Compensatory Nicotine Self-Administration in Rats During Reduced Access to Nicotine: An Animal Model of Smoking Reduction
ABSTRACT 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.
- SourceAvailable from: Mark G. LeSage
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- "Together, these studies suggest that baseline nicotine intake may be useful for identifying those smokers most likely to continue smoking despite gradual reductions in cigarette nicotine content. Nicotine pharmacokinetics: The four-fold range of individual variability in nicotine clearance observed in the present study is similar to our prior studies in rats (Harris et al., 2008, 2009), as well as that reported in humans (Benowitz et al., 1982; Harris et al., 2009). The lack of correlation between nicotine clearance and baseline infusion rate is also in accord with our previous studies using the same nicotine training dose (Harris et al., 2009). "
ABSTRACT: 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. 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. 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. 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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.Drug and alcohol dependence 04/2015; 151. DOI:10.1016/j.drugalcdep.2015.03.030 · 3.42 Impact Factor
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- "s model of nicotine dose reduction . However , withdrawal - induced elevations in ICSS thresholds may be correlated with compensation elicited in a different manner ( e . g . , reduction in access ; Fig . 6 Correlation between magnitude of precipitated withdrawal and magnitude of the peak extinction burst ( see text for definition of these terms ) Harris et al . 2008 ) . Examining whether the severity of withdrawal assessed using different measures ( e . g . , condi - tioned place aversion ) is related to individual differences in compensation in this and other models would also be of interest ."
ABSTRACT: 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. 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. 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. 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. 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.Psychopharmacology 04/2011; 217(2):153-66. DOI:10.1007/s00213-011-2273-9 · 3.88 Impact Factor
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- "The current model also differed from the access-reduction model in certain respects. In contrast to the current study, rats exhibited a transient increase in infusion rates compared to pre-reduction levels during the reacquisition phase of the access reduction protocol (Harris et al. 2008), potentially indicating differences in the characteristics of relapse from different harm reduction interventions. These models therefore each provide unique information and together provide a more complete characterization of compensatory smoking than either model alone. "
ABSTRACT: The ability of tobacco harm reduction strategies 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 and assessing the feasibility of harm reduction interventions. The objective of the study was to use an animal model of human compensatory smoking that involves a decrease in unit dose supporting nicotine self-administration (NSA) to examine potential contributors to individual differences in compensation. Rats were trained for NSA during daily 23-h sessions at a unit dose of 0.06 mg/kg/inf until responding was stable. The unit dose was then reduced to 0.03 mg/kg/inf for at least 10 sessions. Following reacquisition of NSA at the training dose and extinction, single-dose nicotine pharmacokinetic parameters were determined. Decreases in nicotine intake following dose reduction were proportionally less than the decrease in unit dose, indicating partial compensation. Compensatory increases in infusion rates were observed across the course of the 23-h sessions. The magnitude of compensation differed considerably between rats. Rats exhibiting the highest baseline infusion rates exhibited the lowest levels of compensation. Nicotine pharmacokinetic parameters were not significantly correlated with compensation. Infusion rates immediately returned to pre-reduction levels when baseline conditions were restored. These findings provide initial insights into correlates of individual differences in compensation following a reduction in nicotine unit dose. The present assay may be useful for characterizing mechanisms and potential consequences of the marked individual differences in compensatory smoking observed in humans.Psychopharmacology 06/2009; 205(4):599-611. DOI:10.1007/s00213-009-1567-7 · 3.88 Impact Factor