Role of dopamine in the behavioural actions of nicotine related to addiction

doi:10.1016/S0014-2999(00)00122-9

European Journal of Pharmacology

Volume 393, Issues 1–3, 30 March 2000, Pages 295-314

https://doi.org/10.1016/S0014-2999(00)00122-9 Get rights and content

Abstract

Experimental impairment of dopamine function by 6-hydroxydopamine lesions or by dopamine receptor antagonists shows that dopamine is involved in nicotine's discriminative stimulus properties, nicotine-induced facilitation of intracranial self-stimulation, intravenous nicotine self-administration, nicotine conditioned place-preference and nicotine-induced disruption of latent inhibition. Therefore, nicotine depends on dopamine for those behavioural effects that are most relevant for its reinforcing properties and are likely to be the basis of the abuse liability of tobacco smoke. On the other hand, in vivo monitoring studies show that nicotine stimulates dopamine transmission in specific brain areas and in particular, in the shell of the nucleus accumbens and in areas of the extended amygdala. These effects of nicotine resemble those of a reward like food except that nicotine-induced release of dopamine does not undergo single-trial, long-lasting habituation. It is speculated that repeated non-habituating stimulation of dopamine release by nicotine in the nucleus accumbens shell abnormally facilitates associative stimulus-reward learning. Acute effects of nicotine on dopamine transmission undergo acute and chronic tolerance; with repeated, discontinuous exposure, sensitization of nicotine-induced stimulation of dopamine release in the nucleus accumbens core takes place while the response in the shell is reduced. It is speculated that these adaptive changes are the substrate of a switch from abnormal incentive responding controlled by consequences (action-outcome responding) into abnormal habit responding, triggered by conditional stimuli and automatically driven by action schemata relatively independent from nicotine reward. These two modalities might coexist, being utilized alternatively in relation to the availability of tobacco. Unavailability of tobacco disrupts the automatic, implicit modality of abnormal habit responding switching responding into the explicit, conscious modality of incentive drug-seeking and craving.

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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Role of dopamine in the behavioural actions of nicotine related to addiction

Abstract

Introduction

Section snippets

Terminology

Discriminative stimulus effects

Motivational stimulus effects

Locomotion

Latent inhibition

Acute effects in nicotine-naive subjects

Commonalities between nicotine and other dependence-producing drugs

Dopamine release by motivational stimuli

Role of dopamine in associative stimulus reward learning

Drugs of abuse as false neurochemical homologues of reward

Differences between drugs of abuse and incentives

Adaptive changes in dopamine responsiveness to nicotine and tobacco addiction

Nicotine dependence as dopamine-induced learning disorder

Acknowledgements

Pharmacol. Biochem. Behav.

Neuroscience

Brain Res.

Progress in Neurobiology

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Neuroscience

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Eur. J. Pharmacol.

Drug Alcohol Depend.

Life Sci.

Brain Res.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Brain Res.

Eur. J. Pharmacol.

Neuron

Pharmacol. Biochem. Behav.

J. Biol. Chem.

Trends Pharmacol. Sci.

Drug Alcohol Depend.

Eur. J. Pharmacol.

Alcohol

Biol. Psychiatry

Mol. Brain Res.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neuroscience

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Life Sci.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens and medial frontal cortex

J. Neurochem.

SCH23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine receptor blockade?

Psychopharmacology

D1 receptors blockade stereospecifically impairs the acquisition of drug-conditioned place-preference and place-aversion

Behav. Pharmacol.

Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons: II. The rundown and inward rectification of agonist-elicited whole-cell currents and identification of receptor subunits by in situ hybridization

J. Pharmacol. Exp. Ther.

The biological, social, and clinical bases of drug addiction: commentary and debate

Psychopharmacology

Diagnostic and Statistical Manual of Mental Disorders

Diagnostic and Statistical Manual of Mental Disorders

The discriminative stimulus properties of intravenously administered cocaine in rhesus monkeys

Ultrastructural localization of the a4-subunit of the neuronal acetylcholine nicotinic receptor in the rat substantia nigra

J. Neurosci.

Expression of neuronal nicotinic acetylcholine receptor subunit mRNAS within rat midbrain

Soc. Neurosci.

Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum

J. Neurosci.

D₁ receptors blockade stereospecifically impairs the acquisition of drug-conditioned place-preference and place-aversion