspects of Context Theory.

Renewal of extinguished operant behavior following changes in social context.

Renewal is the reoccurrence of previously extinguished behavior following a change in the context in which extinction was conducted. Despite an extensive body of research examining renewal, little is known about the role of social stimuli in renewal. The present experiments provided a novel examination of renewal of operant behavior by changing social stimuli across phases in an ABA renewal preparation. In both experiments, social stimuli were arranged by placing another rat in a second compartment of a divided operant chamber. In Experiment 1, the presence of another rat defined the extinction context, whereas an empty second compartment defined the baseline and testing contexts. We reversed these contextual manipulations in Experiment 2 such that the presence of another rat defined the baseline and testing contexts and the second compartment was empty during extinction. Renewal of lever pressing occurred when the other rat was removed from the chamber in Experiment 1 and when the other rat was returned to the chamber in Experiment 2. Thus, social stimuli may function as contextual stimuli, and changes in social contexts may produce renewal of previously extinguished behavior.

Longer treatment with alternative non-drug reinforcement fails to reduce resurgence of cocaine or alcohol seeking in rats.

Provision of alternative non-drug reinforcement is among the most effective methods for treating substance use disorders. However, when alternative reinforcers become unavailable during treatment interruptions or upon cessation of treatment, relapse often occurs. Relapse following the loss of alternative reinforcement is known as resurgence. One factor that could reduce resurgence is longer duration of treatment with alternative reinforcement, but the available data are mixed. Further, the effects of length of treatment have previously only been examined with food seeking. The present experiments directly examined if duration of treatment impacted the magnitude of resurgence of cocaine or alcohol seeking in rats. First, rats were trained to self-administer cocaine (Experiment 1) or alcohol (Experiment 2) by performing a target behavior. Second, target behavior was extinguished and performing an alternative behavior produced an alternative non-drug (i.e., food) reinforcer. Finally, resurgence was assessed following removal of alternative reinforcement after either 5 or 20 sessions of treatment. Treatment duration did not differentially affect resurgence of cocaine seeking in Experiment 1 or Alcohol seeking in Experiment 2. These results suggest that extended treatment with alternative non-drug reinforcement may not decrease propensity to relapse. Further, these results may have implications for treatment of substance use disorders and for theories of resurgence.

Stimuli previously associated with reinforcement mitigate resurgence.

Resurgence refers to the recurrence of an extinguished target behavior following subsequent suspension of alternative reinforcement. Delivery of reinforcers during extinction of alternative behavior has been shown to mitigate resurgence. The present experiment aimed to determine whether delivering stimuli associated with reinforcers during resurgence testing similarly mitigates resurgence. Three groups of rats pressed target levers for food according to variable-interval 15-s schedules during Phase 1. In Phase 2, lever pressing was extinguished, and an alternative nose-poke response produced alternative reinforcement according to a variable-interval 15-s schedule. Food reinforcement was always associated with illumination of the food aperture and an audible click from the pellet dispenser during Phases 1 and 2. Phase 3 treatments differed between groups. For one group, nose poking continued to produce food and food-correlated stimuli. Both of these consequences were suspended for a second group. Finally, nose poking produced food-correlated stimuli but not food for a third group. Target-lever pressing resurged in the group that received no consequences and in the group that received only food-correlated stimuli for nose poking. Resurgence, however, was smaller for the group that received food-correlated stimuli than for the group that received no consequences for nose poking. Target-lever pressing did not increase between phases in the group that continued to receive food and associated stimuli. Thus, delivery of stimuli associated with food reinforcement after suspension of food reduced but did not eliminate resurgence of extinguished lever pressing. These findings contribute to potential methodologies for preventing relapse of extinguished problem behavior in clinical settings.

Resurgence and alternative-reinforcer magnitude.

Resurgence is defined as an increase in the frequency of a previously reinforced target response when an alternative source of reinforcement is suspended. Despite an extensive body of research examining factors that affect resurgence, the effects of alternative-reinforcer magnitude have not been examined. Thus, the present experiments aimed to fill this gap in the literature. In Experiment 1, rats pressed levers for single-pellet reinforcers during Phase 1. In Phase 2, target-lever pressing was extinguished, and alternative-lever pressing produced either five-pellet, one-pellet, or no alternative reinforcement. In Phase 3, alternative reinforcement was suspended to test for resurgence. Five-pellet alternative reinforcement produced faster elimination and greater resurgence of target-lever pressing than one-pellet alternative reinforcement. In Experiment 2, effects of decreasing alternative-reinforcer magnitude on resurgence were examined. Rats pressed levers and pulled chains for six-pellet reinforcers during Phases 1 and 2, respectively. In Phase 3, alternative reinforcement was decreased to three pellets for one group, one pellet for a second group, and suspended altogether for a third group. Shifting from six-pellet to one-pellet alternative reinforcement produced as much resurgence as suspending alternative reinforcement altogether, while shifting from six pellets to three pellets did not produce resurgence. These results suggest that alternative-reinforcer magnitude has effects on elimination and resurgence of target behavior that are similar to those of alternative-reinforcer rate. Thus, both suppression of target behavior during alternative reinforcement and resurgence when conditions of alternative reinforcement are altered may be related to variables that affect the value of the alternative-reinforcement source.