Roles of dopamine signaling in nicotine addiction

More than 3 million deaths a year are attributable to smoking worldwide, and the use of tobacco is on the rise in developing countries. Consequently, tobacco use is one of the few causes of mortality that is increasing, with deaths projected to reach 10 million annually in 30–40 years.1 In developed countries, smoking is presently estimated to cause 20% of all deaths, making it the largest single cause of preventable death. In the United States alone, smoking-related illness causes more than 430 000 deaths and $150 billion in medical costs and lost productivity annually.2

Nicotine is the primary addictive component of tobacco.3,4,5,6,7 It motivates smoking by about 1.1 billion people, representing approximately one-third of the global population aged 15 and over.8 The addictive power of tobacco is exemplified by the difficulty in quitting. Most attempts to quit smoking fail, and success is usually achieved only after repeated attempts. In the United States, nearly three-fourth of adult smokers want to stop. About one-third of these smokers try to quit each year, but only a few percent succeed.9 Since it is such a serious health problem, nicotine addiction arising from tobacco use has been the focus of much research. For nicotine and other psychostimulant drugs of abuse, the accumulation of evidence supports the hypothesis that mesocorticolimbic dopamine (DA) systems mediate the reinforcement for continued drug use despite the harmful consequences.3,4,5,6,10,11

Useful hypothesis of dopamine signaling in reward-based behaviors

Rewards obtained from the environment serve as positive reinforcers that shape behaviors for success. Rewards provide the incentive to achieve goals that can yield pleasure and perpetuate life. Since the environment is variable and achieving desirable goals requires continual adjustments, rewards serve in an ongoing learning process that updates an animal's repertoire of behaviors. Exploiting the environment to achieve the natural rewards of food, shelter and, ultimately, reproductive success has evolutionarily produced important systems in the brain for the processing of reward-based learning. A wide range of studies, including electrical self-stimulation, self-administration, place preference, in vivo imaging, pharmacology, and cellular electrophysiology have indicated that the neurotransmitter, DA, participates in these reward-based events.3,4,5,6,10,11 Dopaminergic projections originating in the ventral tegmental area (VTA) and innervating the striatum, the amygdala, and the prefrontal cortex compose the mesocorticolimbic DA systems that have been specifically identified to be of primary, but not exclusive, importance.

Addictive drugs tap into the reward-related neuronal systems, reinforcing and ultimately solidifying maladaptive behaviors. Years of experimentation have indicated that drugs such as cocaine, amphetamine, and nicotine mediate their reinforcing properties via the mesocorticolimbic DA systems. These drugs are self-administered in controlled animal studies, and the self-administration is dependent on the elevation of DA, particularly in the nucleus accumbens (NAc) of the ventral striatum. A basic tenet that has inspired and guided much research is that the positive reinforcement mediated by psychostimulant drugs is associated with enhanced DA release from the mesocorticolimbic systems in specific brain areas, such as the NAc.12

Newer developments in dopamine signaling in relation to nicotine addiction

An over simplification of the standard hypothesis of addiction applied to nicotine may be summarized as follows: nicotine elevates DA in the NAc, and that elevation reinforces tobacco use, particularly during the acquisition phase. Blocking DA release in the NAc with antagonists or lesions attenuates the rewarding effects of nicotine, as indicated by reduced self-administration.13 Although much progress has been made along this line, more sophisticated theories of how DA participates in neuronal processing have been developed to explain the mounting data that contradict this simple hypothesis.6,10,11,14 DA concentrations in the NAc are not a direct indication of reward.

One hypothesis is that the DA signal conveys novelty and errors in reward expectation, with the DA neurons of the VTA responding to unpredicted rewards.11,14 The firing of DA neurons changes based on the difference between the actual and the expected reward. The DA neurons indicate the deviation of the environmental input from the animal's expectations, which developed based upon previous experience in the environment (learning). Since the firing of DA neurons does not produce uniform DA release (due, in part, to local controls within the targets),15,16 a broader theory that encompasses the previous ideas is warranted. The functions of DA within the overall mesocorticolimbic systems involve the integration of salient environmental information. Then, this information is used in the preparation, initiation, and execution of movement that serves the desired goal.10,11 This view encompasses the concept that the DA signal participates in ongoing associative learning of adaptive behaviors as an animal continually updates a construct of environmental saliency. This broader view of DA signaling accounts for data that are inconsistent with the notion that DA simply mediates reward. DA also participates in responses to other salient information, such as aversive stimuli. This versatility of the mesocorticolimbic systems arises because the distribution of released DA elicited by noxious stimuli is different from the distribution elicited by rewarding stimuli.6,10 Thus, the processing of diverse kinds of information can be influenced by the mesocorticolimbic systems.

Another wrinkle in the nicotine addiction story

The strongest evidence for the reinforcing influence of nicotine is that it supports self-administration, which is attenuated by preventing DA signaling in the NAc.13 It is well known, however, that nicotine, like other addictive drugs, also mediates aversive influences. The self-administration of nicotine is dose dependent, falling off at both lower and higher concentrations. Responding rates sometimes continue until rats experience toxic effects. At these and higher concentrations, nicotine causes vomiting, tremors, convulsions, and death at extreme doses. Laviolette and van der Kooy, in this issue, present further data suggesting that the roles of DA go well beyond mediation of reward. They find that nicotine microdialyzed directly into the VTA causes conditioned place (CP) aversion at low concentrations and CP preference at higher concentrations. The broad-spectrum DA receptor antagonist, α-flupenthixol, had no effect on CP preference at higher nicotine concentrations. However, this same neuroleptic treatment potentiated the rewarding effects of nicotine at the low concentrations, switching CP aversion to CP preference at one nicotine concentration. The authors interpret these results as suggesting that the rewarding properties of intra-VTA nicotine are mediated by non-DA mechanisms, and that the mesocorticolimbic DA activity stimulated by intra-VTA nicotine mediates aversive properties. They also conclude that the neuroleptic treatment creates a nicotine-susceptible condition by removing the aversive stimulus properties of nicotine. That process, they conclude, contributes to the extremely high prevalence of smoking by schizophrenic patients, who are treated with neuroleptics.

This interesting paper further indicates that there is more to the mesocorticolimbic signaling and the addiction process than is presently appreciated. Certainly, other neurotransmitter signals are important during reward-based behaviors and contribute to the addiction process.7 Nevertheless, the evidence that nicotine use is reinforced in association with elevated DA at specific targets is vast and varied.3,4,5,6 Some of that evidence, however, has depended on microdialysis measurements of DA, and those measures are spatially crude and kinetically slow, measuring background changes on the time scale of minutes. Much additional DA signaling occurs more rapidly and on finer spatial scales where synaptic events take place.15,16,17 Thus, there are reasons to pause and reanalyze even valued hypotheses. On the other hand, the interpretations of Laviolette and van der Kooy also can be questioned. For example, most schizophrenics smoke even before treatment with neuroleptics,18 diminishing the conclusion that removal of nicotine's aversive properties leads to smoking. The authors also found no effect of neuroleptic treatment at higher nicotine concentrations. If their interpretation were completely correct, an increase in CP preference at higher nicotine concentrations should have been expected. Clearly, and as we should expect, not all the answers are available yet, but this thought-provoking paper may push us toward new avenues of research.

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Correspondence to J A Dani.

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