The neurobiological basis for partial agonist treatment of

The neurobiological basis for partial agonist treatment of nicotinedependence: varenicline

J . FOULDS

Tobacco Dependence Program, UMDNJ School of Public Health, New Brunswick, NJ, USA

SUMMARY

Smoking cessation has major health benefits for men and

women of all ages. However, most smokers are addicted to

nicotine and fail repeatedly in their attempts to quit.

Stimulation of nicotinic receptors in the brain, particularly

a4b2 receptors, releases dopamine in the meso-limbic area of

the brain and is reinforcing. Nicotine abstinence reduces

dopamine release, and this is associated with withdrawal

symptoms and craving for nicotine. Eight current pharma-

cotherapies – bupropion, nortriptyline, clonidine and

nicotine patch, gum, inhaler, lozenge and nasal spray – are

moderately effective aids to smoking cessation. Each is

significantly better than placebo, but approximately 80% of

patients using one of these medications return to smoking

within the first year. Varenicline, a specific a4b2 nicotinic

receptor partial agonist, is a new pharmacotherapy that sti-

mulates dopamine and simultaneously blocks nicotine recep-

tors. Phase II and III trials have yielded promising results

suggesting that varenicline could be an important advance in

the treatment of nicotine dependence.

Keywords: Smoking; cessation; tobacco; nicotine; depend-

ence; treatment; varenicline pharmacotherapy

� 2006 Blackwell Publishing Ltd

INTRODUCT ION

Tobacco smoking is the number one cause of premature

death in developed countries. It is responsible for approxi-

mately 400,000 premature deaths per year in the United

States alone (1) and roughly 4.9 million deaths per year

worldwide, or 8.8% of all global deaths (2). Approximately,

half of all long-term smokers die prematurely as a result of

smoking (3), and the life span of the continuing smoker will

be reduced by an average of 10 years (4).

Smoking cessation confers major health benefits for men

and women of all ages. For example, people who quit smok-

ing by age 50 have half the risk of dying in the next 15 years

compared with continuing smokers (around 10% vs. 20% at

age 50, varying by sex and amount smoked) (5).

Although it is nicotine and its psychological effects that

engender addiction (6,7), it is tobacco’s other components –

the ‘tar’, volatile oxidant gases and carbon monoxide – that

cause the most of the harms to health (7,8). This article aims

to summarise recent research on the neurobiology of nicotine

dependence and discuss the effectiveness of current pharma-

cotherapies for smoking cessation. The rationale for a

promising new approach involving partial agonist therapy

will also be presented.

THE CHARACTER IST ICS OF NICOTINE

DEPENDENCE

The criteria for nicotine dependence according to both the World

Health Organization’s ‘International Statistical Classification

of Diseases’, 10th Revision (9) and the American Psychiatric

Association’s ‘Diagnostic and Statistical Manual of Mental

Disorders’, Fourth Edition, (10) include (i) unsuccessful

attempts to stop smoking (ii) difficulty controlling tobacco

use and (iii) previous experience of withdrawal symptoms

during a period of abstinence. Withdrawal symptoms occur

following abrupt cessation or reduction of nicotine use and

include depressed mood, insomnia, irritability, anxiety,

difficulty concentrating, restlessness, increased appetite and

cravings for tobacco/nicotine (10). It is this withdrawal

syndrome – together with nicotine’s subtle but powerful

reinforcing effects, repeated 73,000 puffs per year for a

1-pack-per-day smoker – that makes smoking so addictive

(8). Nicotine has a half-life of approximately 2 h; therefore,

the onset of withdrawal symptoms is within 4–6 h of last

nicotine use. These symptoms peak within the first few days

of abstinence and typically resolve within 1 month. However,

most smokers who make a quit attempt relapse within the

first month. How does nicotine act at a neurobiological level

to produce these behavioural effects, and how can new

Correspondence to:Jonathan Foulds PhD, Associate Professor and Director, Tobacco

Dependence Program, UMDNJ School of Public Health, 317

George Street, Suite 210, New Brunswick, NJ 08901, USA

Tel.: þ 1 732 2358213

Fax: þ 1 732 2358297

Email: [email protected]

REVIEW d o i : 1 0 . 1 1 1 1 / j . 1 3 6 8 - 5 0 3 1 . 2 0 0 6 . 0 0 9 5 5 . x

ª 2006 The AuthorJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, May 2006, 60, 5, 571–576

pharmacotherapies target these neurobiological mechanisms

more effectively?

THE NEUROBIOLOGY OF NICOT INE

DEPENDENCE

The primary effects of nicotine are mediated by nicotinic

acetylcholine receptors (nAChRs), many subtypes of which

are widely distributed throughout the central nervous system.

Seventeen nicotinic receptor subunit genes have been identi-

fied to date, and each receptor is composed of five subunits.

The functional properties of each receptor are determined by

its subunit composition. The subtype of nAChRs, composed

of two a4 and three b2 subunits (Figure 1), is known to form

the high-affinity binding sites in the brain (7). A particularly

high concentration of a4 subunits can be found in the ventral

tegmental area (VTA) of the brain, where a dense supply of

dopamine neurones is linked to the brain’s main ‘reward

centre’, the nucleus accumbens. The loss of nicotine self-

administration behaviour in knockout mice lacking the b2

subunit suggests that it contributes to nAChRs relevant to

nicotine dependence (11). The effects of a4-receptor activation

have been shown to be important in dependence, including

reinforcement, tolerance and sensitisation (12). The a4b2

nAChR also has the highest sensitivity to nicotine – 50% of

its maximal activation is produced at a concentration (EC50) of

0.1–1.0 mM, but it can be desensitised by lower concentrations.

Nicotinic receptors pass through three main states. In the

first, or ‘resting’ state, the receptor is not active (ion channel

closed) but is open to activation by contact with agonist

(typically nicotine or acetylcholine). In the ‘active’ state,

binding with an agonist causes the receptor ion channel to

open and remain open for a brief period, during which an

inward flux of Naþ produces local depolarisation. The third,

‘desensitised’ state typically follows activation, in which the

channel is closed to ions and is refractory to activation by

agonist, although agonist can still bind to the receptor. Low

concentrations of agonist can push the receptor into the

desensitised state without going through the open (active)

state, and high concentrations of agonist can stimulate activa-

tion of an otherwise resting or desensitised receptor (7).

When a sufficient concentration of nicotine is carried in

the blood to activate a4b2 receptors in the VTA, a burst firing

of dopamine neurones occurs (13). The terminals of these

neurones are in the medial shell and core areas of the nucleus

accumbens. This stimulation of dopamine neurones causes an

increased release of extra-synaptic dopamine in the nucleus

accumbens (13). The anatomic locations of these areas of the

brain are shown in Figure 2.

Considerable evidence suggests that repeated nicotine

exposure results in an increase in functional nicotinic recep-

tors in the brain and, specifically, a sensitisation of the meso-

limbic dopamine response to nicotine (13). This dopamine

response (i.e. an increase in extra-synaptic dopamine in the

extracellular space between fibres in the accumbens) appears

to be associated with the reinforcing and addictive properties

not only of nicotine but also of other psychostimulant drugs

of abuse (e.g. amphetamine, cocaine) (14). This response

confers hedonic properties on the behaviours associated with

the dopamine activation. An animal that has experienced

repeated nicotine boosts and accumbens dopamine stimula-

tion by pressing a bar (or inhaling on a cigarette) will quickly

learn that the behaviour itself (bar pressing, cigarette puffing)

is enjoyable and comes to acquire reinforcing properties. Over

time and repeated exposures, the smoking ritual (e.g. opening

the pack, lighting the cigarette, feeling the smoke hit the back

of the throat) becomes capable of stimulating meso-limbic

dopamine and therefore acts as a reinforcer itself, even in the

absence of agonist (nicotine)-stimulated dopamine activation

(13). This may be the reason why smokers often state that

they enjoy the ritual of smoking.

The dysphoric symptoms of nicotine withdrawal start to

occur when the regular smoker is deprived of nicotine for at

least 4–6 h and when more nAChRs become resensitised but

unstimulated by nicotine. Animal studies have shown that

Surface ofdopamineneuron

β2

β2

β2α4

α4

Figure 1 Simplified structure of a4b2 nicotinic receptor

located on surface of a dopamine cell body

Prefrontalcortex

Nucleusaccumbens

Hippocampus

Ventraltegmentalarea

Figure 2 Simplified diagram of the brain showing the

anatomic locations of the ventral tegmental area and

the nucleus accumbens

572 VARENICLINE FOR TREATMENT OF NICOTINE DEPENDENCE


VTA dopamine neuronal activity is reduced during the first

day of nicotine withdrawal (15).

CURRENT PHARMACOTHERAPIES FOR

TOBACCO DEPENDENCE

The basic rationale for many of the effective pharmacothera-

pies for nicotine addiction has been to mimic or replace the

effects of nicotine. The most obvious way to do this is by

providing the exogenous agonist itself (i.e. via nicotine gum,

patch, nasal spray, lozenge or inhaler).

Other effective pharmacotherapies, such as bupropion and

nortriptyline, appear to affect neurobiological mechanisms

similar to those affected by nicotine replacement. Typically

they ameliorate nicotine withdrawal by inhibiting reuptake of

dopamine and noradrenaline (norepinephrine) in the central

nervous system, but without the need for a direct agonist

effect (16). Bupropion has also been shown to antagonise

nAChR function. Its principal mode of action appears to be

via reduction of withdrawal symptoms following smoking

cessation via its ability to mimic nicotine effects on dopamine

and noradrenaline (norepinephrine). Thus bupropion

increases dopamine and noradrenaline concentration in the

extracellular space by inhibiting reuptake. Its ability to antag-

onise nicotinic receptors may prevent relapse by attenuating

the reinforcing properties of nicotine (17). The active bupro-

pion metabolite subtype (2S,3S)-hydroxybupropion is a

potent antagonist of the a4b2 nicotinic receptor (18). While

the primary mechanism of bupropion’s effects on smoking

cessation remains unclear, it seems that these effects are not

limited to an antidepressant action as its efficacy is indepen-

dent of baseline-depressive symptoms (19).

Nortriptyline is a tricyclic antidepressant that has noradre-

nergic properties and some dopaminergic activity. It also has

been effective in smoking cessation (16). Other antidepres-

sants, however, such as selective serotonin reuptake inhibitors,

do not appear to be effective aids to smoking cessation.

The a-noradrenergic agonist clonidine suppresses sympa-

thetic activity and has been used for hypertension and to

reduce symptoms associated with alcohol or opiate withdra-

wal. Both the oral and the patch formulations of clonidine

increased smoking cessation rates in eight of nine trials, but

side effects include sedation and postural hypotension (16).

Meta-analyses of randomised trials of nicotine replacement

therapy, bupropion, nortriptyline and clonidine have shown

these medications to be significantly more effective than

placebo in achieving tobacco abstinence (19–21). However,

as summarised in Table 1, the long-term (i.e. 6–12 months)

tobacco abstinence rates are typically just under double those

achieved by placebo (18% vs. 10%). Evidence suggests that

abstinence rates can be increased when the medications are

combined with more intensive counselling (22–25), or when

combinations of medications are used (22,23,26,27). That

long-term abstinence rates are typically 25%�35% even in

ideal circumstances underscores the need for new and more

effective smoking cessation aids.

Although this article focuses on the role of a4b2 nicotinic

receptors, considerable evidence shows that a7 nicotinic recep-

tors likely play a role in the processes that cause nicotine

addiction. These receptors have much lower affinity for nico-

tine than a4b2 receptors and therefore are not desensitised

rapidly, but they can also stimulate dopamine release via

presynaptic stimulation of glutamatergic afferents. The com-

bined action of these two receptor subtypes has been postu-

lated to produce long-term potentiation of dopamine

stimulation by nicotine (28). Similarly, noradrenergic stimu-

lation likely has a role in nicotine dependence, as suggested by

the efficacy of nortriptyline (which primarily has noradrener-

gic effects) for smoking cessation (19,24).

THE RATIONALE FOR A SELECT IVE a4 b2

N ICOT IN IC RECEPTOR PART IAL AGONIST FOR

SMOKING CESSAT ION

Compounds that act as a4b2 nAChR partial agonists and

simultaneously block the action of nicotine (29,30) offer a

particularly promising new approach to helping smokers quit.

Partial agonists aim to provide a low-to-moderate level of

dopamine stimulation to reduce craving and withdrawal

symptoms. The lower level of dopamine release may be less

dependence forming than the intermittent spikes in dopa-

mine release produced by inhaled nicotine. The antagonist

effect blocks the reinforcing effects of nicotine and potentially

reduces the risk that a lapse to smoking would turn into a full-

blown relapse.

The plant alkaloid, cytisine, has been used for smoking

cessation in Bulgaria and has weak partial agonist activity but

limited absorption in the brain. However, scientists at Pfizer

Inc. were able to modify the structure of the compound to

create varenicline, a new, highly selective and potent a4b2

nAChR partial agonist (30). Varenicline has recently com-

pleted phase III trials and is undergoing expedited review by

the US Food and Drug Administration. In rat studies of the

drug, sustained extracellular dopamine levels were observed in

the nucleus accumbens at about half the level of an acute dose

of nicotine, and the effects of a simultaneous dose of nicotine

were blocked.

Figure 3 presents a greatly simplified model for (i) nicotine

activating nicotinic receptors and stimulating dopamine

release (ii) nicotine withdrawal decreasing dopamine release

and (iii) varenicline blocking nicotinic receptors, with the

partial agonist effect producing moderate levels of dopamine

release and reducing withdrawal and craving.

Early studies (including phase II and III clinical trials

involving over two thousand participants) of varenicline

have been presented at scientific meetings prior to their

VARENICLINE FOR TREATMENT OF NICOTINE DEPENDENCE 573


publication in peer-reviewed journals. The results of these

studies suggest that varenicline is an effective smoking cessa-

tion therapy.

Oncken and colleagues (31) presented data from two phase

II randomised trials in which varenicline produced short-term

(�14 weeks) quit rates on the 2 mg/day dose that were

approximately four times higher than the placebo quit rates.

More recently, Tonstad and colleagues (32) presented data

from three phase III randomised trials wherein long-term

(1 years) abstinence rates were more than twice those of

placebo. In one study, those who were quit at 12 weeks

were more likely to remain abstinent at 24 weeks if they

continued on varenicline (32). The phase III placebo-

controlled trials included randomisation to bupropion and

found that varenicline produced significantly higher 1-year

abstinence rates than bupropion, which was in turn significantly

better than placebo. Importantly, varenicline appears to have

a good side effect profile (mild to moderate nausea is the most

frequent symptom), with adverse events rates leading to

discontinuation similar to those of placebo. When taken

orally, it reaches a peak blood concentration in 2–4 h and

has a half-life of 20–30 h in healthy smokers. Eighty percent

or more of the drug is excreted unchanged in the urine (33).

COMMENT

Although this article focuses on pharmacotherapy as an

important factor in helping smokers quit, it is recognised

that smoking is a multifaceted phenomenon. Societal inter-

ventions such as increases in taxes on cigarettes, laws requiring

that public places be smoke-free and restrictions on the mar-

keting of tobacco have all been shown to impact societal

tobacco use. It is also clear that tobacco dependence is best

conceptualised as a chronic condition. Like other chronic

conditions (e.g. hypertension, diabetes and asthma), tobacco

dependence is frequently not cured by a single short-term

pharmacological intervention and more commonly requires

repeated, and sometimes longer-term (i.e. >3 months)

Table 1 Pharmacotherapies demonstrating efficacy for smoking cessation in the Cochrane Database of Systematic Reviews

DrugCochrane reviewupdate

Number ofcomparisons

Number of abstinentactive arm (%)

Number of abstinentcontrol arm (%)

Odds ratio(95% C. I.)

Nortriptyline 10/27/04 (19) 7 102/506 (20.2) 46/515 (8.9) 2.14 (1.49, 3.06)

Bupropion 10/27/04 (19) 21 835/4158 (20.1) 323/3013 (10.7) 1.99 (1.73, 2.3)

Clonidine 10/21/04 (20) 6 98/393 (24.9) 55/383 (14.4) 1.89 (1.3, 2.74)

Nicotine gum 11/02/04 (21) 52 1565/8023 (19.5) 1125/9760 (11.5) 1.66 (1.52, 1.81)

Nicotine patch 11/02/04 (21) 42 1493/10216 (14.6) 555/6475 (8.6) 1.81 (1.64, 2.02)

Nicotine inhaler 11/02/04 (21) 4 84/490 (17.1) 44/486 (9.1) 2.14 (1.44, 3.18)

Nicotine nasal spray 11/02/04 (21) 4 107/448 (23.9) 52/439 (11.8) 2.35 (1.63, 3.38)

Nicotine lozenge/tablet 11/02/04 (21) 5 224/1363 (16.4) 121/1376 (8.8) 2.05 (1.62, 2.59)

Nicotinereceptors

A B C

NicotineVarenicline ( )blocks nicotinereceptors

Partial agonisteffects stimulatemoderatedopaminerelease

Cell body of dopamineneuron in ventraltegmental area

Rapid/burst firing

Dopamine ( ) releasefrom dopamine terminalin the nucleus accumbens

Figure 3 Highly simplified scheme showing effects of (A) nicotine from cigarettes (B) nicotine withdrawal and (C) varenicline on

nicotinic receptors and dopamine release



interventions. More intensive behavioural interventions and

combination of pharmacotherapies improve smoking cessa-

tion outcomes (24,25,27). This may also be true for

varenicline.

CONCLUS ION

Varenicline is the first smoking cessation treatment specifi-

cally designed to target the neurobiological mechanism of

nicotine dependence. If the results of the early clinical trials

can be replicated in clinical practice, varenicline will represent

an important advance in helping patients to quit smoking.

ACKNOWLEDGEMENTS

Jonathan Foulds is primarily funded by a grant from the New

Jersey Department of Health and Senior Services through

New Jersey’s Comprehensive Tobacco Control Program.

While writing this article, he was also receiving support

from the Robert Wood Johnson Foundation, the Cancer

Institute of New Jersey and the National Institute on Drug

Abuse (USA). He has worked as a consultant and received

honoraria from pharmaceutical companies involved in

production of tobacco dependence treatment medications

(including Pfizer Inc., manufacturer of varenicline), as well

as a variety of agencies involved in promoting health (e.g.

WHO, USNIH, etc.). He has also worked as an expert

witness in litigation, including law suits against tobacco

companies. Thanks to Vanessa Sypko for help with the figures

in this article.

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