There is strong evidence that nicotine exerts its positive reinforcing effects through the dopaminergic reward system. However, recent literature has shown that nicotine can modulate other neurotransmitter systems, mainly through pre-synaptic cholinergic receptors. This paper focuses on some of the systems that could participate in the nicotine dependence process.
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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. Nicotine is a psychoactive drug that can improve both mood and cognitive functioning; these effects are rewarding for smokers and contribute to their addiction, but the exact mechanisms involved in such effects remain to be established. The rewarding properties of nicotine, like other addictive drugs, have been demonstrated using a self-administration paradigm in which experimental animals are trained to respond for an intravenous injection of the test drug (Stolerman 1992). There is strong experimental evidence that nicotine, like amphetamine and cocaine, can serve as a robust reward in this type of experiment (Corrigall and Coen 1989). The ability of these drugs to reinforce self-administration seems to depend critically upon their stimulatory effects on dopamine (DA) release in the principal terminal field of the mesolimbic system (see Balfour, 2000) a pathway integral to the brain's reward system. However, little attention has been drawn to other neurohumoral pathways (GABA, nordrenaline, serotonin, glutamate, ACTH ...), and the degree to which they could participate in the nicotine addiction process.
2. A review by Shoaib (1998), pointed out that if DA appears to be critical in mediating the reinforcing effects of nicotine, evidence derived from studies with local microinjections of the drug suggests that its other stimulus properties may be produced via multiple neuroanatomical substrates. For example, the aversive stimulus effects are resistant to dopamine receptor antagonists. The discriminative stimulus effects of nicotine, despite showing some modification with dopaminergic compounds, appear not to be solely mediated via the mesolimbic dopamine system. The authors conclude that the neurobiology of nicotine dependence remains complex, but that such dissociation between stimulus properties may permit the development of more effective therapies in combating tobacco dependence.
3. The purpose of the present paper is not to take into account all the effects of nicotine, but to focus on some neurotransmitter systems that have not been thoroughly studied in past and recent research. A more complete review has been recently published in Nicotine & Tobacco Research, the Journal of the Society for Research on Nicotine and Tobacco (Watkins et al, 2000). In their paper, Watkins and colleagues review the neural mechanisms underlying nicotine addiction, and attempt to disentangle the complex effects of nicotine on the brain, and to propose a theoretical model of the neurobiological mechanisms involved in both the acute positive reinforcement and withdrawal of nicotine.
4. Nicotine produces its central effects through the nicotinic acetylcholine receptors. The different nicotinic receptors present in the brain are gated-ion channels made of five subunits. Ten subunits have been identified in the brain (alpha2-alpha9 and Beta2-Beta4). Different combinations make different types of receptors which vary in terms of affinity and localisation within the brain. When nicotine (or acetylcholine) binds to the receptor, it opens the channel and lets ions passing through (Na+, K+ and Ca++). The calcium permeability is important because when localised pre-synaptically, it facilitates the release of neurotransmitters (see Wonnacott 2001). Modulation of synaptic activity by presynaptic calcium influx may represent a physiological role of acetylcholine in the brain, as well as a mechanism of action of nicotine. Radcliffe et al (1999) have shown that presynpatic nAChR, probably made of alpha 7 subunits, mediated a calcium influx that enhanced the release of both glutamate and GABA in primary culture of hippocampal neurons (spontaneous vesicular release and evoked release of glutamate and GABA were enhanced by nicotine).
5. The interactions between nicotine and the GABAergic system has been quite recently discovered (Lna et al 1993). Since then, several electrophysiological studies have demonstrated that nicotinic agonists stimulate the release of GABA from rodent brain tissue. Lu et al (1998) found that nicotine increased GABA release from synaptosomes preloaded with [3H]-GABA in a concentration-dependent manner, and that this release was Ca2+ dependent. Differences in [3H]-GABA release were detected in 12 brain regions and maximal release was significantly correlated with [3H]-nicotine binding. The pharmacological and regional comparisons suggested that the nAChR that stimulates GABA release is the high affinity nAChR (alpha4beta2). This was confirmed in a study using wild-type, heterozygous and homozygous beta2 null mutant mice. GABA release and nicotine binding decreased along with the number of copies of the null mutant gene.
6. Zhu & Chiappinelli (1999), have studied the effects of nicotine on evoked GABAergic synaptic transmission using whole cell recordings from neurons of the lateral spiriform nucleus in embryonic chick brain slices. Nicotine enhanced electrically evoked GABAergic transmission only at relatively low concentrations of 50-100 nM (but not 25 nM), which approximate the concentrations of nicotine in the blood produced by cigarette smoking. These data imply that nicotine levels attained in smokers are sufficient to enhance evoked GABAergic transmission in the brain, and that this effect is most likely mediated through activation of presynaptic nicotinic receptors.
7. More recently, Yin and French (2000) have examined the actions of nicotine on ventral tegmental GABAergic interneurons, which play an important modulatory role in mesolimbic dopamine neuronal excitability. Using extracellular recording techniques in rat brain slices, nicotine was found to markedly increase the firing rate of both DA and non-dopamine neurons, although the dopamine neuronal response pattern was considerably different and more vigorous than that in the non-dopamine neurons. The nicotine-induced excitations were also reversed by mecamylamine. Desensitisation occurred in both kind of neurons, but was more pronounced in non-dopamine neurons, and obtained with low nM concentrations of nicotine comparable to plasma levels of nicotine found after smoking a cigarette or even with passive inhalation of tobacco smoke. If these results were confirmed, it would mean that nicotine could stimulate the firing rate of ventral tegmental area dopamine neurons, but also that GABAergic neurons may be an important target for nicotine's central nervous system effects. The less robust response in the non-dopamine presumptive GABAergic population and their more pronounced desensitisation could lead to disinhibition of dopamine neurons thereby facilitating a more sustained increase in the response of mesolimbic dopamine neurons to nicotine.
8. The principal noradrenergic innervation to forebrain arises in the locus coeruleus. Like the DA-secreting neurons these neurons express nAChR on both somatodendritic membranes in the locus coeruleus and on the terminal membranes. Studies have shown that acute nicotine stimulates the release of noradrenaline (NA) in different part of the brain, and that nicotine acts primarily at the locus coeruleus level (Fu et al 1998a). However, in contrast to nicotine injections, and because many effects of nicotine are subject to tolerance, chronic infusion often leads to opposite effects. Balfour and Benwell showed that chronic infusions of nicotine resulted in decreased NA levels in the hippocampus (unpublished results cited in Balfour and Fagerstrom 1996). In contrast, others have found that chronic administration (not infusions), resulted in a regionally selective sensitisation of NA release and turn-over (Mitchell et al 1989, Joseph et al 1990, Mitchell 1993). In a more recent study, NA release was reduced after a second nicotine infusion (0.135 mg/kg over 15 min) given 40 to 100 min later, but was not reduced further by a third infusion (Fu et al 1998b). NA release was unchanged with a 200 minute inter-infusion interval. Therefore, the authors concluded that in the hippocampus, maximal desensitisation of nicotine-stimulated NA release occurs as early as 40 minutes and persists for at least 100 minutes; thereafter, resensitisation becomes the dominant process. These effects arealpha- bungarotoxin-sensitive, showing that probably hippocampal NAChRs contain alpha 7 subunits (Fu et al 1999). These results tend to confirm Balfour and Benwell's observations, although the short infusion paradigm is more likely to reflect human smoking behaviour.
9. Moreover, Britton et al (1992) have shown that the increase in NA in the hippocampus overflow evoked by exposure to a noise stress is of fairly short duration and does not persist for the full period of stress. If this is the case, and to the light of the Fu et al (1998b) study, then it seems reasonable to speculate that this could mediate the 'calming' effects of cigarette smoking. More research is needed on nicotinic receptors and their desensitisation state(s) to better understand the role of nicotine in different aspects of the dependence process.
10. Currently, little is known of the consequences of the changes in nicotinic receptor density which occur as a consequence of chronic exposure to nicotine (Benwell et al 1988). However, it seems reasonable to suggest that some withdrawal symptoms may be mediated by reactivation of nicotinic receptors following prolonged nicotine withdrawal (Watkins et al 2000).
11. Tobacco smoking and chronic nicotine administration are associated with a regionally selective reduction in the concentration of serotonin (5-HT) in the hippocampus (Benwell et al 1990). This effect may reflect repetitive or prolonged reductions in the release of 5-HT because smoking is associated with a selective increase in the density of 5-HT1A receptors in this area of the brain (Benwell et al 1990).This conclusion has been strengthened by recent data showing that nicotine injections inhibit 5-HT release and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in rat hippocampus (Balfour and Ridley 2000). Graeff et al (1996) have proposed that 5-HT-secreting projections to the hippocampus may play an important role in the mechanisms underlying 'resistance' to unavoidable stressors and that reduced 5-HT release from these neurons may give rise to depression. Thus, the changes evoked in this pathway by chronic nicotine provide an alternative explanation for the depression observed following nicotine withdrawal.
12. The hippocampus receives its primary serotonergic innervation from the median raphe nucleus (the sole serotonergic innervation to the dorsal hippocampus - see Balfour and Ridley 2000). There is evidence that these neurons may be implicated in the expression of anxiety, since Andrews et al (1997) have reported that anxiety associated with the withdrawal of chronic benzodiazepine treatment is mediated by increased 5-HT release from these neurons. Suppression of 5-HT release in this part of the hippocampus may also explain the anxiolytic response to nicotine when given locally by microinjection into the dorsal hippocampus (Ouagazzal et al 1999). Alternatively, as mentioned above, it has been proposed that the projections to the dorsal hippocampus from the median raphe nucleus play a pivotal role in promoting resistance to chronic unavoidable stressors. This conclusion is consistent with the results of recent dialysis studies (Petrie and colleagues, unpublished observations cited in Balfour and Ridley 2000)showing that repeated exposure to an unavoidable stressor causes an increase in 5-HT overflow in the dorsal hippocampus that is not apparent in rats exposed acutely to the stressor. These data suggest that increased 5-HT overflow in the dorsal hippocampus may be an adaptive response to repeated exposure to the stressor.
13. Here again, the effects of nicotine on 5-HT are difficult to dissociate from those on DA neurons. Increased exposure to stressful stimuli is likely to increase the desire to smoke reported by smokers (Gilbert 1979; Pomerleau and Pomerleau 1987). Morrison trained rats to perform a stressful task under the influence of nicotine (Morrison1974). Upon withdrawal of nicotine, the performance of rats on the stressful task was significantly impaired compared to performance on a less stressful task. Subsequent studies also showed that (1) this effect was observed in rats trained with amphetamine at doses that were likely to act preferentially on DA terminals; and (2) amphetamine injections could ameliorate the effects of nicotine withdrawal (Balfour 1989). Hence, the effects of nicotine withdrawal on DA release in the brain may be exacerbated by exposure to stressful stimuli and may underlie the role of stress as a factor in tobacco smoking, as well as the role of nicotine on reducing these effects by acting on 5-HT neurons within the hippocampus. Globally, there is little evidence for the involvement of the serotonergic system in the positive reinforcing effects of nicotine, but there is some evidence that this system might be involved in the negative reinforcing effects of nicotine withdrawal.
14. There is an extensive literature documenting thenicotine-stimulated release of endogenous opioids in various brain regions involved in the mediation of opiate reinforcement. Although animal models have demonstrated commonalties between nicotine withdrawal and the opiate abstinence syndrome, attempts to demonstrate opioid modulation of smoking reinforcement (cigarette consumption and nicotine self- administration) have been fraught with difficulty (Pomerleau 1998). Houdi et al (1998) have studied the effect of acute and chronic nicotine treatment, and its withdrawal, on preproenkephalin A mRNA levels in rat brain. Acute treatment with nicotine produced a significant increase in preproenkephalin A mRNA in striatum and hippocampus. Chronic treatment with nicotine caused a significant decrease in preproenkephalin A mRNA in these brain regions. A rebound increase was observed in both striatum and hippocampus 24 hours after nicotine cessation, which approached the saline level 7 days later. These effects of nicotine were blocked by pretreating rats with mecamylamine. These data suggest that brain opioid system(s) might be involved in mediating nicotinic responses and its withdrawal, but again further research is needed.
15. The effects of nicotine on appetite regulation is also possibly a strong reinforcer of tobacco smoking, and the weight gain associated with tobacco abstinence is often a cause of relapse. A recent study in rats by Miyata et al (1999) has shown that nicotine's hypophagic effect was associated with an increase in 5HT and DA in lateral hypothalamic area, whereas hyperphagia after nicotine cessation was accompanied by decreased concentrations of these neurotransmitters. These findings suggest that nicotine could affect appetite regulation, in part by modulation of DA and 5HT in the lateral hypothalamic area.
16. Although cognitive facilitation is often cited as a motivation for smoking, little is known about the mechanisms involved. NA and ACh are often cited as mediators of such effects, particularly in frontal- cortex, and nicotine may facilitate their release. A recent study shown that nicotine may facilitate the release of glutamate in the prelimbic area of the rat prefrontal cortex (Gioanni et al 1999). These results provide evidence for nAChR-mediated modulation of thalamocortical input to the prefrontal cortex. Such a mechanism may be relevant to the cognitive effects of nicotine and nicotinic antagonists.
17. Finally, little is known about the psychopharmacological effects of other tobacco alkaloids, or cotinine, the major nicotine metabolite. A recent study suggests that cotinine stimulates nicotinic receptors to evoke the release of DA in a calcium-dependent manner from super fused rat striatal slices (Dwoskin et al 1999).
18. The recent literature is full of evidence that nicotine interacts with most neurobiological systems. This reinforces the idea that nicotine dependence and hence tobacco smoking is a complex behaviour that we do not understand fully yet. In summary, it is clear that nicotine can exert effects in the brain on non-dopaminergic structures that may account for its positive rewarding effects and for at least some of the symptoms of nicotine withdrawal (negative reinforcement). In addition, it is clear that individuals smoke tobacco in such a way that results in changes in brain biochemistry sufficiently robust to be measured at postmortem and which, as far as they have been measured, are very similar to those observed in experimental animals treated with pure nicotine. However, we still need intensive research on the nicotinic cholinergic system in order to better understand both the nicotine addiction process and the normal function of this system within the brain. For this, it will be necessary to study the chronic effects of nicotine, but we are desperately in need of a realistic animal model of nicotine chronic administration that better reflects human smoking behaviour.
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