Nicotine as a typical drug of abuse in experimental animals and humans (original) (raw)
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The scientific case that nicotine is addictive
1995
Despite the wide-ranging and authoritative 1988 review by the US Surgeon General, views questioning the addictiveness of nicotine contine to be expressed in some quarters. This lack of complete consensus is not unexpected, since no universally agreed scientific definition of addiction exists. In this paper we briefly consider a number of lines of evidence from both the human and animal literature bearing on the addictiveness of nicotine. Patterns of use by smokers and the remarkable intractability of the smoking habit point to compulsive use as the norm. Studies in both animal and human subjects have shown that nicotine can function as reinforcer, albeit under a more limited range of conditions than with some other drugs of abuse. In drug discrimination paradigms there is some cross-generalisation between nicotine on the one hand, and amphetamine and cocaine on the other. A welldefined nicotine withdrawal syndrome has been delineated which is alleviated by nicotine replacement. Nicotine replacement also enhances outcomes in smoking cessation, roughly doubling success rates. In total, the evidence clearly identifies nicotine as a powerful drug of addiction, comparable to heroin, cocaine and alcohol.
Nicotine dependence – human and animal studies, current pharmacotherapies and future perspectives
Pharmacological Reports, 2009
Nicotine dependence is a disease of constantly growing importance. This mini-review describes the effects of nicotine in humans and focuses on the various laboratory animal models developed to study the dependence-related behavioral effects of nicotine. In addition, we outline the current therapeutic approaches designed to substitute nicotine from cigarette smoke with safer compounds or to relieve symptoms of nicotine withdrawal during smoking abstinence. Since several pharmacotherapies have failed to be efficacious in all patients, we also assess the clinical effectiveness of newer agents in relation to existing drugs.
Environmental stimuli promote the acquisition of nicotine self-administration in rats
Psychopharmacology, 2002
Abstract Rationale. Environmental stimuli associated with drugs of abuse are believed to play a major role in the motivation to take drugs, drug dependence, and relapse. Previous work from this laboratory demonstrated that the response-contingent presentation of drug-related, visual cues was at least as important as nicotine in the maintenance, extinction and reacquisition of self-administration in experienced rats. Objectives. In the present research, we asked whether these same visual cues are effective in promoting the acquisition of operant responding in drug naive rats. Methods. Male Sprague-Dawley rats were tested for self-administration of IV nicotine (0.03 mg/kg, free base) in 1-h daily sessions when infusions were or were not paired with two lighting events: a 1-s cue light, followed by a 1-min period during which the chamber light was turned off and responding was not reinforced. Results. Rats tested with cues plus nicotine rapidly acquired self-administration and increased their lever pressing rates as the schedule progressed from FR1 to FR5. Without cues, the rate of nicotine self-administration was low and no adjustments were made in response to increasing schedule demands. While one of the stimuli, turning off the chamber light, was shown to have primary reinforcing properties, its association with nicotine produced a synergistic enhancement of lever pressing. Acquisition of operant responding was also enhanced, but to a lesser extent, by a previously neutral compound stimulus, i.e. the nicotine-paired cue light presented with a 1-s tone. Conclusions. These results illustrate a powerful interaction between environmental stimuli and nicotine in the acquisition of operant responding and indicate that both intrinsically reinforcing and previously neutral cues can participate in this effect.
Pharmacology and Markers: Nicotine Pharmacology and Addictive Effects
INTRODUCTION Dosing characteristics of cigarette brands are estimated using machines that smoke representative cigarettes from each brand according to a protocol termed the Federal Trade Commission (FTC) method (Peeler, this volume; Pillsbury, this volume). This technology and methodology provide tar-and nicotine-dosing estimates of cigarettes that are misleading to consumers and do not accurately predict what level of tar and nicotine intake consumers will obtain by smoking a given brand of cigarettes ). An understanding of the dependence-producing and other behavior-modifying effects of cigarette smoke is necessary to understand why the FTC method is a poor predictor of the nicotine, tar, and carbon monoxide levels people obtain from cigarettes. Cigarette smoking behavior is influenced by nicotine dose, and smokers tend to maintain nicotine intake within upper and lower boundaries . In brief, nicotine produces dose-related tolerance, physical dependence, and discriminative effects (i.e., effects that people can feel, which modify mood and physiology), and smokers change their behavior in response to these effects. Unlike human smokers, machines are not nicotine dependent, nor do they modify their behavior based on the flavor of the smoke.
Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats
Drug and Alcohol Dependence, 2012
Background-Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.
Psychopharmacology, 2004
Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. Objectives To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. Methods The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. Results Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. Conclusion There was no escalation in nicotine intake with extended access conditions, unlike cocaine self-administration. Nevertheless, daily nicotine self-administration seven days per week, for either 1 or 6 h per day, was sufficient to induce long-lasting adaptations in nicotinic acetylcholine receptor activity reflected in spontaneous and antagonist-precipitated somatic signs of withdrawal, possibly reflecting aspects of nicotine dependence.
European Journal of Pharmacology, 2008
The effect of 7-week forced oral nicotine exposure on acquisition of intravenous nicotine self-administration, nicotine place conditioning, and nicotine preference was studied in mice. The nicotine solution was given in stepwise increased concentrations as the sole source of liquid for 7 weeks. Nicotine exposed animals selfadministered nicotine intravenously at lower unit dose than nicotine-naïve ones, indicating that the forced 7-week nicotine exposure, followed by 7-day withdrawal, had rendered them more sensitive to nicotine's reinforcing effects. At the dose of 0.5 mg/kg, nicotine induced conditioned place preference both in drug-naïve and nicotine exposed mice, but the 0.3 mg/kg dose of nicotine failed to do so. The forced nicotine pre-exposure did not alter the nicotine preference in the 2-bottle free-choice paradigm. In conclusion, these results suggest that nicotine preexposure enhances the reinforcing effects of acutely administered nicotine only in the intravenous selfadministration model.
Importance of nonpharmacological factors in nicotine self-administration
Physiology & Behavior, 2002
There is mounting evidence that nonpharmacological factors critically modulate the effects of several drugs of abuse both in humans and experimental animals. This paper reviews research from this laboratory on one factor that influences the degree to which nicotine is selfadministered: environmental stimuli that form the context within which nicotine is taken. The results suggest that the direct, pharmacological actions of nicotine are necessary but not sufficient to explain either the high rates of self-administration exhibited by laboratory animals or cigarette smoking by humans, and that future investigations on the neurophysiological effects of nicotine that underlie smoking behavior must take into account the environmental context within which the behavior occurs. D
Cue dependency of nicotine self-administration and smoking
Pharmacology Biochemistry and Behavior, 2001
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. D
Rodent models of nicotine reward: What do they tell us about tobacco abuse in humans?
Pharmacology Biochemistry and Behavior, 2009
Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrate in these products that produces addiction. Based on this assumption, several pre-clinical studies have utilized animal models to measure various aspects of nicotine addiction. Most of this work has focused on behavioral measures of nicotine and how other variables contribute to these effects. Here we discuss the most commonly used animal models including, self-administration (SA), place conditioning (PC), and the intracranial self-stimulation (ICSS) paradigms in rodents. The strengths, limitations and procedural variables of these models are reviewed, followed by a discussion of how the animal models have been used to study factors such as age, sex, stress, and the effects of tobacco products other than nicotine. These factors are discussed in light of their influences on human tobacco abuse. The rodent models are evaluated in the context of face, predictive, and construct validity, and we propose that inclusion of factors such as age, sex, stress and other constituents of tobacco aside from nicotine can increase the utility of these animal models by more closely mimicking human tobacco abuse.