Double target concept for smoking cessation

ABSTRACT Tobacco use is estimated to be the largest single cause of premature death in the world. Nicotine is the major addictive substance in tobacco products. After cigarette smoking,

nicotine quickly acts on its target, nicotinic acetylcholine receptors (nAChRs), which are widely distributed throughout the mammalian central nervous system and are expressed as diverse

subtypes on cell bodies, dendrites and/or nerve terminals. Through the nAChRs in brain reward circuits, nicotine alters dopaminergic (DA) neuronal function in the ventral tegmental area

(VTA) and increases dopamine release from VTA to nuclear accumbens (NA), which leads to nicotine reward, tolerance and dependence. After quitting smoking, smokers experience withdrawal

symptoms, including depression, irritability, difficulty concentrating or sleeping, headache, and tiredness. Recently, evidence has been accumulated to reveal the molecular and cellular

mechanisms of nicotine reward, tolerance and dependence. The outcomes of these investigations provide pharmacological basis for smoking cessation. Here, I briefly summarize recent

advancements of our understanding of nicotine reward, tolerance and dependence. Based on these understandings, I propose a double target hypothesis, in which nAChRs and dopamine release

process are two important targets for smoking cessation. Dysfunction of nAChRs (antagonism or desensitization) is crucial to abolish nicotine dependence and the maintenance of an appropriate

level of extracellular dopamine eliminates nicotine withdrawal syndromes. Therefore, the medications simultaneously act on these two targets should have the desired effect for smoking

cessation. I discuss how to use this double target concept to interpret recent therapies and to develop new candidate compounds for smoking cessation. SIMILAR CONTENT BEING VIEWED BY OTHERS

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potent addictive substance in the tobacco that is thought to promote the use of tobacco products by about one-quarter of the world's population. Tobacco use is the leading preventable

cause of disease, disability, and death. Cigarette smoking results in more than 400 000 premature deaths each year — about 1 in every 5 US deaths. Economically, more than $75 billion per

year of total US healthcare costs is attributable directly to smoking. China is the world's largest producer and consumer of tobacco. It estimates that there are 0.35 billion cigarette

smokers in China. Economically, more than $166 billion per year of total Chinese healthcare costs are attributable directly to smoking-associated diseases. Therefore, there is a considerable

need to reduce the population of smokers. Unfortunately, nicotine addiction severely confounds attempts to end tobacco product use. Nicotine addiction has been clinically delineated into

two specific diagnosable disorders: dependence and withdrawal symptoms. Nicotine dependence refers to the maladaptive and chronic use of tobacco that meets the same types of criteria that

are applied to other forms of drug addiction. Recent research has revealed two important features of nicotine addiction: (1) nAChRs play a critical role in developing nicotine addiction ,

and (2) nicotine addiction is a dynamic process including different stages such as nicotine-induced reward, tolerance, dependence and withdrawal-relapse symptoms1. Nicotine reward means that

nicotine, acting on brain nAChRs, stimulates brain reward-associated circuits, which allows the smoker to be in a euphoric state. Dopamine is one of the key neurotransmitters actively

involved within the reward circuits in the brain. Accumulating lines of evidence indicate that nicotine increases DA release from VTA to NA, which represents its nature of reward and intense

addictive qualities. Mounting evidence demonstrates that nAChR subtypes with different distributions within reward circuits mediate nicotine reward. Dopaminergic (DA) neurons in the VTA

express diverse nAChR subunits, including α3–α7 and β2–β42, 3, 4, 5, 6, 7, which can combine to form at least two pharmacologically distinct nAChR subtypes. One of these functionally

distinct nAChRs is homomeric α7-nAChRs, which are mainly expressed on glutamatergic presynaptic terminals, where they mediate nicotine-induced increase of glutamate release onto DA neurons6.

Another group of nAChRs is non-α7-nAChRs, which seems to be more complex. For example, electrophysiological studies, combined with single-cell RT-PCR technique, show α4α6α5(β2)2 or

α4α5(β2)2 combinations of nAChRs in midbrain reward center6. Immunoprecipitation approaches using nAChR subunit knockout mice show that functional α6β2-nAChRs are mainly located on DA

neuronal terminals, whereas α4β2-nAChRs represent the majority of functional heteromeric nAChRs on DA neuron somata8. Interestingly, GABAergic neurons located in the VTA likely express

relatively-simple nAChR subtypes, mainly (α4)2(β2)3-nAChRs6 and these α4β2nAChRs contribute to cholinergic modulation of GABA tonic release onto DA neurons9. Recently, we have characterized

three functional subtypes (ID, IID, IIID) of nAChRs in VTA DA neurons7 that may mediate nicotine reward and dependence. For example, nicotine, in the same concentrations and time ranges as

obtained from cigarette smoking, enhances glutamatergic excitation in the VTA DA neurons by increasing glutamate release via stimulating presynaptic α7-nAChRs10. Nicotine also activates then

desensitizes α4β2-nAChRs on both DA and GABAergic neurons9. Since cholinergic innervations in GABAergic neurons have much higher density than that in DA neurons 11, the nicotine-induced

α4β2-nAChR desensitization (after brief activation) mainly decreases GABA release onto DA neurons, and consequently increases DA neuronal activity. It has been proposed that nicotine-induced

desensitization is at least one of the major mechanisms for nicotine addiction12, 13, 14. In the VTA, nicotine activates (α7-) and/or desensitizes (α4β2) nAChRs, and in turn increases DA

neuronal activity. The short-lived direct excitation of the DA neurons coupled with the enhanced glutamatergic afferent activity provides the presynaptic and postsynaptic coincidence

necessary to initiate synaptic potentiation and plasticity (LTP)15, 16. Taken together, these synaptic events lead to a relatively long-lasting heightened activity of midbrain DA neurons,

which release more DA to NA and results in positive reinforcement. The nicotine reward is an important early event to initiate and develop to nicotine dependence. As mention before,

nicotine, in addition to activating nAChRs, also desensitizes them 17, which plays an important role in the developing nicotine tolerance and dependence. After repetitive exposure to

nicotine, nAChR desensitization represents a low functional status of nAChRs in the presence of low level of nicotine, and the recovery from receptor desensitization is relative slow. Under

this desensitization condition, the same concentrations of nicotine are not enough to induce the same level of reward signals (the level of extracellular DA in the NA), which consequently

causes nicotine tolerance. On one hand, to overcome nicotine tolerance (to get the same level of reward stimulation), smokers increase cigarette smoked per day, which results in the nicotine

dependence. On the other hand, nAChR desensitization triggers receptor upregulation, and the upregulated nAChRs imbalances cholinergic signaling and modulation, which causes withdrawal

symptoms when smoker quits cigarette smoking. In summary, nicotine addiction is the major reason why smokers continue to rely on tobacco products. Nicotine dependence and withdrawal symptoms

are two pathophysiological changes brought on by cigarette smoking. Based on these lines of evidence, I propose a “double target” hypothesis to interpret pharmacotherapuetic mechanisms of

smoking cessation. In this hypothesis, I assume that the medications that eliminate both nicotine dependence and withdrawal-relapse will exert more desired effect for smoking cessation

(Figure 1). To reduce nicotine dependence, medications should block nAChRs (in particular α4β2-nAChRs), while to eliminate withdrawal-relapse, they also should appropriately (mildly)

increase extracellular DA level in the NA. Using this double target concept, one can explain pharmacological mechanisms of existing smoking cessation medications. For instance, recent market

drugs available for smoking cessation are bupropion and varenicline18. Bupropion is used to treat mental depression, but it is also used as part of a support program to help people stop

smoking19. This medicine exhibits double target properties since it not only blocks dopamine transporter (maintain a mildly elevated level of extracellular DA in the NA), but also blocks

nAChRs, in particular α4β2-nAChRs19, 20, 21. Varenicline is another example of a smoking cessation medication22 that matches the double target concept. It is a partial agonist at

α4β2-nAChRs, and is also a full agonist at α7 nAChRs23. As a partial agonist of α4β2-nAChRs, varenicline mimics nicotinic effect to activate/desensitize its first target, α4β2-nAChR, and

diminishes nicotine dependence. In addition, as a full agonist at α7 nAChRs, it also mimics nicotinic stimulation on its second target, presynaptic α7-nAChR, to increase glutamate release

onto DA neurons in the VTA, which in turn appropriately increases DA release from the VTA to NA, and eliminates withdrawal symptoms. Based on this double target concept, one also can develop

new medications for smoking cessation. Recently, my laboratory has developed two different compounds that exhibit high potential to be novel smoking cessation medications. One group of

compounds is called tetrahydroprotoberberine analogs (THPBs) which include tetrahydroberberine (THB), l-stepholidine (l-SPD) and l-hydroparmatine (l-THP). THPBs are purified from several

Chinese herbs in the magnoliidae superorder. Mounting evidence indicates that THPBs exhibit dopamine receptor (D2) antagonist effects on sedation, hypnosis, antinociception,

anti-schizophrenia and anti-hypertension24, 25, 26, 27. The major pharmacological targets for THPBs are dopamine receptors, and THPBs exhibit D1 partial agonist and D2 antagonist effects. As

a D2 receptor antagonist in VTA DA neurons, systemic exposure to THPBs increase DA neuronal firing by blocking D2 auto-receptors on DA neurons and increase DA level in NA. It has been

reported that l-THP effectively eliminates heroin addiction in human28, suggesting that THPBs may have a potential for treating drug addiction. Recent research in my laboratory also shows

that THPBs potently inhibit either human α4β2-nAChRs heterologously expressed in SH-EP1 cell line or rodent α4β2-nAChRs in midbrain DA neurons. This double-target feature suggests that THPBs

are good candidates that can be developed into new smoking cessation medications. Another compound we are working on is iptakalim hydrochloride (Ipt). Ipt was initially designed and

synthesized as an antihypertensive drug29. It is a small, water soluble molecule that freely penetrates the blood-brain barrier and has minimal toxic side effects following long-term

systemic administration30. Possible pharmacological mechanisms underlying its antihypertensive action include KATP channel activation and endothelin antagonism. Tests in a variety of _in

vivo_ and _in vitro_ ischemia and Parkinson's disease models indicate that Ipt has neuroprotective effects30, 31, 32. Furthermore, Ipt can potentially prevent drug addiction since it

inhibits cocaine challenge-induced enhancement of dopamine release in rat NA33. The major pharmacological target of Ipi is thought to the cytoplasmic and/or mitochondrial KATP channels30. My

laboratory has evaluated the effects of Ipt on nAChR function and found that Ipt potently blocks α4β2-nAChRs heterologously expressed in human SH-EP1 cell line34 or natively expressed in

rat midbrain DA neurons35. Currently, we have also found that Ipt significantly prevents systemic nicotine-induced behavioral (locomotor activity) sensitization, further confirmed its nAChR

antagonism (Wu _et al_, unpublished data). Interestingly, systemic injections of Ipt along (30 mg·kg−1·day−1, ip for 7 days) increase rat locomotor activity (Wu _et al_, unpublished data),

suggesting that on one hand, Ipt can block α4β2-nAChR function, and on the other hand, it also can appropriately increase DA level at NA although the reason and mechanisms of this effect are

still unclear. Nevertheless, Ipt also exhibits double-target feature and it likely can be developed as a novel smoking cessation medication. In conclusion, nicotine addiction is a complex

brain disorder, which involves functional alterations in multiple brain circuits and exhibits different stages. Based on the new concept of network pharmacology36, 37, I propose a double

target hypothesis, which may help to understand the pharmacotherapeutic mechanisms of smoking cessation, and also help to develop new medications for quitting tobacco use. REFERENCES *

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toward this project was supported by grants from the Arizona Biomedical Research Commission, the Institute for Mental Health Research, and Philip Morris International through their External

Research Program. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Shantou University Medical College, Shantou, 515041, China Jie Wu * Barrow Neurological Institute, St Joseph's Hospital

and Medical Center, Phoenix, 85013, AZ, USA Jie Wu Authors * Jie Wu View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence

to Jie Wu. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wu, J. Double target concept for smoking cessation. _Acta Pharmacol Sin_ 31, 1015–1018 (2010).

https://doi.org/10.1038/aps.2010.137 Download citation * Received: 30 May 2010 * Accepted: 20 July 2010 * Published: 16 August 2010 * Issue Date: September 2010 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * nicotine * nicotine addiction * nicotine reward *

nicotine dependence * nicotine withdrawal syndromes * nicotinic acetylcholine receptor * smoking cessation