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

Abstract

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.

Fig 1

Timeline for experimental procedure for the NSA group. Also shown is the nicotine unit dose (mg/kg/inf) available and number of ICSS sessions conducted (range) during each experimental phase. Pre-Red, Pre-Mec, and Pre-Ext Baselines = Pre-reduction, premecamylamine, and pre-extinction baselines, respectively.

Fig 2

(A) Mean (±SEM) total number of infusions earned per daily session, total daily nicotine intake, and ICSS thresholds (expressed as percent of pre-reduction baseline) during baseline (0.06 mg/kg/inf), the first and final five days of reduction (0.03 mg/kg/inf), and reacquisition of NSA (0.06 mg/kg/inf) in the NSA group. The dotted line during the reduction phase represents predicted total daily nicotine intake if intake had decreased proportionally to reduction in nicotine unit dose (i.e., no compensation had occurred). * Significantly different from the pre-reduction baseline, p < 0.05 or 0.01. ^# Significantly different from predicted total daily nicotine intake if no compensation had occurred (reduction day 5 excluded), p < 0.05 or 0.01. Intracranial self-stimulation threshold data during comparable periods in the control group are shown in (B).

Fig 3

Mean (±SEM) ICSS thresholds (expressed as percent of pre-mecamylamine baseline; A) and total somatic signs (B) following s.c. injection of saline or 1.5 mg/kg mecamylamine in the NSA group and control groups. *Significantly different from saline for that group, p < 0.05.

Fig 4

(A) Mean (±SEM) number of infusions per 22 hr session (expressed as % of pre-extinction baseline) during pre-extinction (P) and extinction in the NSA group. (B) Mean (±SEM) hourly infusion rate per 2-hr block during pre-extinction and on extinction day 1. Dark = dark phase of the light/dark cycle. Light = light phase of the light/dark cycle. *,** Significantly different from the pre-extinction baseline during that session (A) or at that 2-hr block (B), p < 0.05 or 0.01. (C) ICSS thresholds (expressed as percent of pre-extinction baseline, mean ± SEM) during each extinction session in the NSA and control groups. *Significantly different from the control group (averaged across extinction sessions 1–3), p < 0.05. #Significantly different from extinction session 1, p < 0.05.

Fig 5

(A) Correlation between each rat's stable CI (i.e. CI during the final 5 days of reduction) and daily infusion rates during the pre-reduction baseline. Also shown is the correlation between each rat's initial CI (i.e. CI during the first 5 days of reduction) and changes in ICSS thresholds during that same period of reduction testing (B), magnitude of mecamylamine-precipitated withdrawal (C), and magnitude of spontaneous withdrawal (D; see text for definitions of these terms). Fig 5A – 5D also illustrate the considerable degree of between-subject variability associated with compensation in this model.

Fig 6

(A) Correlation between magnitude of precipitated withdrawal and magnitude of the peak extinction burst (see text for definition of these terms).