Cue dependency of nicotine self-administration and smoking

Abstract

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Introduction

Tobacco smoking is the most important preventable cause of death in developed countries and is rapidly becoming a significant health problem in developing countries. Although the prevalence of smoking has gradually declined among adults (but not teens) in developed countries, worldwide consumption of tobacco is still rising. It is predicted that about 3 million smokers worldwide die annually from smoking, and that the rapid increase in smoking in developing countries (Peto et al., 1996) will cause this toll to rise to about 10 million annually by the year 2030. Several hundred million adults who are current smokers are expected to die from smoking (Peto et al., 1996). Although the harmful health effects from smoking are widely known, only an estimated 3% of smokers successfully quit each year, less than 10% of those who attempt smoking abstinence (Shiffman et al., 1998).

With these risks associated with smoking, it is relevant to question why people smoke, why they develop an addiction to smoking, and why many of them cannot quit? The widely accepted answers are that they smoke because smoking is a very efficient way of rapidly delivering nicotine to the brain, nicotine has powerful reinforcing effects like cocaine, heroin and other drugs of abuse, and like those other drugs, chronic usage leads to dependence and addiction Benowitz, 1996, Stolerman and Shoaib, 1991. Based on the very reasonable assumption that people smoke tobacco primarily to obtain nicotine, much animal research has focused on the neurophysiological consequences of nicotine and pharmacological treatments that can reduce its effects Balfour et al., 2000, Di Chiara, 2000. In the human clinical literature, a similar emphasis has been placed on the development of strategies for reducing cigarette smoking, such as nicotine gum or patch, that are directed at the actions of nicotine Benowitz, 1993, Rose and Corrigall, 1997.

However, a paradox exists in both the animal and human literature that is not adequately addressed by these approaches. The abuse liability, frequency of consumption, and rate of relapse associated with smoking are at least equal to other addictive drugs such as stimulants or opiates (Anthony et al., 1994). In contrast, the euphoric, reinforcing and other psychological effects of nicotine, compared to other drugs, are more subtle, are manifested under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence Goldberg et al., 1981, Rose and Corrigall, 1997, Rose and Levin, 1991. The limited success rates of smoking cessation treatments that are directed at nicotine's pharmacological actions (Balfour and Fagerstrom, 1996) also suggest that nonnicotine factors may also be involved in maintaining smoking behavior and fostering relapse.

One possible resolution to this paradox is that in addition to its intrinsic reinforcing properties, nicotine is particularly effective in establishing or magnifying the incentive properties and reinforcing effects of associated, nonpharmacological stimuli, such as the predictive visual and/or auditory cues typically found in animal self-administration paradigms, or the taste and smell of tobacco smoke for smokers Balfour et al., 2000, Di Chiara, 2000, Goldberg and Henningfield, 1988, Goldberg et al., 1981, Perkins et al., 2001a, Rose and Corrigall, 1997, Rose and Levin, 1991. Smoking may be a more effective way of establishing these stimuli as conditioned reinforcers, compared to other routes of nicotine administration (e.g., smokeless tobacco) that are likely to be associated with fewer salient environmental cues and, therefore fewer discrete pairings of cues with nicotine delivery (i.e., inhaled versus absorption through the mucous membrane).

In the present paper, we will briefly review the results of human and animal research in support of the hypotheses that: (a) nicotine is the major psychoactive factor in tobacco that drives smoking behavior; (b) the primary (unconditioned) reinforcing effects of nicotine, when considered in isolation, are inadequate to explain the tenacity of smoking behavior or the only modest success of nicotine-based treatment strategies; and (c) environmental stimuli associated with exposure to nicotine play a critical role in maintaining drug-taking behavior and in promoting relapse. We will then present new studies from our laboratory that test the hypothesis regarding the importance of drug-related environmental cues in an animal model of nicotine reinforcement. Our results indicate that the high rate of nicotine self-administration exhibited by rats, which has been reported by several laboratories including our own, is heavily dependent on environmental cues associated with the drug.