⋅교신저자 : 함대현, 서울시 동대문구 회기동 1번지 경희대학교 침구경락과학연구센터, Tel. 031-201-2176, Fax. 031-204-4237, E-mail: [email protected]
⋅본 연구는 과학기술부/한국과학재단 우수연구센터 육성지원사업 의 지원으로 수행되었음(R11-2005-014).
⋅투고 : 2007/01/08 심사 : 2007/03/09 채택 : 2007/03/13
금연치료 요법으로의 침 자극에 대한 신경학적 기전
염미정1ㆍ이혜정1,3ㆍ심인섭4ㆍ박히준3ㆍ함대현1,2
경희대학교 침구경락과학연구센터1, 한의학연구소2, 경락학교실3, 가톨릭대학교 의과대학 통합의학교실4
Neural mechanism of acupuncture therapy for aiding in smoking cessation
Mi-jung Yeom1, Hye‐Jung Lee1,3, In-sop Shim4, Hi‐Joon Park3, Dae‐Hyun Hahm1,2
1Acupuncture & Meridian Science Research Center, 2Institute of Oriental Medicine,
3Dept. of Meridian & Acupuncture, College of Oriental Medicine, Kyunghee University,
4Dept. of Integrative Medicine, College of Medicine, The Catholic University Abstract
목 적 : 흡연에 따른 건강적 피해가 많이 알려져 있음에도 불구하고 특히 여성 및 청소년 계층의 흡연이 증 가하고 있으며 폐암 사망자수는 급격히 늘어나고 있는 상황이다. 완전한 금연이 실패하는 주요 이유는 담배의 중 독성에서 비롯되며 금단현상을 극복하지 못해 일어나는 것으로 알려져 있다. 흡연의 중독성은 담배 주요성분 중 의 하나인 니코틴(nicotine)에 의해 유발되며 따라서 모든 금연 요법 및 금연 치료보조제 들은 이 니코틴 작용을 어떻게 효과적으로 억제 또는 대체하느냐에 초점을 맞추고 있다. 최근 금연치료 요법으로 한방 침이 주목 받고 있으며 본 논문을 통해 한방 침의 금연효과에 대한 신경학적 기전을 고찰하고자 한다.
방 법 : 금연을 돕는 전형적인 보조 치료제 및 치료법이 몇 종류 개발되어 사용 중에 있으며 대표적으로 니 코틴 대체 요법(nicotine replacement therapy, NRT)이나 항우울제로 사용되는 bupropion 등을 들 수 있다. 이 치료 방법들은 뇌의 도파민계 신경전달 체계에 영향을 미쳐 금연 효과를 발휘하게 되는데 실질적인 금연 성공확 률은 그리 높지 않은 것으로 알려져 있다. 따라서 침의 자극에 대한 도파민계 신경전달 조절효과를 중심으로 고 찰함으로써 침의 금연효과에 대한 의과학적 기전을 설명하고자 하였다.
결 과 : 침자극은 우수한 금연효과를 가져올 수 있는 치료법으로 기존의 금연 치료요법 및 치료제 들을 보 완할 수 있는 보다 확실한 치료요법 중의 하나이며 특히 금연 후에 오는 금단현상을 효과적으로 완화시키는 작용 을 한다. 그리고 이 같은 효과는 부분적으로 도파민계를 비롯한 신경전달계를 조절함으로써 가능한 것으로 판단 된다.
결 론 : 본 논문을 통해 니코틴에 의한 금단현상의 신경학적 기전과 금연과 관련된 신경전달체계에 대한 침 자극의 효능에 대해 고찰하였으며 기존의 금연보조치료법을 대체할 수 있는 우수한 의학적 치료법으로써의 침치 료법을 제시하였다.
Key words : acupuncture, neurotransmitter, smoking cessation, nicotine withdrawal, dopamine
Ⅰ. INTRODUCTION Tobacco is the second major cause of death in the world. There are about 1.2 billion smokers worldwide and half of these smokers, about 600 million people, will eventually die of various diseases, caused by their smoking, losing several years of
life. It represents deaths of 5 million smok- ers every year worldwide. If current smok- ing patterns continue, it will become the largest single health problem worldwide, and cause some 10 million deaths each year by 20201-3). Nicotine is at least as ad- dicting as cocaine or heroine. In spite of the harmful effects, gradually increased consumption of tobacco is due to the ad- dictive power of nicotine in tobacco.
Nicotine addiction plays a pivotal role in maintaining the tobacco smoking and re‐
smoking habits4). Most people who quit smoking or chewing tobacco have some symptoms of withdrawal from nicotine, and smoking cessation thus brings about dozens of withdrawal symptoms such as nicotine craving, headaches, increased appetite, trou- ble sleeping, shaky hands, nervousness, de- pression, anxiety, anger, irritability etc.5). These severities of withdrawal symptoms often lead to smoking relapse. Therefore, some kind of aided quit interventions have been needed for successful cessation of to- bacco smoking.
The main purpose of the pharmacother- apy is to ameliorate the symptoms and signs of nicotine withdrawal. The repre- sentative pharmacological aids, currently available and being known to be effective in smoking cessation, are nicotine replace- ment therapy (NRT), in which nicotine, in several forms including patch, gum, inhaler,
nasal spray and lozenges, is administered, and bupropion hydrochloride, which is an antidepressant6). Although both NRT and bupropion are relevant and effective inter- ventions to aid smoking cessation7,8), these therapies have critical weak points such as unsatisfactory stopping of tobacco smoking or remaining a long abstinent period. It is thus apparent that new drugs or other types of therapy are still required for aid- ing complete cessation of smoking without withdrawal symptoms and side effects. In this review, we will attempt to briefly summarize the medicinal effects and func- tional mechanism of acupuncture for smok- ing cessation.
1. Smoking Cessation and Depression
It is well known that nicotine is a major component of tobacco smoke contributing to smoking addiction9). Nicotine affects many aspects of behavior such as locomo- tion, nociception, anxiety, learning and memory, as well as several behavioral re- sponses related to its addictive properties such as rewarding effects and physical de- pendence10,11).
Chronic nicotine exposure produces addic- tion and tolerance or sensitization to the acute effects of nicotine12-14). The addiction is likely to be developed by neuroplasticity following activation of signaling pathways in response to repeated treatment with
drugs of abuse15-17). Although the neuro- biological mechanisms underlying nicotine addiction remain to be established, it is now widely accepted that nicotine activates the mesolimbic dopamine system in the brain and this is important for the re- inforcing properties of the drug18-20).
Smoking cessation is known to produce aversive withdrawal symptoms21). The aver- sive effects of the nicotine withdrawal after chronic nicotine exposure are thought to be powerful motivational factors, contributing to the maintenance of the smoking and re
‐smoking habits. Indeed, smoking relapse is related to withdrawal duration and se- verity22). Withdrawal symptoms in smoking cessation are characterized by somatic symptoms, such as bradycardia, insomnia, gastrointestinal discomfort, and increased appetite leading to weight gain, and affec- tive symptoms, such as depression, irrita- bility, anxiety, frustration, difficulty in con- centrating, and craving for tobacco11,23,24). Although the somatic symptoms of nicotine withdrawal are annoying, the affective symptoms, particularly depression, play more important role in the maintenance of tobacco smoking and re‐smoking in smok- ers than the somatic symptoms of nicotine withdrawal25,26).
The association between depression and smoking has been consistently established in numerous epidemiological studies24,27).
Actually, the increasing rate of smoking is much higher in depression patients than in the general population by up to 65%28-30). Furthermore, the persons who have a his- tory of depression have a much harder time to give up cigarette smoking than non
‐depressed individuals24). It was suggested that smoking can be used as a self‐medi- cation by the depressed individuals to alle- viate some symptoms of depression because nicotine in smoke has an anti‐depressive property. Indeed, there are many reports describing nicotine acts as an anti‐depres- sant in human24,31).
When taken altogether, although the neu- robiological basis of nicotine withdrawal has not been clear yet, smoking habit may be causally related to avoidance of negative affects, particularly depression, due to the nicotine withdrawal.
2. Neurobiology of Smoking Cessation
The acute positive reinforcing effects of an addictive drug are critically important in establishing self‐administration.
However, neuroadaptation within brain cir- cuitries that produce positive reinforcement may contribute to a negative affective state upon drug termination, and eventually bring about drug dependence32). Maintenance of nicotine dependence may be also facilitated by the avoidance of certain withdrawal symptoms through further nic-
otine administration. The neuronal sub- strates, involved in the positive reinforcing properties of drugs, are compromised during chronic exposure, and other neuronal sub- strates, not involved in acute reinforcing properties, are recruited. These alterations contribute to the negative motivational and affective states during withdrawal33-35)
For the acute positive reinforcing effect, nicotine first activates nicotinic acetylcho- line receptors in mesocorticolimbic dop- aminergic system that projects from the ventral tegmental area (VTA) to the nu- cleus accumbens and prefrontal cortex20). However, unlike most agonists, chronic nic- otine administration leads to desensitization and inactivation of nicotinic acetylcholine receptors (nAChRs)28), which is followed by up‐regulation of nAChR sites36). During nicotine abstinence that leads to decreased nicotine level, a portion of inactive nAChRs recover to a responsive state, whereas the rest of inactive nAChRs par- ticipate to non‐reward‐related cholinergic system contributing to negative affective or somatic withdrawal symptoms35,37).
The negative affective aspects of nicotine withdrawal are regulated by a number of different neurotransmitter systems. After chronic exposure to nicotine, extracellular dopamine levels in the NAcc are decreased during mecamylamine‐precipitated or spontaneous nicotine withdrawal38,39). The
reduction in dopamine release during nic- otine abstinence may be due to putative nAChR desensitization. The effect of nic- otine withdrawal on dopamine transmission has also been examined in the central nu- cleus of the amygdala (CNA).
Mecamylamine‐precipitated nicotine with- drawal significantly reduced dopamine over- flow40). The reduction in dopamine output during nicotine abstinence in the CNA may be involved in mediating the increase in anxiety associated with nicotine withdrawal.
However, until now, the role of DA trans- mission in the CNA in mediating anxiety state is unclear and further studies are re- quired41). In conclusion, dopamine may play a role in mediating nicotine withdrawal, particularly in deficits in reward and moti- vational processes.
Serotonergic neurotransmission are also likely to be associated with nicotine withdrawal. Serotonin (5‐TH), and the 5
‐HT1A receptor in particular, plays a role in nicotine withdrawal41). Nicotine with- drawal significantly increased the auditory startle response, resembling to the increased irritability, observed in smokers undergoing nicotine withdrawal. Systemic admin- istration of 5‐HT1A receptor agonist, 8‐
OH‐DPAT exacerbates this response, whereas 5‐HT1A receptor antagonists, WAY‐100635, alleviate this enhanced re- sponse41). Nicotine withdrawal increases the
inhibitory influence of 5‐HT1A receptor located within the raphe nuclei and thereby decreases 5‐HT release into forebrain and limbic brain site41). In conclusion, serotonin and 5‐HT1A receptors are involved in nicotine withdrawal, although at present it is unclear exactly what roles they play.
Recently, the role of glutamate trans- mission in nicotine withdrawal has been investigated. For example, stimulation of the Group II metabotropic glutamate re- ceptor (mGluR) decreased glutamate re- lease throughout the hippocampus, striatum, and cortex42-44). Interestingly, a selective ag- onist of the Group II mGluR, LY354740, ameliorated the increase in sensorimotor re- activity, observed in rats undergoing nic- otine withdrawal45). These results suggest that glutamate release may play a key role in mediating the aversive aspects of nic- otine withdrawal.
Other neurotransmitter systems might al- so have a role during nicotine abstinence.
For example, clonidine, which acts to de- crease noradrenergic neurotransmission, has shown efficacy in smoking cessation tri- als46). It is possible that noradrenaline may play a role in mediating aversive signs of nicotine withdrawal in rats, although fur- ther studies are required to address this possibility. In addition to these neuro- transmitter system, it is like that neuro- peptides, such as endogenous opiate, chol-
ecystokinin‐B, and corticotropin‐releasing factor, intracellular signaling protein like cyclic AMP response element DNA binding protein (CREB) and c‐fos, and/or neuro- trophic factor including brain‐derived neu- rotrophic factor (BDNF), nerve growth factor (NGF), and fibroblast growth factor
‐2 (FGF‐2) play a role in nicotine de- pendence and withdrawal.
3. Pharmacological Approaches to Smoking Cessation
Among 70% of the smokers, who want to completely quit smoking, only half makes a deliberate attempt to cease smok- ing every year. However, tobacco with- drawal without any assistance is associated with very low success rates in the huge majority of smokers who decide to quit smoking, and only about 6% of quitters re- main abstinent47). In order to aid smoking cessation, more effective treatment and management are required.
Two types of pharmacological therapies, NRT and bupropion, have been approved for smoking cessation by the US Food and Drug Administration48). NRT refer to the use of various forms of the delivery system of nicotine without the risk of the harmful tar, carbon monoxide and other harmful substances in cigarettes smoke by several modalities, including a skin patch, an oral inhalant, a nasal spray, and a chewable or-
al preparation49). It is the first successful pharmacological intervention, approved for smoking cessation and is the most widely used therapy. Indeed, smokers using NRT increase about 1.5 to 2 times more likely to be abstinent from smoking, compared to placebo50). Although NRT is an effective treatment for smoking cessation, the abso- lute majority of smokers who use NRT products do not stop smoking completely or remain abstinent for a long time; first year relapse rates are about 70 to 90%47,51). Such high relapse rates are associated with all forms of NRT. One suggestion about the relatively poor effects of NRT is based on the fact that all of the reinforcing ef- fects of tobacco are not only attributable to nicotine. For example, non‐nicotine cig- arettes have been shown to temporarily suppress tobacco craving and withdrawal symptoms in abstinent smokers49,52,53).
Then, some anti‐depressants are at- tracted as another medication for tobacco dependence. Bupropion, an anti‐depressant that works by reducing craving for tobacco by blocking the severity of withdrawal symptoms, is a useful option for motivated smokers who prefer non‐nicotine treatment or for those in whom NRT has failed.
However, in spite of its prominent effect on preventing nicotine addiction, bupropion therapy give rise to the most common side
‐effects, such as dry mouth, insomnia, and
occasionally seizure31,49,54). And like NRT, over 70% of bupropion‐treated individuals also relapse after one year47,55). Therefore, further research is required to establish the effectiveness of combined NRT and bupro- pion treatments, and to discover new therapies to replace these types of treat- ments to aid smoking cessation.
Besides NRT product and bupropion, several other drugs including nortriptyline and clonidine and other medication have been used in smoking cessation49). There are also non‐pharmacological treatments, such as counseling, group behavioral ther- apy, and aversive smoking to assist smok- ers to quit56-58).
4. Acupuncture for Smoking Cessation
Acupuncture is now one of the most popular forms of alternative medicine worldwide. The term “Acupuncture” con- sists of two words, originated from the Latin: acus; needle, and puncture;
insertion. It is a treatment procedure in which, generally, steel, silver, or gold nee- dles are inserted into specific acupuncture points. Traditional Chinese acupuncture has a history of over 3,000 years. Although the history of acupuncture dates back to an- cient times, it has not lost its popularity.
Recently, acupuncture is widely accepted in the United States and Europe as a safe al- ternative treatment for treating chronic
pains. Acupuncture is also widely applied for treating various kinds of chronic dis- eases, including musculoskeletal pain, hemi- plegia, the psychological illnesses and obe- sity31,59).
Various types of needle or electrical stimulation have been used as a treatment for dependence on various addictive drugs, with the specific aim of reducing with- drawal symptoms and aiding cessation.
Auricular acupuncture is now used in about 500 centers in the USA for narcotic drug dependency, mainly cocaine and heroin addiction. However, there has been still the rack of the number and quality of clinical trials as well as basic researches. For smoking cessation, sometimes, electro- acupuncture therapy is also performed for the intention of stimulating more precisely the release of neurotrasmitters that seem to be involved in suppression of withdrawal symptoms60).
In a recent meta‐analysis reported in the Cochrane database, authors identified 24 reports of studies about acupuncture therapy and related intervention for smok- ing cessation. This review reports that acu- puncture for smoking cessation may be more effective than either no treatment or sham acupuncture in the short term.
However, long term results show no effect of acupuncture therapy, compared to those of sham acupuncture treatment60). Contrary
to the assessment of the Cochrane meta‐
analysis, Bier and colleagues demonstrated that a 4‐week acupuncture regimen and 5
‐week educational program, alone and in combination, are effective in promoting a decrease in the number of cigarettes smoked as well as smoking cessation61). Also, although it is not a direct proof of the therapeutic effects of acupuncture on smoking cessation, the acupuncture therapy reduced depression and anxiety with in- somnia, one of the nicotine withdrawal symptoms62,63). These conflicting results may be due to the significant methodological problem, the paucity and poor‐quality of the studies. Therefore, extensive clinical re- searches with highly sophisticated and sci- entifically designed protocols are still re- quired to examine the effectiveness of acu- puncture therapy for treating smoking‐re- lated diseases or symptoms that have been empirically claimed to be treatable by acu- puncture therapy64).
5. Neurotransmission and Acupuncture
The action mechanism of acupuncture therapy on treating drug addiction, including nicotine dependence, may be via modulation of neurotransmitters. Electroacupuncture (EA) stimulation at ST36 acupuncture point suppressed the increased alcohol‐
drinking behavior and significantly increased the striatal dopamine levels in a restricted
rat65). Authors have explained that appro- priate stimulation of acupuncture may compensate for the decrease in the striatal dopamine levels in the restricted rats, so that motivation to drink alcohol was sup- pressed and the alcohol‐drinking behavior was reduced in the restricted rats. The in- creases in the levels of dopamine and its metabolites, homovanillic acid (HVA), after EA‐treatment were also reported by Zhu et al. They also observed a significant de- crease in norepinephrine (NE) content and an increase in 5‐hydroxytryptamine (5‐
HT) after EA‐treatment66). EA applica- tion on different acupoints differently influ- ences the change of monoamine level in CNS. And also, EA stimulation at the one acupuncture point differently affects on each region of the brain. For example, EA therapy at ST 36 point more effectively decreases the dopamine levels in the amyg- dale and increases the 5‐HT levels in the prefrontal cortex, when compared to the stimulation at BL23. The DA levels after EA stimulation at ST36 point were sig- nificantly increased in nucleus accumbens, striatum and lateral hypothalamus, while the levels were decreased in dorsal raphe nucleus and amygdale. In the regions of hippocampus and prefrontal cortex, there were no changes of the dopamine levels.
These results implied that EA stimulations restored the changes in the monoamine lev-
els induced by restraining stress, inducing different adaptive responses when applied at different acupuncture points67). A recent experimental research suggested that acu- puncture therapy might modulate dopamine release via the gamma aminobutyric acid (GABA) mechanism68), and that acu- puncture stimulation could modify neural activity in the nucleus accumbens69).
6. Conclusions
Cigarette smoking is a difficult habit to stop. Because of association with sub- stantial morbidity and mortality of smok- ing, aggressive efforts to eradicate smoking are needed. Although NRT and bupropion are known to be effective for smoking ces- sation, with a high relapse rate in NRT and/or bupropion‐treated smokers, new al- ternative strategies is still required for treating nicotine dependence. Acupuncture therapy can be an alternative treatment for reducing withdrawal symptoms in persons who eagerly want to quit smoking. The ef- fect of acupuncture for smoking cessation may be via modulation of neurotransmitters.
Although acupuncture is widely used as an alternative therapy for aiding smoking ces- sation in clinics, more clinical and ex- perimental researches are still required to examine the effectiveness of acupuncture therapy for aiding smoking cessation and treating nicotine withdrawal symptoms.
REFERENCES
1. Edwards R. The problem of tobacco smoking. Bmj. 2004 ; 328(7433) : 217-9.
2. Initiative TF. World Health Organization, Abstract of Geneva meeting, 2006.
3. Murray CJ, Lopez AD. Alternative pro- jections of mortality and disability by cause 1990‐2020: Global Burden of Disease Study. Lancet. 1997 ; 349(9064) : 1498-‐504.
4. Tauras JA, Chaloupka FJ. The demand for nicotine replacement therapies.
Nicotine Tob Res. 2003 ; 5(2) : 237-43.
5. Granger RH. Oxygen as a therapy for reducing nicotine withdrawal symptoms.
Med Hypotheses. 2005 ; 65(6) : 1161-4.
6. McEwen A, West R, Owen L. GP pre- scribing of nicotine replacement and bu- propion to aid smoking cessation in England and Wales. Addiction. 2004 ; 99(11) : 1470-4.
7. Silagy C, Mant D, Fowler G, Lancaster, T Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2000 ; 3 : CD000146.
8. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC et al. A comparison of sustained‐release bupro- pion and placebo for smoking cessation.
N Engl J Med. 1997 ; 337(17) : 1195-202.
9. Stolerman IP, Jarvis MJ. The scientific case that nicotine is addictive.
Psychopharmacology (Berl). 1995 ; 117(1) : 2-10.
10. Decker MW, Brioni JD, Bannon AW, Arneric SP. Diversity of neuronal nic- otinic acetylcholine receptors: lessons from behavior and implications for CNS therapeutics. Life Sci. 1995 ; 56(8) : 545-70.
11. Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW. Symptoms of tobacco withdrawal. A replication and extension. Arch Gen Psychiatry.
1991 ; 48(1) : 52-9.
12. Nakayama H, Numakawa T, Ikeuchi T, Hatanaka H. Nicotine‐induced phosphorylation of extracellular signal‐
regulated protein kinase and CREB in PC12h cells. J Neurochem. 2001 ; 79(3) : 489-98.
13. Changeux JP, Bertrand D, Corringer PJ, Dehaene S, Edelstein S, Lena C et al. Brain nicotinic receptors: structure and regulation, role in learning and reinforcement. Brain Res Rev. 1998 ; 26(2-3) : 198-216.
14. Levin ED, Simon BB. Nicotinic ace- tylcholine involvement in cognitive function in animals. Psychopharmacology(Berl).
1998 ; 138(3-4) : 217-30.
15. Nestler EJ, Genes and addiction. Nat Genet. 2000 ; 26(3) : 277-81.
16. Nestler EJ, Aghajanian GK, Molecular and cellular basis of addiction. Science.
1997 ; 278(5335) : 58-63.
17. Brunzell DH, Russell DS, Picciotto MR. In vivo nicotine treatment regu- lates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. J Neurochem. 2003 ; 84(6): 1431-41.
18. Di Chiara G. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol. 2000 ; 393(1‐3) : 295-314.
19. Mansvelder HD, McGehee DS.
Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol. 2002
; 53(4) : 606-17.
20. Pontieri FE, Tanda G, Orzi F, Di Chiara G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature. 1996
; 382(6588): 255-7.
21. Epping‐Jordan MP, Watkins SS, Koob GF, Markou A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature. 1998 ; 393(6680) : 76-9.
22. Piasecki TM, Niaura R, Shadel WG, Abrams D, Goldstein M, Fiore MC et al. Smoking withdrawal dynamics in unaided quitters. J Abnorm Psychol.
2000 ; 109(1) : 74-86.
23. West R, Hajek P, McNeill A. Effect of buspirone on cigarette withdrawal symp-
toms and short‐term abstinence rates in a smokers clinic. Psychopharmacology (Berl). 1991 ; 104(1): 91-6.
24. Glassman AH. Cigarette smoking: im- plications for psychiatric illness. Am J Psychiatry. 1993 ; 150(4) : 546-53.
25. Balfour DJ, Ridley DL. The effects of nicotine on neural pathways implicated in depression: a factor in nicotine ad- diction? Pharmacol Biochem Behav.
2000 ; 66(1) : 79-85.
26. Markou A, Kosten TR, Koob GF, Neurobiological similarities in depression and drug dependence: a self medication hypothesis. Neuropsychopharmacology.
1998 ; 18(3) : 135-74.
27. Hall SM, Munoz RF, Reus VI, Sees KL. Nicotine, negative affect, and depression. J Consult Clin Psychol.
1993 ; 61(5): 761-7.
28. Picciotto MR, Caldarone BJ, King SL, Zachariou V. Nicotinic receptors in the brain. Links between molecular biology and behavior. Neuropsychopharmacology.
2000 ; 22(5): 451-65.
29. Covey LS, Glassman AH, Stetner F.
Cigarette smoking and major depression. J Addict Dis. 1998 ; 17(1) : 35-46.
30. Breslau N, Kilbey MM, Reski P.
Nicotine dependence and major depression. New evidence from a pro- spective investigation. Arch Gen
Psychiatry. 1993 ; 50(1) : 31-5.
31. Salin‐Pascual RJ, Alcocer‐Castillejos NV, Alejo‐Galarza G. Nicotine de- pendence and psychiatric disorders. Rev Invest Clin. 2003 ; 55(6) : 677-93.
32. Koob GF, Drug addiction: the yin and yang of hedonic homeostasis.
Neuron. 1996 ; 16(5) : 893-6.
33. Koob GF. Le Moal M. Drug abuse:
hedonic homeostatic dysregulation.
Science. 1997 ; 278(5335) : 52-8.
34. Koob GF, Bloom FE. Cellular and mo- lecular mechanisms of drug dependence.
Science. 1988 ; 242(4879) : 715-23.
35. Watkins SS, Koob GF, Markou A.
Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res.
2000 ; 2(1) : 19-37.
36. Bhat RV, Marks MJ, Collins AC.
Effects of chronic nicotine infusion on kinetics of high‐affinity nicotine binding. J Neurochem. 1994 ; 62(2) : 574-81.
37. Dani JA, Heinemann S. Molecular and cellular aspects of nicotine abuse.
Neuron. 1996 ; 16(5) : 905-8.
38. Hildebrand BE, Panagis G, Svensson TH, Nomikos GG. Behavioral and bio- chemical manifestations of mecamyl- amine‐precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area.
Neuropsychopharmacology. 1999 ; 21(4) : 560-74.
39. Fung YK, Schmid MJ, Anderson TM, Lau YS. Effects of nicotine withdrawal on central dopaminergic systems.
Pharmacol Biochem Behav. 1996 ; 53(3) : 635-40.
40. Panagis G, Hildebr BE, Svensson TH, Nomikos GG. Selective c‐fos induction and decreased dopamine release in the central nucleus of amygdala in rats dis- playing a mecamylamine‐precipitated nicotine withdrawal syndrome. Synapse.
2000 ; 35(1) : 15-25.
41. Kenny PJ, Markou A. Neurobiology of the nicotine withdrawal syndrome.
Pharmacol Biochem Behav. 2001 ; 70(4) : 531-49.
42. East SJ, Hill MP, Brotchie JM.
Metabotropic glutamate receptor ago- nists inhibit endogenous glutamate re- lease from rat striatal synaptosomes.
Eur J Pharmacol. 1995 ; 277(1) : 117-21.
43. Di Iorio P, Battaglia G, Ciccarelli R, Ballerini P, Giuliani P, Poli A et al.
Interaction between A1 adenosine and class II metabotropic glutamate re- ceptors in the regulation of purine and glutamate release from rat hippocampal slices. J Neurochem. 1996 ; 67(1) : 302-9.
44. Moghaddam B, Adams BW. Reversal of
phencyclidine effects by a group II me- tabotropic glutamate receptor agonist in rats. Science. 1998 ; 281(5381) : 1349-52.
45. Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ. LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats. Neuropharmacology.
1997 ; 36(11-12) : 1511-6.
46. Gourlay SG, Stead LF, Benowitz NL.
Clonidine for smoking cessation.
Cochrane Database Syst Rev. 2004;
(3): CD000058.
47. Cryan JF, Gasparini F, van Heeke G, Markou A. Non‐nicotinic neuro- pharmacological strategies for nicotine dependence: beyond bupropion. Drug Discov Today. 2003 ; 8(22) : 1025-34.
48. Corelli RL, Hudmon KS. Pharmacologic interventions for smoking cessation. Crit Care Nurs Clin North Am. 2006 ; 18(1) : 39-51.
49. Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy for nicotine dependence. CA Cancer J Clin.
2005 ; 55(5) : 281-99.
50. Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2004 ; 3 : CD000146.
51. Murray RP, Voelker HT, Rakos RF,
Nides MA, McCutcheon VJ, Bjornson W. Intervention for relapse to smok- ing: the Lung Health Study restart programs. Addict Behav. 1997 ; 22(2):
281-6.
52. Rose JE. Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology (Berl). 2006 ; 184(3-4) : 274-85.
53. Butschky MF, Bailey D, Henningfield JE, Pickworth WB. Smoking without nicotine delivery decreases withdrawal in 12‐hour abstinent smokers. Pharmacol Biochem Behav. 1995 ; 50(1) : 91-6.
54. Roddy E. Bupropion and other non‐
nicotine pharmacotherapies. Bmj. 2004
; 328(7438) : 509-11.
55. Ferry LH. Non‐nicotine pharmacother- apy for smoking cessation. Prim. Care.
1999 ; 26(3) : 653-9.
56. Lancaster T, Stead LF. Individual be- havioural counselling for smoking cessation. Cochrane Database Syst Rev.
2005 ; 2 : CD001292.
57. Stead L, Lancaster T. Group behaviour therapy programmes for smoking cessation. Cochrane Database Syst Rev.
2005 ; 2 : CD001007.
58. Hajek P, Stead LF. Aversive smoking for smoking cessation. Cochrane Database Syst Rev. 2004 ; 3 : CD000546.
59. Cabyoglu MT, Ergene N, Tan U. The mechanism of acupuncture and clinical applications. Int J Neurosci. 2006 ;
116(2) : 115-25.
60. White AR, Rampes H, Campbell JL.
Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2006 ; 1 : CD000009.
61. Bier ID, Wilson J, Studt P, Shakleton M. Auricular acupuncture, education, and smoking cessation: a randomized, sham‐controlled trial. Am J Public Health. 2002 ; 92(10) : 1642-7.
62. Pohl A, Nordin C. Clinical and bio- chemical observations during treatment of depression with electroacupuncture:
a pilot study. Hum Psychopharmacol.
2002 ; 17(7) : 345-8.
63. Spence DW, Kayumov L, Chen A, Lowe A, Jain U, Katzman MA et al.
Acupuncture increases nocturnal mela- tonin secretion and reduces insomnia and anxiety: a preliminary report. J Neuropsychiatry Clin Neurosci. 2004 ; 16(1) : 19-28.
64. George TP, Verrico CD, Roth RH.
Effects of repeated nicotine pre‐treat- ment on mesoprefrontal dopaminergic and behavioral responses to acute foot- shock stress. Brain Res. 1998 ; 801(1-2) : 36-49.
65. Yoshimoto K, Kato B, Sakai K, Shibata M, Yano AT, Yasuhara M.
Electroacupuncture stimulation sup-
presses the increase in alcohol drinking behavior in restricted rats. Alcohol Clin Exp Res. 2001 ; 25(6 Suppl) : 63S-8S.
66. Zhu CB, Li XY, Zhu YH, Wu GC, Xu SF. Alteration of monoamine contents in microdialysate following droperidol enhanced electroacupuncture. Sheng Li Xue Bao. 1997 ; 49(4) : 382-8.
67. Yano T, Kato B, Fukuda F, Shinbara H, Yoshimoto K, Ozaki A et al.
Alterations in the function of cerebral dopaminergic and serotonergic systems following electroacupuncture and mox- ibustion applications: possible correlates with their antistress and psychosomatic actions. Neurochem Res. 2004 ; 29(1):
283-3.
68. Yoon SS, Kwon YK, Kim MR, Shim I, Kim KJ, Lee MH et al. Acupuncture mediated inhibition of ethanol‐induced dopamine release in the rat nucleus ac- cumbens through the GABAB receptor.
Neurosci Lett. 2004 ; 369(3) : 234-8.
69. Chae Y, Yang CH, Kwon YK, Kim MR, Pyun KH, Hahm DH et al.
Acupuncture attenuates repeated nic- otine induced behavioral sensitization and c‐Fos expression in the nucleus accumbens and striatum of the rat.
Neurosci Lett. 2004 ; 358(2) : 87-90.
