BIOLOGICAL BASIS OF NICOTINE ADDICTION

Transcription

1 Indian Journal of Pharmacology 2003; 35: EDUCATIONAL FORUM BIOLOGICAL BASIS OF NICOTINE ADDICTION R. JAIN, K. MUKHERJEE National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi Manuscript Received: Revised: Accepted: ABSTRACT Nicotine, the primary component of tobacco produces reinforcing effects both in humans and animals. The neurochemical, anatomical and molecular basis of nicotine dependence is very similar to the other drugs of abuse, particularly the psychostimulants. Nicotine has specific acetylcholine receptors (nachrs) in the brain and other organs. The stimulation of presynaptic acetylcholine receptors increases transmitter release as well as the metabolism. Nicotine, like other drugs of abuse triggers the dopamine reward system and increases the extracellular level of dopamine in nucleus accumbens (NAc), which is thought to be responsible for the reinforcing behavior, stimulant and dependence properties of nicotine. Nicotine also exerts its effect in the brain on non-dopaminergic structures that may account for its positive rewarding effects and some of the symptoms of nicotine withdrawal. Moreover, the actions of nicotine on many systems, including brain stem cholinergic, GABAergic, noradrenergic, and serotonergic nuclei, may also help to mediate nicotine effects related to addiction. Further, the neurochemical pathway to nicotine reinforcement is likely to be due to binding of nicotine to nachrs containing the b 2 subunit, followed by activation of the mesolimbic dopamine system and an initiation of common molecular changes that underlie drug dependence. Furthermore, the constituents in tobacco inhibit both forms of the enzyme monoamine oxidase (MAO-A and MAO-B). This enzyme is important in the breakdown of the amine neurotransmitters, including dopamine, which is thought to mediate the reinforcing effects of nicotine and contribute to tobacco dependence. Several questions remain regarding nicotine addiction and further research is needed in this direction. Molecular genetic techniques, coupled with behavioral analysis, may prove to be very useful tools for addressing these questions in near future. KEY WORDS Dependence dopamine tolerance Introduction Nicotine, is derived from the leaves of tobacco belonging to the family Nicotiana tabacum and has been in use for centuries. It can be smoked, chewed, or sniffed. Nicotine was isolated from tobacco leaves in 1828 by Posselt and Reimanbasic, since then scientists began studying its effects in the brain and body. This research eventually showed that, although tobacco contains thousands of chemicals, the most active ingredient that acts in the brain and produces addiction is nicotine. Nicotine is an alkaloid (1-methyl-2-[3-pyridyl] pyrrolidine). It is the primary component of tobacco that leads to addiction. More recent research has shown that the addiction produced by nicotine is extremely powerful and is atleast as strong as addictions to other drugs such as heroin and cocaine. In recent years, the use of tobacco has taken a great toll on youth and society. In fact, tobacco is the gateway drug to other drugs of abuse such as marijuana and alcohol. The notable aspect about tobacco use is that it consistently occurs early in the sequence of problem behaviors. When a young person starts smoking or using tobacco, it is a signal, an alarm that he or she may get involved in other risky behaviors. Correspondence: Raka Jain [email protected]

2 NICOTINE ADDICTION 282 Some of the effects of nicotine include changes in respiration, blood pressure, constriction of arteries, and increased alertness. Many of these effects are produced through its action on both the central and peripheral nervous system. How nicotine acts? Nicotine acts on the brain and other parts of the nervous system. When tobacco is smoked, nicotine enters the bloodstream through the lungs and reaches the brain faster than the drugs that enter the body directly through the veins. When it is chewed or sniffed, nicotine passes through the mucosal membranes of the mouth and nose to enter the bloodstream. Nicotine can also enter the bloodstream by passing through the skin. Nicotine reaches the brain within seven seconds. This sudden burst of nicotine causes an instant high blood pressure which is caused by the stimulation of the adrenal glands resulting in discharge of epinephrine. The release of adrenaline causes a sudden release of glucose as well as an increase in blood pressure, respiration and heart rate. In addition, nicotine indirectly causes release of dopamine in the brain regions that control pressure and motivation. Nicotine is distributed through out the body and brain where it activates specific types of receptors known as cholinergic receptors. Nicotine and the brain Recent research has shown how nicotine acts on the brain to produce a number of behavioral effects. Nicotine readily crosses the blood brain barrier stimulating the nicotinic acetylcholine receptors (nachr). These nicotinic cholinergic receptors are one of the major acetylcholine receptor subtypes. The stimulation of the presynaptic nachrs on these neurons increases the transmitter release as well as the metabolism. Chronic administration of nicotine results in desensitization and inactivation of nachrs 1,2 with subsequent up-regulation of nachrs sites. Cholinergic receptors are present in many brain regions especially concentrated in the midbrain tegmentum, the striatum, nucleus accumbens and the ventral tegmentum; 3 as well as in muscles, adrenal glands, the heart, and other organs. These receptors are normally activated by the neurotransmitter acetylcholine produced in the brain, and neurons in the peripheral nervous system. Acetylcholine and its receptors are involved in many activities, including respiration, maintenance of heart rate, memory, alertness, and muscle contraction. Besides binding to AChRs nicotine also binds to the cholinergic receptors in the autonomic ganglia, adrenal medulla and the neuromuscular junction. The specific sites for binding in the brain are the hypothalamus, hippocampus, thalamus midbrain, brain stem and cerebral cortex. Nicotine also binds to receptors in the nigrostriatal and mesolimbic dopaminergic neurons. As and when the nicotine receptors are stimulated they release acetylcholine, nor-epinephrine, dopamine, serotonin, vasopressin, growth hormone and ACTH. Nicotine is one of the most potent stimulants of the mid brain dopamine reward pathway 4-6. Nicotine acts on the locus ceruleus regulating vigilance, arousal, concentration and stress reactions making the tobacco users more alert. Nicotine also alters the functions of some of the neurotransmitters implicated in the pathogenesis of some of the major psychiatric disorders. These include dopamine, nor-epinephrine, serotonin (5-HT), glutamate, g-amino butyric acid (GABA) and endogenous opioid peptides 7-9. These effects could be presynaptic, pre terminal or cell body nicotine receptors, rather than mediated through neurotransmission wherein pre-synaptically released acetylcholine acts on postsynaptic, junctional nachrs to cause neuronal firing 10. Biological theories of nicotine addiction I. Dopamine and reward pathways There is substantial evidence to suggest that nicotine plays a vital role in maintaining the tobacco smoking habit and many habitual smokers become dependent on nicotine. Nicotine is a powerful reinforcing agent in both animals and humans. The means by which nicotine produces addiction remain unclear. Behavior studies in animals do indicate that nicotine is an addictive drug that reinforces self-administration, place preference and increases locomotion. The effects of nicotine on tests of reinforcement and behavioral sensitization are primarily mediated through the mesolimbic dopamine system. The mesolimbocortical dopamine system consists of neurons with cell bodies localized in the ventral tegmental area (VTA) and axons projecting to

3 283 the nucleus accumbens (NAc) and the medial prefrontal cortex (PFC), being referred to as mesolimbic and mesocortical projections, respectively. Nicotinic receptors concentrated in the VTA and NAc activate the mesolimbic dopamine system, which is thought to be responsible for the reinforcing behaviors like stimulant and dependence properties of nicotine. In this way nicotine is similar to other abused drugs such as amphetamine, cocaine, opiate and alcohol 11. The VTA and its projections to NAc are involved in reward and mediate the reinforcing actions of drug abuse 12. Recently, it has been shown, that key brain chemical involved in mediating the desire to consume drugs is the neurotransmitter dopamine. In the brain, nicotine stimulates the release of the dopamine in the pleasure circuit. Nicotine increases extracellular levels of dopamine in NAc Lesions of mesolimbic dopamine neurons attenuate nicotine self-administration in rats 16. It also attenuates the locomotor stimulant effect of systemically administered nicotine 17. Local injections of nicotine or nicotine agonists into the VTA can result in increased locomotion 18,19. The strongest effects of nicotine appear to be on the dopamine cell bodies of the VTA. Injection of nicotinic agonists locally into the dopamine terminal fields of NAc stimulates dopamine release 20 or locomotor activity 21 indicating that nicotine receptors on the dopamine terminal are involved in mediating the actions of nicotine. Using microdialysis, a technique that allows minute quantities of neurotransmitters to be measured in precise brain areas, researchers have discovered that nicotine causes an increase in the release of dopamine in the nucleus accumbens. This release of dopamine is similar to that seen for other drugs of abuse, such as heroin and cocaine, and is thought to underlie the pleasurable sensation experienced by many smokers. II. Other biological theories related to addiction to nicotine Other research is providing even more clues as to how nicotine may exert its effects on the brain. Nicotine produces its central effects through the nachrs. The cholinergic receptors are relatively large structures that consist of several components known as subunits. The nicotinic receptors are composed of 12 subunits (alpha 2-alpha 10 and beta2- beta10) which play the central role in autonomic transmission 22. The different nicotinic receptors present in the brain are gated-ion channels made of five subunits. Different combinations make different types of receptors, which vary in terms of affinity and localization within the brain. One of these subunits, the b subunit, has recently been implicated as having a role in nicotine addiction. The alpha 4-beta 2 subunit combination has the greatest sensitivity to nicotine. Using highly sophisticated bioengineering technologies, scientists were able to produce a new strain of mice in which the gene that produces the beta 2 subunit was missing. Without the gene for the beta subunit, these mice, which are known as "knockout" mice because a particular gene has been knocked out, were unable to produce any beta subunit 5. These knockout mice, in contrast to mice, with an intact beta subunit, would not self- administer nicotine. These studies demonstrate that the beta subunit plays a critical role in mediating the pleasurable effects of nicotine. The results also provide scientists with valuable new information about how nicotine acts in the brain, an information that may eventually lead to better treatments for nicotine addiction. It is also important to mention that repeated inhalation of tobacco smoke generates boli of nicotine delivered into the brain, superimposed on a relatively stable level of plasma nicotine maintained through out the smoking day. This basal level of nicotine will keep a proportion of nachr in the desensitized state, while the remaining population of nachr is available for activation by nicotine boli, if appropriate concentrations are achieved. This explains how smokers manipulate their plasma nicotine profiles to achieve balance desensitization versus activation. This also explains why the first cigarette of the day is the most satisfying, as overnight abstinence allows a substantial recovery from nachr desensitization. This further suggests that when a smoker is asleep, plasma level of nicotine decreases and the nicotinic receptors can gradually recover their active functional state. In the morning the smoker has a greater number of nachr active receptor sites (up-regulation) and this might contribute to the development of withdrawal symptoms and craving. Moreover, it is also well documented that the number of [3H] nicotinic binding sites (nachr) are increased in the brain of smokers examined postmortem 23,24 and in the brain of rodents given nicotine daily

4 NICOTINE ADDICTION 284 for a few days 25. Other nachr subtypes may also be upregulated but only at higher concentrations of nicotine. There are conflicting reports about the functional status of nachr after chronic treatment, with increased, decreased and unchanged levels of responsiveness being reported 26. Chronic exposure to nicotine transiently desensitizes nachr but can also result in permanent inactivation. The alpha4 beta2 nachr is more prone to inactivation than alpha3 beta2 nachr 27. The exact cause and mechanisms of up-regulation remain controversial. However, the reversible nature of nachr up-regulation (with a return to normal levels in few days in animal models 25 ) is at odds with a long term susceptibility to relapse (to smoking) suggesting that there are other, long term changes in the brain. The interaction between nicotine and GABAergic system has been quite recently discovered. Since then, several electrophysiological studies have demonstrated that nicotinic agonists stimulate the release of GABA from rodent brain tissue and this release was Ca 2+ dependent 28,29. More recently, the actions of nicotine on ventral tegmental GABAergic interneuron, which modulate the mesolimbic dopamine excitability, have been studied 30. Using extracellular recording techniques in rat brain slices, nicotine was found to increase the firing rate of dopamine and non-dopamine neurons, while the former was more vigorous. These results suggest that nicotine stimulate the firing rate of dopaminergic neurons of VTA and also the GABA-ergic neurons, which may be an important target for the effects of nicotine on central nervous system. The less robust response in the non-dopamine presumptive GABAergic neurons and their more pronounced desensitization eventually leads to disinhibition of dopamine neurons thereby facilitating a more sustained increase in response of mesolimbic dopamine neurons to nicotine. Studies have shown that acute nicotine stimulates the release of NA in different parts of the brain, and nicotine acts primarily at the locus ceruleus level 31. Moreover, it was also found that in the hippocampus, maximal desensitization of nicotine- stimulated NA occurs as early as 40 minutes and persists for at least 100 minutes, thereafter, desensitization becomes the dominant process 32. It seems reasonable to speculate that this could mediate the 'calming' effects of cigarette smoking. More research is needed on nicotinic receptors and their desensitization state(s) to understand better about the role of nicotine in different aspects of the dependence process. Tobacco smoking and chronic nicotine administration decreases the concentration of 5-HT in the hippocampus 33. This effect may reflect reduction in the concentration of 5-HT because smoking is associated with selective increase in the density of 5 HT 1A receptors in this area. There is evidence that hippocampus receives serotonergic innervation from the median raphe nucleus. Suppression of 5- HT release in this part of hippocampus brings about anxiolytic response to nicotine when given locally by microinjection into the dorsal hippocampus 34. The effects of nicotine on 5-HT are difficult to dissociate from those on dopamine neurons. Increased exposure to stressful stimuli is likely to increase the desire to smoke as reported by smokers 35. The effects of nicotine withdrawal on dopamine release in the brain may exacerbate by the 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 the effects by acting on 5-HT neurons within the hippocampus. Currently, 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. Recently, animal models have demonstrated commonalties between nicotine withdrawal and opiate abstinence syndrome. These studies suggest that nicotine stimulation induce the release of endogenous opioid peptides in various brain regions resulting in overactivation of opiate receptors. The consequence would be a state resembling opiate dependence. Abrupt termination of the sequence of nicotine stimulated endogenous opioids release and opiate receptor stimulation might then precipitate an opiate abstinence -like state 36. Attempts to demonstrate opioid modulation of smoking reinforcement (cigarette consumption and nicotine self-administration) have been fraught with difficulty 37. Further, it has also been reported that acute treatment with nicotine produced a significant increase in preproenkephalin A mrna levels in striatum and hippocampus, whereas the chronic treatment

5 285 decreases the same in these brain areas 38. Pre-treating rats with mecamylamine blocked these effects of nicotine. This suggests that brain opioid system(s) might be involved in mediating nicotinic responses and its withdrawal, but again further research is needed. There are some informations regarding 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 straital slices 39. Using advanced neuro- imaging technology, it is possible to actually see the dramatic effect of tobacco smoking on the brain of an awake and behaving human being. Using positron emission tomography (PET), scientists discovered that cigarette smoking causes a marked decrease in the levels of an important enzyme, monoamineoxidase (MAO), that is responsible for breaking down dopamine. The decrease in two forms of this enzyme MAO- A and B, results in an increase in dopamine levels. Research has shown that although nicotine causes increase in brain dopamine, nicotine itself does not alter MAO levels. It affects dopamine through other mechanisms. These leads to the possibility of another component of cigarette smoke other than nicotine may be inhibiting the MAO. Thus, there may be multiple ways by which smoking alters the neurotransmitter dopamine to ultimately produce feelings of pleasure and reward In recent years research on the genetic component of cigarette smoking has increased our understanding of nicotine dependence. CYP2A6 is the enzyme responsible for the majority of the inactivation of nicotine in humans. This enzyme is also responsible for activating tobacco-related procarcinogens such as the nitrosamines. A common genetic defect in nicotine metabolism decreases smoking. Genetic variation in the CYP2A6 gene may protect individuals from becoming nicotine- dependent smokers. Recent findings suggest that mimicking this gene defect by inhibiting CYP2A6 decreases nicotine metabolism 43. Further research is needed in order to improve our understanding of how genetic variation in CYP2A6 alters the risk for nicotine dependence and lowers nicotine consumption. Furthermore, cigarette smoking, like other behaviors, shows evidence of genetic heterogeneity. Dopamine transporter (DAT) gene (SLC6A3) encodes proteins that regulates synaptic levels of dopamine in the brain and is a candidate gene for addictive behaviors 44. It is hoped that recent advances in molecular biology, including the completion of the draft sequence of the human genome may help in identifying gene markers that predict a heightened risk of using tobacco and will increase our understanding of nicotine dependence 45. Preclinical studies I. Learning and Memory The potential role of nicotine has been a cognition enhancer 46. Earlier studies reported that nicotine improves learning or performance in several procedures of complex mazes, shock avoidance and attentional tasks. Recent studies have been more systematic in their approach and have been reassessing the effects of the nicotine in the light of current concepts of learning and memory. Effects of nicotine can be defined more specifically in terms of biological processes (attention tasks, spatial tasks, non -spatial tasks) 47,48. Details of these are beyond the scope of this review article. In brief, nicotine has been shown to produce a sort of place preference in rats and mice 49,50. The self-administration of nicotine has also been demonstrated in rats 51,52 and mice 53. In rodents nicotine has anxiolytic-like actions in different behavioral tests namely the mirror chambered 54, the elevated plus maze 55, the two compartment lightdark transition test 56 and fear potentiated startle 57. Nicotine and nicotinic agonists improve performance in a variety of cognitive tasks by animals with basal forebrain lesion 58. Chronic nicotine intake affects attention and working memory in rodents 55. Nicotine enhances acquisition of spatial radial maze and water maze tasks in normal animals. Rats treated with chronic nicotine for a week and then stopping it also showed enhanced acquisition of tasks as compared to the controls 59. II. Tolerance and dependence Research on tolerance to nicotine in non-human animals is extensive and research on dependence in animals is expanding that includes studies of withdrawal signs upon cessation of chronic nicotine treatment 60 and studies of the onset and persistence of nicotine self administration 61. However, to the best of our knowledge, no animal study has directly related chronic nicotine tolerance to a measure of

6 NICOTINE ADDICTION 286 nicotine dependence, such as withdrawal severity or persistence of nicotine self-administration. Wonnacott (1990) suggested that chronic exposure to nicotine increases high affinity binding of nicotinic agonists to brain tissue and induces chronic tolerance to many of the drug's behavioral and physiological effects. The increase in receptor number (upregulation) has been interpreted as a compensation for agonist-induced desensitization of nachrs and this prolonged desensitization has been proposed as a mechanism to chronic tolerance to nicotine 25,62. Singer et al have shown the effects of 6-hydroxydopamine infusion in the nucleus accumbens on the acquisition of nicotine self administration. Similar attenuation lesions have also shown to produce in the locomotor activity by nicotine self-administration in a procedure that generates robust baseline 59. The effects of acute and chronic administration of nicotine on locomotor activity have been studied. Administration of nicotine to experimentally naive rats can depress locomotor activity, an effect to which acute and chronic tolerance can develop. In a conditioned taste aversion paradigm, rats learn to avoid consuming distinctively flavoured solutions that have previously been paired with nicotine solutions. In rats exposed to test apparatus, nicotine produces moderate increase in activity and with repeated exposure to the drug, sensitization occurs. Effect of selective dopaminergic drugs in nicotine tolerance has also been studied. The result suggests that tolerance to nicotine may be mediated through dopaminergic system 63. Commonalties between nicotine and other drugs of abuse The brain feels the effect of nicotine faster than it feels the effect of a shot of heroin in the arm. A common feature that nicotine shares with nonpsychostimulant drugs such as narcotic analgesic, delta-9-tetrahydrocannabinol and ethanol, is the ability of stimulating dopamine transmission preferentially in the shell of the nucleus accumbens by activating dopamine neurons that project to this area 11,13,14,64. Psychostimulant drugs like amphetamine, cocaine and phencyclidine preferentially stimulate dopamine transmission in the shell, but reduce the firing activity of dopamine neurons as a result of an interference with the dopamine reuptake carrier, leading to accumulation of dopamine extracellularly and stimulation of dopamine autoreceptors. Nicotine dependence resembles non-psychostimulant drugs with regard to its dopamine-stimulating property upon an endogenous tone on m-opioid receptors and on 5HT 3 -receptors. Evidence also suggests that nicotine addiction, like addiction to other drugs of abuse, is likely to be the result of molecular changes in the brain areas that mediate reinforcement. Nicotine withdrawal has been shown to result in changes in the firing pattern of VTA neurons, implying that adaptation takes place in the mesolimbic dopamine neurons following chronic treatment 65. Many drugs of abuse such as cocaine, morphine and ethanol alter the mrna levels, proteins or activity of tyrosine hydroxylase (TH) in the mesolimbic dopamine system. Like acute cocaine administration, acute administration of nicotine increases TH activity in the NAc 66. In addition, chronic administration of nicotine can increase TH, mrna levels and activity in the locus ceruleus, that has been reported following chronic morphine treatment 67. These changes in the activity and levels of the rate-limiting biosynthetic enzyme for catecholamines are likely to be common markers for the development of dependence for these drugs of abuse. Furthermore, recently it has been reported that selfadministration of either nicotine or cocaine results in increased expression of chronic fos-related antigens (fras) in the NAc, the prefrontal cortex and the medial caudate 68. The common biochemical response to nicotine and cocaine suggests that similar mechanisms may be involved in the development of dependence to these different drugs of abuse. Finally, repeated exposure to nicotine induces adaptive changes such as tolerance, and sensitization, in the level of the dopamine in the shell and in the core of the nucleus accumbens that resemble those of other drugs of abuse. Conclusion In conclusion, nicotine serves as a major reinforcer both in humans and animals. It is a complex behavioral phenomenon comprising effects on several neural systems. Recent studies have expanded initial observations that the actions of nicotine on dopaminergic systems increase dopaminergic activity and release, leading to nicotine-induced reinforcement. Further, the actions of nicotine on many

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