The relative reinforcing efficacy of nicotine in an adolescent rat model of attention-deficit hyperactivity disorder.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is an independent risk factor for tobacco use disorder. Individuals with ADHD are more likely to begin smoking at a younger age, become a daily smoker sooner, smoke more cigarettes per day, and exhibit greater nicotine dependence than individuals without ADHD. It is unclear whether these findings are due to the reinforcing efficacy of nicotine per se being greater among individuals with ADHD. The purpose of the present study was to examine this issue using an animal model of ADHD, the spontaneously hypertensive rat (SHR) strain. Methods: Adolescent SHR and Wistar (control) rats were given access to a typically reinforcing nicotine unit dose (30 µg/kg), a threshold reinforcing nicotine dose (4 µg/kg), or saline under an FR 1 (week 1) and FR 2 (week 2) schedule during 23 h sessions to examine acquisition of self-administration. Behavioral economic demand elasticity was then evaluated at the 30 µg/kg dose through an FR escalation procedure. Results: At the 30 µg/kg dose, SHR rats exhibited a lower average response rate, lower mean active to inactive lever discrimination ratio, and lower proportion of rats acquiring self-administration compared to control rats. During demand assessment, SHR rats showed no significant difference from Wistars in demand intensity (Q0) or elasticity (α; i.e., reinforcing efficacy). In addition, no strain difference in acquisition measures were observed at the 4 µg/kg dose. Discussion: These findings suggest that the increased risk of tobacco use disorder in adolescents with ADHD may not be attributable to a greater reinforcing efficacy of nicotine, and that other aspects of tobacco smoking (e.g., non-nicotine constituents, sensory factors) may play a more important role. A policy implication of these findings is that a nicotine standard to reduce initiation of tobacco use among adolescents in the general population may also be effective among those with ADHD.

Evidence of Accidental Dosing Errors with Immediate-Release Sodium Oxybate: Data from the US Food and Drug Administration Adverse Event Reporting System.

INTRODUCTION: Sodium oxybate has been approved by the US Food and Drug Administration (FDA) to treat narcolepsy for 20 years; however, the only available products have been immediate-release (IR) formulations given twice nightly-once at bedtime and a second dose 2.5-4 h later-creating inherent risks with dosing administration errors. OBJECTIVES: Evidence and risks associated with accidental ingestion of the second IR oxybate dose < 2.5 h after the first dose were examined. METHODS: The FDA Adverse Event Reporting System database was searched for "inappropriate schedule of product administration" with IR sodium oxybate or calcium/magnesium/potassium/sodium oxybates; reports classified as serious and with IR oxybate as the suspect product were further analyzed. RESULTS: Of 541 reports meeting the search criteria, 178 were classified as serious: accidental early administration of the second dose resulting in adverse events (AEs; n = 41); "near miss" (no harm reported following early dosing; n = 9); intentionally taking second dose early (n = 25); other inappropriate use (late dosing/not taking daily; n = 102); and one duplicate report. Of the 41 reports of taking the second dose too early resulting in AEs, 22% (9/41) used emergency services and 27% (11/41) resulted in hospitalizations. AEs reported with accidentally taking the second dose too early included CNS depression, bradycardia, respiratory depression, dizziness, seizure, confusion, delirium, difficulty awakening, drowsiness, falls, nausea, vomiting, and enuresis. CONCLUSIONS: Patients, caregivers, clinicians, and Poison Control Centers should be aware of the risk of accidentally dosing twice-nightly IR oxybates earlier than 2.5 h after the first dose and the subsequent harm that may occur with early dosing.

Sodium oxybate and calcium, magnesium, potassium, and sodium oxybates (both medicines are called "oxybates") are medicines used to treat narcolepsy. People with narcolepsy need to take these medicines twice every night. They take one dose at bedtime and then wake up 2.5­4 h later to take the second dose. People could make mistakes taking their oxybate medicine because of this schedule. We looked in the US Food and Drug Administration's (FDA's) database called the FDA Adverse Event Reporting System to learn if there were reports of people accidentally taking the second dose of their oxybate medicine earlier than 2.5 h after taking the first dose. People who accidentally took the second dose too early experienced side effects like slowing down of the brain, breathing, and heart; feeling dizzy; having a seizure; being confused; having trouble waking up; being sleepy; falling down; feeling sick to their stomach; throwing up; and wetting the bed. Some people used emergency help and some went to the hospital. We found that harm may occur if people take the second dose of these oxybates too soon after the first dose. These risks were not previously reported. People with narcolepsy, their families, and their doctors need to know about these risks with the oxybates that are taken twice every night.

The reinforcement threshold and elasticity of demand for nicotine in an adolescent rat model of depression.

BACKGROUND: The Food and Drug Administration (FDA) is considering setting a nicotine standard for tobacco products to reduce their addictiveness. Such a standard should account for the apparent greater vulnerability to nicotine addiction in some subpopulations, such as adolescents with depression. The present study examined whether the reinforcement threshold and elasticity of demand (i.e., reinforcing efficacy) for nicotine in a genetic inbred rat model of depression (Flinders Sensitive Line [FSL]) differs from an outbred control strain. METHODS: Acquisition of nicotine self-administration (NSA) across a wide range of nicotine doses was measured in both FSL and Sprague-Dawley (SD) control adolescent rats. At the highest dose, elasticity of demand was also measured. Nicotine pharmacokinetics was examined to determine whether it might modulate NSA, as it does smoking in humans. RESULTS: FSL rats acquired self-administration quicker and showed more inelastic demand (greater reinforcing efficacy) than SDs at the highest unit dose. However, there was no strain difference in the reinforcement threshold of nicotine. FSL rats exhibited faster nicotine clearance, larger volume of distribution, and lower plasma and brain nicotine concentrations. However, these differences were not consistently related to strain differences in NSA measures. CONCLUSION: These findings are consistent with studies showing greater dependence and reinforcing efficacy of cigarettes in smokers with depression and those with relatively fast nicotine metabolism. However, these findings also suggest that a nicotine standard to reduce initiation of tobacco use should be similarly effective in both the general adolescent population and those with depression.

Substitutability of nicotine alone and an electronic cigarette liquid using a concurrent choice assay in rats: A behavioral economic analysis.

BACKGROUND: For the Food and Drug Administration to effectively regulate tobacco products, the contribution of non-nicotine tobacco constituents to the abuse liability of tobacco must be well understood. Our previous work compared the abuse liability of electronic cigarette refill liquids (EC liquids) and nicotine (Nic) alone when each was available in isolation and found no difference in abuse liability (i.e., demand elasticity). Another, and potentially more sensitive measure, would be to examine abuse liability in a choice context, which also provides a better model of the tobacco marketplace. METHODS: Demand elasticity for Nic alone and an EC liquid were measured when only one formulation was available (alone-price demand) and when both formulations were concurrently available (own-price demand), allowing an assessment of the degree to which each formulation served as a substitute (cross-price demand) when available at a low fixed-price. RESULTS: Own-price demand for both formulations were more elastic compared to alone-price demand, indicating that availability of a substitute increased demand elasticity. During concurrent access, consumption of the fixed-price formulation increased as the unit-price of the other formulation increased. The rate of increase was similar between formulations, indicating that they served as symmetrical substitutes. CONCLUSION: The cross-price model reliably quantified the substitutability of both nicotine formulations and indicated that the direct CNS effects of non-nicotine constituents in EC liquid did not alter its abuse liability compared to Nic. These data highlight the sensitivity of this model and its potential utility for examining the relative abuse liability and substitutability of tobacco products.

The effects of nicotine self-administration and withdrawal on concurrently available chow and sucrose intake in adult male rats.

Carbohydrate intake, preference, and taste thresholds may be altered in current and former cigarette smokers, which may mediate weight gain and risk for obesity in individuals who quit smoking. Attempts to model these effects in rodents have primarily used noncontingent nicotine administration. The purpose of this research was to characterize changes in chow and sucrose intake in rats during a 23-h access model of i.v. nicotine self-administration (NSA), in which rats lever-pressed for chow, sucrose, and nicotine under concurrent fixed-ratio (FR) 1 schedules. Male rats were assigned to one of three groups that differed in food and drug availability. The Nicotine C+S group had concurrent access to nicotine, chow, and sucrose. The Saline C+S group had access to saline, chow, and sucrose. The Nicotine C-Only group had access to nicotine and chow, but not sucrose. Changes in food intake and weight gain were assessed during baseline, NSA, and nicotine withdrawal (i.e., saline extinction). Weight gain was significantly slowed during NSA and increased during withdrawal, but did not differ between the nicotine groups. NSA produced a significant decrease in both chow and sucrose intake. Gradual tolerance to nicotine's effects on sucrose, but not chow intake, occurred. During withdrawal, chow and sucrose intake increased, with a larger percent increase in sucrose intake compared to chow. The proportion of total food intake from sucrose was greater at the end of withdrawal compared to baseline, indicating a history of nicotine intake changed dietary preference. Combined, these results indicate that sucrose intake is more resistant to nicotine's appetite suppressant effects and withdrawal from nicotine produces a greater increase in sweet food intake alongside general increases in chow intake. Changes in overall food intake in current and ex-smokers may lead to increased risk for obesity and other health problems, potentially limiting the benefit of quitting smoking.

Self-Administration of Smokeless Tobacco Products in Rats.

OBJECTIVE: Preclinical abuse liability assessment is an essential component of tobacco regulatory science. The goal of this project was to evaluate the relative abuse liability of smokeless tobacco products in rats using aqueous extracts of those products. These extracts provide exposure to an extensive range of nicotine and non-nicotine tobacco constituents as occurs in humans. METHODS: Rats were trained to self-administer either nicotine alone or extracts of Camel Snus or Kodiak smokeless tobacco at an equivalent nicotine unit dose. In Experiment 1, the relative reinforcing efficacy of these formulations was assessed in adults and adolescents using a progressive ratio schedule under limited-access conditions. In Experiment 2, relative reinforcing efficacy was assessed in adolescents under unlimited-access conditions using behavioral economic demand curve analysis. RESULTS: The reinforcing efficacy of nicotine formulations was higher in adolescents than adults, but no difference was observed between formulations in either age group. Similarly, there was no difference in elasticity of demand between formulations in adolescents. CONCLUSIONS: The present findings suggest that the abuse liability of these smokeless tobacco products is similar to nicotine alone, and that nicotine dose is the primary determinant of the reinforcing efficacy of systemic exposure to these products.

Predictors of the nicotine reinforcement threshold, compensation, and elasticity of demand in a rodent model of nicotine reduction policy.

BACKGROUND: The FDA is considering reducing the nicotine content in tobacco products as a population-based strategy to reduce tobacco addiction. Research is needed to determine the threshold level of nicotine needed to maintain smoking and the extent of compensatory smoking that could occur during nicotine reduction. Sources of variability in these measures across sub-populations also need to be identified so that policies can take into account the risks and benefits of nicotine reduction in vulnerable populations. METHODS: The present study examined these issues in a rodent nicotine self-administration model of nicotine reduction policy to characterize individual differences in nicotine reinforcement thresholds, degree of compensation, and elasticity of demand during progressive reduction of the unit nicotine dose. The ability of individual differences in baseline nicotine intake and nicotine pharmacokinetics to predict responses to dose reduction was also examined. RESULTS: Considerable variability in the reinforcement threshold, compensation, and elasticity of demand was evident. High baseline nicotine intake was not correlated with the reinforcement threshold, but predicted less compensation and less elastic demand. Higher nicotine clearance predicted low reinforcement thresholds, greater compensation, and less elastic demand. Less elastic demand also predicted lower reinforcement thresholds. CONCLUSIONS: These findings suggest that baseline nicotine intake, nicotine clearance, and the essential value of nicotine (i.e. elasticity of demand) moderate the effects of progressive nicotine reduction in rats and warrant further study in humans. They also suggest that smokers with fast nicotine metabolism may be more vulnerable to the risks of nicotine reduction.

Sex differences in nicotine self-administration in rats during progressive unit dose reduction: implications for nicotine regulation policy.

Reducing the nicotine content in tobacco products is being considered by the FDA as a policy to reduce the addictiveness of tobacco products. Understanding individual differences in response to nicotine reduction will be critical to developing safe and effective policy. Animal and human research demonstrating sex differences in the reinforcing effects of nicotine suggests that males and females may respond differently to nicotine-reduction policies. However, no studies have directly examined sex differences in the effects of nicotine unit-dose reduction on nicotine self-administration (NSA) in animals. The purpose of the present study was to examine this issue in a rodent self-administration model. Male and female rats were trained to self-administer nicotine (0.06mg/kg) under an FR 3 schedule during daily 23h sessions. Rats were then exposed to saline extinction and reacquisition of NSA, followed by weekly reductions in the unit dose (0.03 to 0.00025mg/kg) until extinction levels of responding were achieved. Males and females were compared with respect to baseline levels of intake, resistance to extinction, degree of compensatory increases in responding during dose reduction, and the threshold reinforcing unit dose of nicotine. Exponential demand-curve analysis was also conducted to compare the sensitivity of males and females to increases in the unit price (FR/unit dose) of nicotine (i.e., elasticity of demand or reinforcing efficacy). Females exhibited significantly higher baseline intake and less compensation than males. However, there were no sex differences in the reinforcement threshold or elasticity of demand. Dose-response relationships were very well described by the exponential demand function (r(2) values>0.96 for individual subjects). These findings suggest that females may exhibit less compensatory smoking in response to nicotine reduction policies, even though their nicotine reinforcement threshold and elasticity of demand may not differ from males.

Combined active and passive immunization against nicotine: minimizing monoclonal antibody requirements using a target antibody concentration strategy.

Nicotine vaccines have shown preliminary evidence of efficacy for enhancing smoking cessation rates, but the serum nicotine-specific antibody (NicAb) concentrations produced are highly variable and many subjects do not develop effective levels. As an alternative to vaccination, passive immunization with nicotine-specific monoclonal antibodies could produce more uniform serum NicAb concentrations, but its use is limited by their high cost and shorter elimination half-life. This study investigated supplementing vaccination with monoclonal antibodies in a targeted fashion to increase vaccine efficacy while minimizing the required monoclonal antibody dose. Rats were vaccinated and then given individualized supplemental doses of the nicotine-specific monoclonal antibody Nic311 to achieve a target total serum NicAb concentration known to be effective for blocking locomotor sensitization (LMS) to nicotine. Rats received vaccine, Nic311, both, or neither, followed by 0.3 mg/kg nicotine s.c. for 10 days to produce LMS. Combination immunotherapy completely blocked the development of LMS, while monotherapy with vaccine or Nic311 alone was only minimally effective. Lower brain nicotine levels were associated with reduced locomotor activity averaged over days 7-10. Despite its greater efficacy, combination immunotherapy did not reduce the variability in the resulting total serum NicAb concentrations. Variability in total serum NicAb concentrations was contributed to by both vaccine-generated antibody and by Nic311. These data show that combination immunotherapy, using a Nic311 dose that is by itself only minimally effective, can substantially enhance nicotine vaccine efficacy. However, variability in serum NicAb levels with combination immunotherapy may make translation of this approach challenging.

A lack of association between severity of nicotine withdrawal and individual differences in compensatory nicotine self-administration in rats.

RATIONALE: Compensatory smoking may represent an adverse consequence of smoking reduction or the use of reduced-nicotine tobacco products. Factors contributing to individual variability in compensation are poorly understood. OBJECTIVE: The objective of this study was to examine whether severity of nicotine withdrawal as measured by elevated intracranial self-stimulation (ICSS) thresholds is related to individual differences in compensatory nicotine self-administration (NSA) following unit dose reduction. METHODS: Rats were trained for ICSS and NSA (0.06 mg/kg per infusion). After stabilization, effects of reducing the nicotine unit dose to 0.03 mg/kg per infusion were examined. Following reacquisition of NSA (0.06 mg/kg per infusion), effects of antagonist-precipitated withdrawal and saline extinction (spontaneous withdrawal) were examined. RESULTS: Reducing the NSA unit dose produced partial compensation as indicated by the increased infusion rates, but a 35% mean decrease in daily nicotine intake. The magnitude of compensation varied considerably among rats. Dose reduction did not elicit withdrawal in rats as a group, although there were substantial increases in ICSS thresholds in some animals. Intracranial self-stimulation thresholds were consistently elevated during precipitated and spontaneous withdrawal, confirming that rats were nicotine-dependent. Individual differences in compensation were not correlated with changes in ICSS thresholds during dose reduction, precipitated withdrawal, or spontaneous withdrawal. In a secondary analysis, greater precipitated withdrawal severity predicted greater initial nicotine seeking during extinction. CONCLUSIONS: Severity of nicotine withdrawal was not related to the degree of compensation in this protocol. These data do not support a role for nicotine withdrawal in individual differences in compensation during reduced nicotine exposure, but do suggest that withdrawal may contribute to nicotine seeking during early abstinence.

Compensatory nicotine self-administration in rats during reduced access to nicotine: an animal model of smoking reduction.

The ability of smoking reduction (e.g., decreasing cigarettes per day) to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon. The goal of the current study was to develop an animal model of smoking reduction and to begin to examine potential behavioral and pharmacokinetic contributors to compensation. Rats trained for nicotine self-administration (NSA) in unlimited access sessions were exposed to a progressive decrease in duration of access to nicotine from 23-hr/day to 10-, 6-, and 2-hr/day. Following a return to 23 hr/day access and extinction, single-dose nicotine pharmacokinetic parameters were determined. Rats exhibited a reduction in total daily nicotine intake during reduced access to NSA, but decreases in nicotine intake were not proportional to decreases in access duration. Compensatory increases in hourly infusion rate were also observed when access was decreased. The magnitude of compensation differed considerably among animals. Early session infusion rate during baseline was significantly correlated, while nicotine clearance was moderately correlated, with 1 measure of compensation. Infusion rates were transiently increased compared to prereduction levels when unlimited access was restored, and this effect was greatest in animals that had exhibited the greatest levels of compensation. These findings indicate that rats exhibit compensatory increases in NSA during reduced access to nicotine, with substantial individual variability. This model may be useful for characterizing underlying factors and potential consequences of compensatory smoking.

Effects of pregnancy on nicotine self-administration and nicotine pharmacokinetics in rats.

RATIONALE: Because of the adverse effects of smoking during pregnancy, understanding the factors that influence maternal smoking may help in developing better treatments to help women quit smoking during pregnancy. Animal models could be useful for this purpose. OBJECTIVE: The purpose of the present study was to begin the development of an animal model of smoking during pregnancy by initially characterizing nicotine self-administration (NSA) in pregnant rats. Another purpose was to begin to explore the effects of pregnancy on nicotine pharmacokinetics in rats. MATERIALS AND METHODS: In experiment 1, female rats self-administering nicotine during 23-h sessions were examined throughout gestation and lactation. In experiment 2, locomotor activity was measured during pregnancy to assess further potential motor effects of pregnancy. Experiments 3 and 4 compared the single-dose pharmacokinetics of nicotine in male, nonpregnant female, and pregnant females in the first and third trimester of pregnancy and the first week of lactation. RESULTS: NSA decreased over the course of pregnancy with NSA significantly lower in the third trimester compared to nonpregnant controls. NSA remained suppressed for up to 10 days into lactation. Locomotor behavior was also significantly suppressed during the second and third trimesters and throughout lactation. Nicotine elimination was slower in pregnant females compared to nonpregnant females only in the third trimester. CONCLUSIONS: NSA, locomotor behavior, and nicotine elimination in rats are decreased during late pregnancy. The present study is the first to characterize NSA during pregnancy in animals, providing a potential model of maternal smoking in humans.

Effects of nicotine withdrawal on performance under a progressive-ratio schedule of sucrose pellet delivery in rats.

Although numerous studies have examined the motivational effects of nicotine withdrawal using intracranial self-stimulation (ICSS) threshold assays, relatively few have employed other methods for assessing motivation that use naturally reinforcing stimuli (e.g., food). The objective of the present study was to determine the effects of nicotine withdrawal on motivation using a progressive-ratio (PR) schedule of sucrose pellet delivery. Rats were trained to respond for sucrose pellets under a PR schedule. When stable breaking points and response rates were achieved, PR sessions were suspended and rats were exposed to a continuous infusion of saline or nicotine (3.2 or 8.0 mg/kg/day of the base) via subcutaneous osmotic minipump for nine days. On day nine, pumps were removed. PR sessions resumed 22 h later and continued daily for five consecutive days. Only rats exposed to 8.0 mg/kg/day nicotine exhibited a significant decrease in breaking point and overall response rate compared to saline-exposed rats on day one of nicotine withdrawal. These rats also showed an increasing trend in breaking point and overall response rate over the course of withdrawal, such that these measures were significantly increased on day five of withdrawal compared to baseline. Response rates under each ratio in the PR progression in rats exposed to 8.0 mg/kg/day did not differ from baseline or from those in saline-treated rats, suggesting suppression of breaking points and overall response rates were not attributable to nonspecific motor impairment. In addition, changes in performance throughout the protocol were not associated with changes in body weight. Consistent with findings from ICSS studies, the present study demonstrates that nicotine withdrawal can produce a motivational deficit as indexed under a PR schedule. However, in contrast to ICSS, PR performance appears to be sensitive to increases in motivation late in the withdrawal period. Therefore, PR schedules of natural reinforcement may provide information on the motivational effects of nicotine withdrawal complimentary to that obtained from ICSS threshold studies.

Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats.

RATIONALE: Immunization of rats against nicotine using a nicotine conjugate vaccine reduces the distribution of nicotine to brain in rats and attenuates some of nicotine's physiological and behavioral effects. It is not known whether such a vaccine can attenuate nicotine's reinforcing effects. OBJECTIVE: The present experiment was conducted to determine whether a nicotine conjugate vaccine could interfere with the acquisition and maintenance of nicotine self-administration (NSA) in rats given 23 h day(-1) access to nicotine. METHODS: To examine acquisition of NSA, rats were vaccinated with nicotine or control immunogen prior to being given access to a 0.01 mg kg(-1) infusion(-1) nicotine under a fixed-ratio(FR) 1 schedule for week 1, FR 2 for week 2, and FR 3 for week 3. Acquisition of cocaine self-administration (CSA) was similarly examined to determine the specificity of vaccination effects. To examine maintenance of NSA, rats were initially trained to self-administer nicotine under an FR 3 schedule, and then vaccinated with nicotine or control immunogen while NSA continued to be monitored. RESULTS: NSA was significantly lower in vaccinated rats compared to controls during the acquisition protocol, with a 38% decrease in the number of infusions during the last week of training. The percentage of rats meeting acquisition criteria in the vaccinated group was lower (36%) than that in the control group (70%), but this difference was not statistically significant. Vaccination did not affect acquisition of CSA, demonstrating its specificity for nicotine. Maintenance of NSA was significantly reduced in vaccinated rats as compared to controls after the final vaccine injection, with a mean reduction of 57%. There was no evidence in either protocol that vaccinated rats attempted to compensate for altered nicotine distribution by increasing nicotine intake. CONCLUSION: These data suggest that vaccination against nicotine can reduce the reinforcing effects of nicotine in rats and may have therapeutic potential for the treatment of tobacco dependence.

Reinstatement of nicotine self-administration in rats by presentation of nicotine-paired stimuli, but not nicotine priming.

The objective of the present study was to determine the relative efficacy of nicotine priming and nicotine-paired stimuli in reinstating extinguished NSA in rats. The relative efficacy of different stimulus conditions in reinstating NSA was also determined. Rats were trained to self-administer nicotine (0.03 mg/kg/inf) under an FR 5 schedule. Onset of a light above the active lever was correlated with nicotine availability, while offset of the light was paired with each nicotine infusion. In Experiment 1, saline extinction was arranged in the presence of these light stimuli. After extinction criteria were met, the effects of priming doses of nicotine (0.01, 0.03. and 0.06 mg/kg/inf, i.v.) on active lever pressing were determined. In Experiment 2, extinction of NSA was arranged in the absence of the light stimuli. After extinction criteria were met, reinstatement sessions were arranged involving either (1) a priming infusion of nicotine (0.03 mg/kg), (2) presentation of the same light stimuli as during NSA training, (3) constant illumination of the cue light, or (4) a combination of a nicotine priming infusion with one of the stimulus-light conditions. In Experiment 1, nicotine generally failed to reinstate NSA at any priming dose. In Experiment 2, both stimulus conditions reinstated NSA, with the stimulus condition identical to training producing a greater effect. Nicotine priming alone failed to significantly reinstate NSA. Nicotine priming combined with either stimulus condition was no more effective than each stimulus condition alone in reinstating NSA. These findings suggest that nicotine-paired cues are more effective than nicotine alone in reinstating extinguished NSA and are consistent with other studies showing that nicotine-paired stimuli play an important role in the reacquisition of NSA.