It is now widely accepted that a majority of habitual tobacco smokers become addicted to the nicotine present in the smoke. This brief review focuses on the evidence that nicotine exerts on the mesolimbic dopamine (DA) system that are entirely consistent with it having the properties of a psychostimulant drug of abuse. Thus, the ability of nicotine to reinforce self- administration in experimental animals depends upon its ability to stimulate the DA-secreting neurones which project to the nucleus accumbens. Microdialysis studies show that acute nicotine preferentially stimulates DA overflow in the shell of the nucleus accumbens, whereas subchronic nicotine causes sensitisation of its stimulatory effects on DA overflow in the core of the structure. The presentation discusses the evidence that stimulation of DA overflow in the accumbens shell is required to elicit or, more likely, signal the 'rewarding' properties of the drug which reinforce self-administration. Based on the results of studies with other psychostimulant drugs, it is possible that these effects are mediated by the D-3 receptors that are found in relatively high density in the subdivision of the structure. The sensitised effects of subchronic nicotine in the core of the accumbens are thought to mediate the transfer from 'drug-liking' to 'drug-seeking' behaviour and, therefore, to be of fundamental importance to the development of dependence. The nature of the receptor(s) involved remains to be established although there is circumstantial evidence for a role of both D-1 and D-2 receptors. Studies reported in more recent years have suggested that increased DA overflow in the accumbens is not, in itself, sufficient to account for the rewarding properties of addictive drugs. The review concludes by discussing the evidence that drugs of dependence preferentially increase DA overflow into an extra-synaptic compartment where it gains access, by a process of volume transmission, to extra-synaptic DA receptors located on adjacent cells. These receptors, it is proposed, facilitate the way in which we learn about cues associated with pleasurable stimuli and the ways in which the may be experienced again.
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INTRODUCTION FOR NICOTINE ADDICTION WORKSHOP BY MARCUS MUNAFO AND MIKE MURPHY: The ICRF General Practice Research Group in Oxford recently hosted a workshop on the theme of "Neuroscience, molecular genetics and nicotine addiction". It was chaired by Professor Neal Benowitz from the University of California at San Francisco, a specialist in the field of nicotine pharmacology spending an invited week in the University to work with the Group, and included about 30 other experts from groups around the UK and Sweden, including the ICRF Molecular Pharmacology Unit in Dundee and the ICRF Health Behaviour unit in London. Their backgrounds included neuroscience, molecular genetics, genetic epidemiology, pharmacology, psychology and clinical medicine, but they were united in a belief about the importance of tobacco control.
It is now recognised that addiction to nicotine lies at the heart of the tobacco control problem. Without the marketing of tobacco its use would dwindle. But while it is so widely promoted smoking research focuses heavily on factors affecting why people continue smoking after trying it and how to get them to stop with psychological support and the use of effective drugs. Although tobacco use is rightly viewed as a social and psychological problem we also need to see it as a pharmacological one with a potential genetic contribution to the addictive process. The need to integrate knowledge about the brain chemistry underlying addiction, the molecular genetics of these cellular processes, and how the drugs which are effective work, was the workshop's subject.
Each of the meeting's 4 sessions kicked off with a brief introduction by speakers who had precirculated draft papers. The sessions considered in turn: (1)how nicotine is metabolised and cleared from the body (2)the brain receptors in which nicotine "docks" to exert its effects (3)the brain pathways involving the neurotransmitter,dopamine,which are thought to contribute to the rewarding properties of nicotine which reinforce a smoker's desire to smoke (4)other non-dopamine pathways that are activated by nicotine and may underly such effects as nicotine withdrawal symptoms.
Understanding how the drugs which are effective (Nicotine Replacement Therapy and some antidepressants) interact with the expression of individual genotypes in the brain and elsewhere to predict success in quitting smoking will help to shed light on which bits of the brain are important in nicotine addiction at both the anatomical and cellular level. The workshop participants emerged pleased to have caught up with advances in fields which were not their speciality and with a strong sense that more enduring closer contact and cooperation will be possible in the future.
1. Studies in the 1950s by Olds and colleagues showed that experimental rats could be trained to stimulate electrodes located in specific sites within the brain using a technique called intracranial self-stimulation (ICSS). In the late 50s/early 60s, the principal dopamine (DA) pathways of the brain were described. These studies showed that mammalian forebrain is innervated by two major pathways originating in two areas of the midbrain, the substantia nigra and ventral tegmental area. As our understanding of the anatomy of the brain evolved, it became clear that many of the sites which reinforced ICSS were located in one of these DA pathways, the mesolimbic system, which projects from the ventral tegmental area to limbic areas such as the nucleus accumbens and olfactory tubercle. These observations led to the concept that the mesolimbic DA system forms a pivotal component of a reward system in the brain that responds to and signals pleasurable stimuli. Wise and Bozarth  summarised the evidence that psychostimulant drugs of dependence had the common property of enhancing the release of DA from this pathway. They suggested that the positive reinforcing properties of drugs of abuse depended upon this response to the drugs.
2. The hypothesis was supported by the evidence that the self- administration of drugs of dependence in experimental animals is attenuated substantially by lesions of these DA neurones. Additionally, animals can be trained to self-administer addictive drugs, such as amphetamine or cocaine, directly into the accumbens. Since this pathway also mediates the locomotor stimulant response to these drugs, Wise and Bozarth called their hypothesis the psychostimulant theory of addiction. They suggested that all drugs of dependence shared an ability to stimulate these neurones and, providing an appropriate dose was used, an ability to elicit locomotor stimulation. This theory gained considerable support from the results of subsequent studies, employing in vivo microdialysis, which showed that most drugs of dependence increased DA overflow preferentially in the nucleus accumbens [Di Chiara & Imperato 1988]. Thus, it soon became axiomatic that the rewarding properties of these drugs depend upon their ability to stimulate DA release from these neurones. Early studies on the neurobiology underlying nicotine dependence provided evidence that the drug shared this important property and that both the locomotor stimulant response to the drug and its ability to reinforce self-administration were associated with its effects on mesoaccumbens DA neurones [see Balfour et al 1998 for a review]. Thus, nicotine appears to have the principal neurobiological properties required of a psychomotor drug of dependence.
3. Studies reported by Heimer and his colleagues in 1991 suggested that the nucleus accumbens could be divided into two subdivisions, the core and the shell. The core sends major projections to areas of the brain involved in motor function and is thought to be involved in the regulation of locomotor activity. The shell, in contrast, appears to be an extension of an important limbic structure, the amygdala. Recent studies have shown that the acute administration of many drugs of dependence causes a preferential increase in DA release from the terminals in the shell of the accumbens. The results of experiments with animals trained to self-administer cocaine suggest that increased DA release in the shell of the accumbens is a primary mechanism underlying the rewarding properties of the drug. Thus, it has been proposed that this response plays a pivotal role in the development of dependence by facilitating incentive learning of the cues associated with the delivery of the drug [Di Chiara 1998; 1999]. Di Chiara argues that, unlike natural rewarding stimuli, drugs of dependence have the ability to sustain this effect when given repetitively and that this effect is pivotal to their ability to cause dependence. Studies reported in the last few years have confirmed that acute injections of nicotine also act preferentially on the projections to the accumbens shell and that the response is maintained, albeit at a reduced level, in animals treated repetitively with the drug [Cadoni et al 2000]. Thus, nicotine also shares this property with other drugs of dependence.
4. DA exerts its effects in the brain by acting upon a family of receptors. These receptors can be divided into two broad categories, D-1 type and D-2 type, which are defined primarily by their pharmacology although each group also retains significant sequence homology. Two D-1 type receptors have been identified, D-1 and D-5. They are excitatory and stimulate the formation of cAMP. The D-2 type receptor family has three main subtypes, D-2, D-3 and D-4, although additional splice variants of the D-2 receptor have also been described. These receptors are inhibitory and have a number of transduction mechanisms including inhibition of cAMP formation. D-1 and D-2 receptors are expressed quite widely in areas of the brain innervated by DA- secreting neurones and compose approximately 80 percent of all DA receptors. Thus, both subtypes are found in the two principal subdivisions of the accumbens. D-3 receptors are found predominantly in limbic areas of the brain such as the shell of the accumbens. The role of DA receptor subtypes in the psychopharmacology of dependence has been explored most extensively with cocaine. Studies with this drug suggest that the rewarding properties of the drug, measured using a self-administration paradigm, reflect stimulation of D-1 and D-3 receptors located in the accumbens [Caine et al 1995; Caine & Koob 1994;1995]. The locomotor stimulant response to cocaine seems to reflect stimulation of accumbal D-2 receptors [Baker et al 1996]. The specific subdivisions of the structure, involved in specific responses to cocaine, have not been defined with certainty although it is thought that the rewarding properties of the drug, which reinforce its self-administration, are mediated by stimulation of receptors in the shell of the accumbens [Caine et al 1995; Di Chiara 1998; 1999]. Relatively little is known specifically about nicotine although a study by Corrigall and Coen  showed that nicotine self-administration was reduced in rats that were pretreated with either a D-1 or a D-2 antagonist.
5. The repeated administration of psychostimulant drugs of abuse characteristically leads to sensitisation of their effects on DA overflow in the nucleus accumbens and, often, to sensitisation of their effects on locomotor activity. It is possible that the two phenomena may be related. However, some years ago Robinson and Berridge  suggested that sensitised mesolimbic DA responses may also be involved in the attribution of incentive salience to the cues associated with acquisition of the drug, and that the sensitisation reflected the transition from drug-liking to drug-seeking behaviour. This implied that sensitisation of the system may be related to the loss of control of behaviour which is a characteristic of the development of drug dependence. This hypothesis is consistent with the evidence that self-administered cocaine elicits a greater increase in DA overflow in the accumbens than the non-contingent administration of the drug delivered to yoked animals [Hemby et al 1997]. Our group was the first to report that the repetitive administration of nicotine also results in sensitisation of its effects on DA overflow in the nucleus accumbens [Benwell & Balfour 1992]. This was, initially, a controversial observation. In our studies, the microdialysis probes, used to make the measurements, were targeted at the core of the accumbens. A recent study by Cadoni et al  has confirmed our observation and shown that sensitisation is restricted to the core of the structure. This would seem a surprising finding since most workers in the field would expect the sensitisation to occur in the subdivision of the structure, the shell, which is thought to mediate the rewarding property of the drug. However, Cadoni and colleagues have also shown that nicotine is not unique in this, sensitisation of the DA response to other psychostimulant drugs of abuse also being restricted to the accumbal core. The psychopharmacological significance of this effect remains to be established. Di Chiara , however, has suggested that sensitisation of the DA projections to core of the accumbens is related to the development of behaviours driven by cues that have been paired with exposure to nicotine. This idea is consistent with the hypothesis, first proposed by Robinson and Berridge , which also implied that the evolution of sensitised mesoaccumbens DA responses to an addictive drug was implicated in the switch from liking to needing or craving the drug.
6. Cocaine and amphetamine exert their effects on DA overflow in the nucleus accumbens by binding to the DA transporters located along the axons. In contrast, systemic injections of nicotine appear to exert their effects on DA release by acting on nicotinic receptors located on or close to the cell bodies in the midbrain [see Balfour et al 1998 for review]. Thus, the effects of nicotine depend upon its ability to influence impulse flow to the terminal field. The effects of all three drugs, nevertheless, is to elicit a marked increase in extracellular DA in the accumbens, and it seems reasonable to suggest that this is the pivotal effect which they share. Recent studies suggest that most of the DA transporters in the accumbens are located outside synapses and it has been suggested that their primary role is to regulate the DA concentration in this extra-synaptic space [Nirenberg et al 1998]. The data from our laboratory are, in our view, most consistent with the hypothesis that psychostimulant drugs of dependence share the ability to increase specifically the concentration of DA in this extra- synaptic space, and that this effect mediates the behavioural responses attributed to mesolimbic DA by Robinson and Berridge  and Di Chiara [1998; 1999]. This hypothesis implies that psychostimulant drugs of abuse enhance the paracrine release of DA in the accumbens which then acts predominantly on extra-synaptic DA receptors through a process of volume transmission. The hypothesis predicts that this effect is central to the development of dependence.
7. It will be clear from the foregoing discussion that the psychostimulant theory of dependence, first proposed by Wise and Bozarth, has undergone some revision. However, for many workers in the field, the central tenet of the hypothesis remains valid. This implies that stimulation of the DA projections to the accumbens, probably specifically the shell of the structure, confers upon stimuli associated with the effect a pleasurable or rewarding property that promotes the desire to repeat the experience. This hypothesis predicts that drugs that act on the system in this way are addictive because they elicit an effect that is significantly larger and/or more prolonged than that elicited by natural rewarding stimuli. As a result they confer exceptional rewarding properties upon the drug to the extent that acquisition of the compound comes to dominate behaviour. By contrast, withdrawal of addictive drugs often depresses the release of DA in the shell of the accumbens and renders the neurones which project to the accumbens more resistant to stimulation [Koob et al 1997]. This effect is thought to represent the neural correlate of the dysphoria or anhedonia (an inability to respond to pleasurable stimuli) experienced by many addicts when they first stop taking drugs. The withdrawal of nicotine has been shown to elicit these effects [Epping- Jordan et al 1998; Hildebrand et al 1998], although the reduction in DA overflow seems to require the administration of a nicotinic receptor antagonist rather than the simple withdrawal of the drug. Thus, changes in DA release in the nucleus accumbens may serve to maintain drug taking behaviour by contributing to both the positive reinforcing properties of nicotine when it is inhaled in tobacco smoke and the avoidance of the anhedonia or dysphoria experienced when habitual smokers try to quit the habit.
8. Much of the foregoing discussion is consistent with the hypothesis that stimulation of DA projections to the nucleus accumbens and, especially, the shell of structure, confers rewarding properties on any activity associated with it. This concept has generated the idea that DA neurones which project to the accumbens form a pivotal component of a reward system in the brain whose primary role is to respond to pleasurable stimuli. An extension of this hypothesis posits that drugs are addictive because they artificially stimulate pathway, often to an extent not achievable by natural rewarding stimuli. While this hypothesis continues to form the focus of many studies on the neurobiology of drug dependence, it also important to remember that, in recent years, other possible explanations for its role have been proposed. For example, Berridge and Robinson  have reported results which suggest that mesolimbic DA neurones do not directly mediate hedonic response to stimuli but may be involved more in the processes underlying the way in which we learn about pleasurable stimuli and the behaviours by which we can re-experience them. It is unlikely that the simplistic view of the role of mesolimbic DA in drug dependence, which evolved in the late 80s, provides a complete explanation for the development of dependence upon psychostimulant drugs. However, the data still support the concept that the pathway plays a central role in the development of drug dependence and a more complete understanding of this role may enable us to tackle one of the principal problems of the treatment of drug abuse which is particularly applicable to tobacco smoke, the issue of relapse following a period of successful cessation.
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