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Effects of nicotine on the mesolimbic dopaminergic reward system in brain
S. 15. Nicotine: @om receptor to abstinence [3] Paterson D, Nordberg A. Neuronal nicotinic receptors brain. Progress in Neurobiology 20001 61: 75-111.
in the human
IS.15.021 Effects of nicotine on the mesolimbic dopaminergic
reward system in brain
T.H. Svensson. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Tobacco smoking represents the single largest preventable cause of morbidity and mortality in the Western world and compelling evidence demonstrates that it represents a form of drug addiction to nicotine. Thus, nicotine’s effects on major brain reward pathways, such as the mesolimbic dopamine (DA) system, is of major medical interest. Nicotine exerts a prominent activating effect on the midbrain DA neurons in the ventral tegmental area (VTA), which is the major cause of the associated, increased DA release in nerve terminal areas, such as the nucleus accumbens. Our recent evidence indicates that nicotine stimulates these DA neurons via a dual mechanism of action, i.e. both through l!&subunit containing nicotinic acetylcholine receptors (nAChRs) located at the level of the DA cell membrane, and through a7 nAChRs located on glutamatergic afferents to the VTA DA neurons, some of which originate in the prefrontal cortex. Whereas the p2 subunit containing nAChRs seem to primarily control basal (tonic) firing rate, the a7 n4ChRs seem to specifically regulate burst firing of the DA neurons, i.e. the physiologically most effective (phasic) type of activity of the cells, that is of major significance for the expression of immediate early genes in DA target areas and synaptic plasticity. Both mechanisms may, in different ways, contribute to the acquisition and maintenance of nicotine dependence. Following sudden withdrawal of a chronic nicotine treatment, which in both animals and man is associated with a behavioral abstinence syndrome, DA release in the nucleus accumbens, a major projection area of the VTA DA neurons that is specifically involved with reward, is dramatically reduced. This effect may explain the associated elevation of reward thresholds which has been observed in experiments using intracranial self-stimulation. The accumbal DA depletion may, if occurring also in humans undergoing nicotine withdrawal, be of major significance for dysphoric or even depressive reactions following smoking cessation. It may also have bearing on the efficacy of bupropion in this situation, since this drug has been shown to elevate DA output in the nucleus accumbens. Another way to counteract the purported reduction in mesolimbic DA output following smoking cessation is, of course, to administer nicotine, albeit not in the form of tobacco smoke. Finally, novel approaches to treat nicotine dependence, e.g. by means of immunological treatment which generates high titers of antibodies against nicotine, will be briefly reviewed, as it may prevent the nicotine induced DA release in brain.
[S.l5.04] Chronic nicotine treatment and nicotinic receptor function S. Wonnacott, A. Mogg. University of Bath, Department of Biology & Biochemistg Bath BA2 7AY, UK Numbers of high afhnity [3H]nicotine binding sites, corresponding to the a@2 subtype of nicotinic acetylcholine receptor (nAChR),
s139
are upregulated in post-mortem brain tissue from human smokers, compared with age-matched non-smoking controls’, This observation has been reproduced in rodent brain from animals chronically treated with nicotine in oivo, and in cell cultures exposed to nicotine in vitro for a few da~s~,~. Upregulation of nAChR in response to nicotine is paradoxical, as agonists conventionally down-regulate their receptors. However, upregulation may be a response to nicotine-induced nAChR desensitisation (or long term inactivation), that is, loss of function. The mechanism of nAChR upregulation appears to be post-transcriptional: no increase in mRNA for the a4 or 62 subunit has been observed in rodent brains or cell cultures after treatment with nicotine. Increased nAChR assembly, delivery of nAChR from an inaccessible reserve pool, or decreased nAChR turnover has been proposed3. Analysis is complicated by the fact that [3H]nicotine (and other agonist radioligands) only label the desensitised (high al%nity) state of the nAChR under the conditions of binding assays. Moreover, the lipophilicity of nicotine means that intracellular as well as cell surface nAChR are labelled. Attempts to distinguish these populations indicate that the intracellular pool of nAChR accounts for a large proportion of the upregulation observed, at least in cell culture systems where this analysis has been undertaken. It is assumed that the upregulation of [3H]nicotine binding sites (and hence a4fi2 nAChR) observed in human smokers is germane to nicotine dependence. Indeed, studies of knockout mice implicate l32-containing nAChR in nicotine self-administration4. Other nAChR subtypes are also upregulated in cell culture, but require higher nicotine concentrations that may not be achieved during tobacco smoking. What are the implications of nAChR desensitisation and upregulation for nicotine consumption? The functional consequences of chronic nicotine treatment are various: decreased, unchanged and increased nAChR responses have been reported. Similarly, physiological and behavioural responses to chronic nicotine range from tolerance to sensitisation. This repetoire of altered nicotinic activities will arise from the heterogeneity of nAChR (which differ in their propensity to desensitise and to upregulate) and the functional status of upregulated nAChR, as well as their particular physiological roles within brain circuitry. Human nicotine consumption achieved through tobacco smoking is a complex behaviour that is difficult to model experimentally. Smokers tend to maintain a constant plasma nicotine concentration throughout the smoking day, with peaks of nicotine, corresponding to each bolus of inhaled smoke, superimposed upon this basal level. It is argued that the sustained level of nicotine will desensitise a population of susceptible nAChR, whereas the transient peaks of nicotine might activate other nAChR. There are two commonly used strategies for nicotine administration experimentally, that attempt to replicate some of the aspects of nicotine pharmacokinetics: (i) once or twice daily injections of nicotine (0.1-l mgkg in rats) produce high but transient peaks of plasma nicotine, (ii) continuous infusion horn implanted osmotic minipumps mimics the steady state plasma levels of nicotine in the human smoker. Both regimes upregulate numbers of brain [3H]nicotine binding sites’. With regard to the functional responses to nicotine, particular attention has been given to dopamine pathways in the brain, in view of the motor stimulating and rewarding properties of nicotine. Chronic nicotine treatment by daily injections can result in enhanced dopamine release in oioo, as measured by microdialysis, in response to a subsequent challenge dose of systemic nicotine. In contrast, constant nicotine infusion has been reported to counteract this sensitisation of dopamine release and locomotor response&. However, nicotine’s effects are influenced by a number
in the human
IS.15.021 Effects of nicotine on the mesolimbic dopaminergic
reward system in brain
T.H. Svensson. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Tobacco smoking represents the single largest preventable cause of morbidity and mortality in the Western world and compelling evidence demonstrates that it represents a form of drug addiction to nicotine. Thus, nicotine’s effects on major brain reward pathways, such as the mesolimbic dopamine (DA) system, is of major medical interest. Nicotine exerts a prominent activating effect on the midbrain DA neurons in the ventral tegmental area (VTA), which is the major cause of the associated, increased DA release in nerve terminal areas, such as the nucleus accumbens. Our recent evidence indicates that nicotine stimulates these DA neurons via a dual mechanism of action, i.e. both through l!&subunit containing nicotinic acetylcholine receptors (nAChRs) located at the level of the DA cell membrane, and through a7 nAChRs located on glutamatergic afferents to the VTA DA neurons, some of which originate in the prefrontal cortex. Whereas the p2 subunit containing nAChRs seem to primarily control basal (tonic) firing rate, the a7 n4ChRs seem to specifically regulate burst firing of the DA neurons, i.e. the physiologically most effective (phasic) type of activity of the cells, that is of major significance for the expression of immediate early genes in DA target areas and synaptic plasticity. Both mechanisms may, in different ways, contribute to the acquisition and maintenance of nicotine dependence. Following sudden withdrawal of a chronic nicotine treatment, which in both animals and man is associated with a behavioral abstinence syndrome, DA release in the nucleus accumbens, a major projection area of the VTA DA neurons that is specifically involved with reward, is dramatically reduced. This effect may explain the associated elevation of reward thresholds which has been observed in experiments using intracranial self-stimulation. The accumbal DA depletion may, if occurring also in humans undergoing nicotine withdrawal, be of major significance for dysphoric or even depressive reactions following smoking cessation. It may also have bearing on the efficacy of bupropion in this situation, since this drug has been shown to elevate DA output in the nucleus accumbens. Another way to counteract the purported reduction in mesolimbic DA output following smoking cessation is, of course, to administer nicotine, albeit not in the form of tobacco smoke. Finally, novel approaches to treat nicotine dependence, e.g. by means of immunological treatment which generates high titers of antibodies against nicotine, will be briefly reviewed, as it may prevent the nicotine induced DA release in brain.
[S.l5.04] Chronic nicotine treatment and nicotinic receptor function S. Wonnacott, A. Mogg. University of Bath, Department of Biology & Biochemistg Bath BA2 7AY, UK Numbers of high afhnity [3H]nicotine binding sites, corresponding to the a@2 subtype of nicotinic acetylcholine receptor (nAChR),
s139
are upregulated in post-mortem brain tissue from human smokers, compared with age-matched non-smoking controls’, This observation has been reproduced in rodent brain from animals chronically treated with nicotine in oivo, and in cell cultures exposed to nicotine in vitro for a few da~s~,~. Upregulation of nAChR in response to nicotine is paradoxical, as agonists conventionally down-regulate their receptors. However, upregulation may be a response to nicotine-induced nAChR desensitisation (or long term inactivation), that is, loss of function. The mechanism of nAChR upregulation appears to be post-transcriptional: no increase in mRNA for the a4 or 62 subunit has been observed in rodent brains or cell cultures after treatment with nicotine. Increased nAChR assembly, delivery of nAChR from an inaccessible reserve pool, or decreased nAChR turnover has been proposed3. Analysis is complicated by the fact that [3H]nicotine (and other agonist radioligands) only label the desensitised (high al%nity) state of the nAChR under the conditions of binding assays. Moreover, the lipophilicity of nicotine means that intracellular as well as cell surface nAChR are labelled. Attempts to distinguish these populations indicate that the intracellular pool of nAChR accounts for a large proportion of the upregulation observed, at least in cell culture systems where this analysis has been undertaken. It is assumed that the upregulation of [3H]nicotine binding sites (and hence a4fi2 nAChR) observed in human smokers is germane to nicotine dependence. Indeed, studies of knockout mice implicate l32-containing nAChR in nicotine self-administration4. Other nAChR subtypes are also upregulated in cell culture, but require higher nicotine concentrations that may not be achieved during tobacco smoking. What are the implications of nAChR desensitisation and upregulation for nicotine consumption? The functional consequences of chronic nicotine treatment are various: decreased, unchanged and increased nAChR responses have been reported. Similarly, physiological and behavioural responses to chronic nicotine range from tolerance to sensitisation. This repetoire of altered nicotinic activities will arise from the heterogeneity of nAChR (which differ in their propensity to desensitise and to upregulate) and the functional status of upregulated nAChR, as well as their particular physiological roles within brain circuitry. Human nicotine consumption achieved through tobacco smoking is a complex behaviour that is difficult to model experimentally. Smokers tend to maintain a constant plasma nicotine concentration throughout the smoking day, with peaks of nicotine, corresponding to each bolus of inhaled smoke, superimposed upon this basal level. It is argued that the sustained level of nicotine will desensitise a population of susceptible nAChR, whereas the transient peaks of nicotine might activate other nAChR. There are two commonly used strategies for nicotine administration experimentally, that attempt to replicate some of the aspects of nicotine pharmacokinetics: (i) once or twice daily injections of nicotine (0.1-l mgkg in rats) produce high but transient peaks of plasma nicotine, (ii) continuous infusion horn implanted osmotic minipumps mimics the steady state plasma levels of nicotine in the human smoker. Both regimes upregulate numbers of brain [3H]nicotine binding sites’. With regard to the functional responses to nicotine, particular attention has been given to dopamine pathways in the brain, in view of the motor stimulating and rewarding properties of nicotine. Chronic nicotine treatment by daily injections can result in enhanced dopamine release in oioo, as measured by microdialysis, in response to a subsequent challenge dose of systemic nicotine. In contrast, constant nicotine infusion has been reported to counteract this sensitisation of dopamine release and locomotor response&. However, nicotine’s effects are influenced by a number