Role of dopamine in the behavioural actions of nicotine related to addiction
Introduction
Nicotine exerts behavioural effects in animals and man related to its actions as a behavioural stimulus. These behavioural stimulus properties of nicotine can be distinguished into discriminative, whereby nicotine is utilized to select responses motivated by stimuli and outcomes different from nicotine itself, and motivational, where nicotine is itself the motive of behaviour. Depending on the condition and previous exposure to the drug, nicotine can act as a primary reward or as a punisher. Among brain neurotransmitters, dopamine is by far the one, if not the only, to have been implicated in the behavioural stimulus effects of nicotine. In this short review, I will summarize the experimental evidence, obtained by pharmacological manipulations or lesions of dopamine function, and the correlative evidence, obtained by monitoring changes in dopamine function in behaving subjects administered with nicotine, that bears a relationship with the role of dopamine in the behavioural stimulus properties of nicotine. Existing hypotheses on how this behavioural role of dopamine can be translated into a role in the addictive properties of nicotine will be also discussed.
Section snippets
Terminology
In the present review, we will utilize the terms dependence and addiction as defined previously (Di Chiara, 2000). Thus, dependence will be utilized in a broad sense to indicate a generic condition of abnormal control exerted by the drug over the subject's behaviour including a milder condition like drug abuse and a severe condition like addiction. Addiction in turn, in agreement with O'Brien (1996) is operationally defined according to DSM-IIIR and DSM-IV criteria for dependence American
Discriminative stimulus effects
Discriminative stimulus effects of nicotine are demonstrated by training subjects to explicitly associate the drug effect to a specific response (e.g., pressing one specific lever among two) that leads to reinforcement (e.g., food presentation). Nicotine allows discrimination between the reinforced and the non-reinforced response. These effects have been reviewed by Stolerman (1987), Rosecrans (1989) and more recently by Stolerman (1999) and by Di Chiara (2000).
Discriminative stimulus
Motivational stimulus effects
No evidence does exist that dopamine is involved in the negative motivational stimulus properties of nicotine (i.e. aversive and punishing effects). Although this negative conclusion cannot be taken as evidence, it is at least consistent with the idea that dopamine is eventually involved in the adaptation to aversive states and stimuli, but not in their mediation (Di Chiara, 1999).
As to the positive motivational effects of nicotine, evidence has been provided for a role of dopamine in the
Locomotion
Nicotine elicits biphasic inhibitory–stimulatory effects on locomotion in a baseline-dependent fashion (see Di Chiara, 2000 for review).
Evidence for a role of dopamine of the mesolimbic system in the locomotor stimulant effects of nicotine derives from three different approaches: 6-hydroxydopamine lesion of dopamine neurons Clarke et al., 1988a, Clarke et al., 1988b, Louis and Clarke, 1998, blockade of dopamine receptors by D1 and D2 receptor antagonists Walter and Kuschinsky, 1989, Corrigall
Latent inhibition
Latent inhibition (LI) describes the circumstance that pre-exposure to a given stimulus without consequences impairs the ability of the same stimulus to be conditioned by a primary reinforcer (either aversive or rewarding).
Nicotine, like amphetamine, abolishes latent inhibition in rats, an effect reversed by haloperidol (Joseph et al., 1993). In humans, an effect of nicotine on latent inhibition has not been demonstrated (Thornton et al., 1996).
The effect of nicotine takes place during
Acute effects in nicotine-naive subjects
Nicotine acutely stimulates dopamine transmission after systemic administration in rats naive to nicotine.
The most direct and specific method available for estimating dopamine transmission in vivo is by monitoring endogenous dopamine in the extracellular fluid by microdialysis Di Chiara, 1990, Di Chiara et al., 1996a, Di Chiara et al., 1996b. Nicotine increases dopamine in dialysates at doses of 0.1–0.6 mg/kg s.c. and 0.05 mg/kg i.v. depending on the area where dopamine transmission is
Commonalities between nicotine and other dependence-producing drugs
Nicotine shares with non-psychostimulant drugs as narcotic analgesics, delta-9-tetrahydrocannabinol and ethanol the ability of stimulating dopamine transmission preferentially in the shell of the nucleus accumbens by activating dopamine neurons that project to this area Di Chiara, 1995, Di Chiara, 1998, Di Chiara, 1999. Psychostimulant drugs like amphetamine, cocaine and phencyclidine preferentially stimulate dopamine transmission in the shell, but reduce the firing activity of dopamine neurons
Dopamine release by motivational stimuli
Major differences do exist among different terminal areas of the dopamine system in the responsiveness of dopamine transmission to different motivational stimuli.
Primary appetitive stimuli (rewards) consistently increase dopamine transmission in the nucleus accumbens shell, in the prefrontal cortex and to a lesser extent in the nucleus accumbens core Bassareo and Di Chiara, 1999, Bassareo et al., 1996, Tanda and Di Chiara, 1998. Primary aversive stimuli consistently stimulate dopamine
Role of dopamine in associative stimulus reward learning
The properties of dopamine responsiveness in the nucleus accumbens shell suggest a role in associative stimulus-reward learning (Di Chiara, 1999). Release of dopamine in the nucleus accumbens shell by unfamiliar and unpredicted primary appetitive stimuli (rewards) might serve to associate the discriminative properties of the rewarding stimulus with its biological outcome. This mechanism might be, in the case of dopamine in the nucleus accumbens shell, specifically related to feeding behaviour
Drugs of abuse as false neurochemical homologues of reward
Drug and non-drug rewards (e.g. food) share the property of activating dopamine transmission preferentially in the nucleus accumbens shell Pontieri et al., 1995, Bassareo and Di Chiara, 1999, Bassareo et al., 1996, Tanda et al., 1997a. Non-psychostimulant drugs like nicotine, opiates, ethanol and cannabinoids also share with a conventional reinforcer like palatable food a μ-opioid component located in the ventral tegmentum (Tanda and Di Chiara, 1998). Therefore, drugs reproduce certain
Differences between drugs of abuse and incentives
The acute effects of drugs of abuse on dopamine transmission, while similar to those of rewards, are quite different from those of incentive stimuli, stimuli that derive their motivational properties from learning of their association (conditioning) with a reward Bolles, 1972, Bindra, 1974. Incentive stimuli do not stimulate dopamine transmission in the shell, but instead they do in the core and in the prefrontal cortex Bassareo and Di Chiara, 1999, Bassareo and Di Chiara, 1999.
Drugs of abuse
Adaptive changes in dopamine responsiveness to nicotine and tobacco addiction
Adaptive changes in the responsiveness of dopamine transmission to drugs of abuse have been attributed to a role in the mechanism of drug-addiction. Thus, it has been assumed that drug-addiction is the result of non-associative, long-lasting, eventually irreversible changes (sensitization) in the responsiveness of the dopamine system to drug-conditioned incentive stimuli induced by the repeated exposure to the drug (Robinson and Berridge, 1993). Direct testing of this prediction, however, has
Nicotine dependence as dopamine-induced learning disorder
We regard addiction to tobacco as the final step of a dependence process resulting from abnormal drug-induced associative learning.
The initial step in this process is thought to be learning of the association between the rewarding properties of nicotine and otherwise neutral stimuli that acquire secondary positive motivational properties. These stimuli can be either intrinsic or extrinsic to nicotine itself and include those arising from substances associated to nicotine in smoke as well as
Acknowledgements
The studies from the author's laboratory have been founded by the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (40% and 60%), the Consiglio Nazionale delle Ricerche, Regione Autonoma della Sardegna, the European Commission and the University of Cagliari.
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