Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose

Abstract

Rationale: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Fig 1

Timeline for experimental procedure for the reduction group. Also shown is the nicotine unit dose (mg/kg/inf) available at each test phase.

Fig 2

(A) Mean (±SEM) total number of infusions earned per daily session during baseline (0.06 mg/kg/inf) and the first and final five days of reduction (0.03 mg/kg/inf) in the reduction group. Daily infusion rate during a comparable period for the control group (0.06 mg/kg/inf throughout) is also shown. *^,** Significantly different from control group, p < 0.05, 0.01. ^#Significantly different from baseline, p < 0.01. (B) Mean (±SEM) total daily nicotine intake (mg/kg/day) during baseline and the final five days of reduction in the reduction group and a comparable period in the control group. Dotted line represents predicted total daily nicotine intake for the reduction group if intake had decreased proportionally to reduction in nicotine unit dose (i.e., no compensation had occurred). ** Significantly different from baseline and control group, p < 0.01. ^#Significantly different from predicted total daily nicotine intake if no compensation had occurred, p < 0.01. (C) Mean (±SEM) hourly infusion rate per 2 hr block during baseline and the final five days of reduction in the reduction group. Light = light phase of the light/dark cycle. Dark = dark phase of the light/dark cycle. The break in the graph represents the 1 hr cage maintenance period from 10:00 – 11:00 hr (see text). *^,** Significantly different from baseline at that 2 hr block, p < 0.05, 0.01.

Fig 3

Correlation between each rat's Compensation Index (CI) and baseline daily infusion rate (A), baseline Diurnal Index (B), nicotine clearance (C), and nicotine half-life (D). Figures 3A – 3D also illustrate the considerable degree of between-subject variability associated with compensation in this model.

Fig 4

Correlation between each rat's daily baseline infusion rate and nicotine clearance (A) and half-life (B). Also shown is the correlation between each rat's baseline infusion rate at the 2 hr block ending at 03:00 hr and nicotine clearance (C), as well as the relationship between each rat's baseline infusion rate at the 2 hr block ending at 01:00 hr and nicotine half-life (D).

Fig 5

(A) Mean (±SEM) number of infusions earned per session during baseline and reacquisition of NSA (0.06 mg/kg/inf) in the reduction group and a comparable period in the control group, expressed as percent of baseline. Data from the intervening sessions are not shown. (B) Mean (±SEM) number of infusions per 23 hr session during pre-extinction (P) and extinction in the reduction and control groups. *^,** Significantly different from pre-extinction (control group), p < 0.05, 0.01. # Significantly different from pre-extinction (reduction group), p <0.01. (C) Correlation between change in infusion rate (compared to pre-extinction) during the first 2 hr block on extinction day 1 (i.e., “within-session extinction burst”, see text) and change in infusion rate (compared to baseline) during the first 2 hr block on the first day of reduction.