Cellular mechanisms of nicotine addiction

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Abstract

In developed countries, tobacco use is estimated to be the largest single cause of premature death [Lancet 339 (1992) 1268]. Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central nervous system (CNS), where they normally respond to acetylcholine (ACh) and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and have varied roles. Presynaptic and preterminal nAChRs enhance neurotransmitter release. Postsynaptic and somal nAChRs mediate a small proportion of fast excitatory transmission and modulate cytoplasmic second messenger systems. Although the impact of nicotine obtained from tobacco is not completely understood, a portion of nicotine's addictive power is attributable to actions upon the dopaminergic systems, which normally help to reinforce rewarding behaviors. As obtained from tobacco, nicotine activates and desensitizes nAChRs, and both processes contribute to the cellular events that underlie nicotine addiction.

Introduction

It is now clear that tobacco use is a major worldwide health problem (Leshner, 2000). The World Health Organization estimates that one-third of the global adult population smokes. Because tobacco usage is on the rise in less developed countries, it is one of the very few causes of mortality that is increasing (Peto et al., 1996). It is common to begin smoking as an adolescent, and about half of those who continue throughout life will die from smoking-related diseases (WHO, 1997). In developed countries, smoking causes 20% of all premature deaths, and is the cause of more than one-third of all deaths in men aged 35–69. Therefore, it is not surprising that in developed countries tobacco use is estimated to be the largest single cause of premature death (Peto et al., 1992).

Tobacco is addictive, and it is difficult to quit smoking. More than 80% of the attempts to quit smoking fail within a year, and those who succeed usually have tried to quit repeatedly Balfour and Fagerstrom, 1996, Schelling, 1992. In the United States, 70% of smokers say that they would like to quit, but only 3% are successful each year (Benowitz, 1999). The accumulated evidence from a wide range of studies indicates that nicotine is the major addictive component of tobacco that drives continued use despite the harmful consequences Balfour et al., 2000, Dani and Heinemann, 1996, Dani et al., 2001, Di Chiara, 2000, Schelling, 1992, Stolerman and Shoaib, 1991.

When studied under laboratory conditions in the absence of smoke or other extraneous factors, nicotine elicits behaviors associated with addictive drugs. Under restricted doses, nicotine functions as a reinforcer for both animals and humans. At higher doses, however, there are aversive effects caused by nicotine that complicate its reinforcing effectiveness when compared with other drugs, which serve as reinforcers over a wider range of doses and test situations. Despite these complications, nicotine elicits drug-seeking behavior in animal studies, where it supports self-administration and reinforces place preference Corrigall, 1999, Corrigall and Coen, 1989, Di Chiara, 2000, Stolerman and Shoaib, 1991. In drug discrimination tasks, there is some cross-generalization between nicotine and other addictive drugs, i.e., nicotine is mistakenly discriminated in place of a different addictive drug Di Chiara, 2000, Stolerman and Jarvis, 1995. Nicotine cessation also produces a withdrawal syndrome, and those symptoms can be relieved by nicotine replacement (Stolerman and Jarvis, 1995). In summary, nicotine produces effects that are commonly seen with other addictive drugs such as amphetamines and cocaine: nicotine reinforces self-administration, increases locomotor activity, enhances reward from brain stimulation and reinforces place preference Clarke, 1990, Clarke, 1991, Corrigall, 1999, Dani and Heinemann, 1996, Di Chiara, 2000, Goldberg and Henningfield, 1988, Stolerman and Jarvis, 1995, Stolerman and Shoaib, 1991.

Section snippets

Neuronal nicotinic acetylcholine receptors (nAChRs)

Nicotine initiates its action by binding to nAChRs. Nicotinic receptors belong to a superfamily of ligand-gated ion channels that include glycine, GABAA and 5-HT3 serotonin receptors Albuquerque et al., 1997, Broide and Leslie, 1999, Buisson and Bertrand, 1998, Dani, 2001, Dani et al., 2001, Jones et al., 1999, Lena and Changeux, 1998, Lindstrom, 1997, Lindstrom et al., 1996, Luetje et al., 1990, McGehee and Role, 1995, Paterson and Nordberg, 2000, Role and Berg, 1996, Sargent, 1993, Wonnacott,

Nicotinic cholinergic mechanisms in the brain

Cholinergic neurons project throughout the CNS, providing diffuse, sparse innervation to practically all of the brain, but a relatively small number of cholinergic neurons innervate each neural area Kasa, 1986, Oh et al., 1992, Woolf, 1991. Thus, the activity of a rather small number of cholinergic neurons can influence diverse and relatively large neuronal structures. Although cholinergic cell bodies are distributed in a loosely contiguous axis running from the spinal cord and brain stem to

Nicotinic influences on dopaminergic neurons

Many recent addiction studies have focused on reward circuitry and modifications of those pathways during drug use Berke and Hyman, 2000, Dani et al., 2001, Di Chiara, 1999, Wise, 2000. Although many psychopharmacological factors contribute to addiction, dopaminergic systems have received much attention because of their roles in reward. Reward, motivation and the roles of the dopaminergic systems are far from completely understood, and are active areas of experimental and theoretical research

Nicotine activates and desensitizes nAChRs on mesolimbic neurons

Smoking a cigarette delivers about 50–300 nM nicotine to the brain Gourlay and Benowitz, 1997, Henningfield et al., 1993, Rose et al., 1999. Fig. 1A shows that nicotine, in exactly the range experienced by smokers, both activates and desensitizes nAChRs on dopaminergic neurons from the VTA (see Pidoplichko et al., 1997). A dopamine neuron from a rat brain slice was whole-cell voltage clamped near its resting potential at −60 mV. A pipette filled with 1 mM ACh was positioned next to the neuron,

Hypotheses to extrapolate the cellular results to smokers

Based on these results (Pidoplichko et al., 1997), we can infer some of the effects of smoking a cigarette, which will deliver about 0.1 μM nicotine to the brain Gourlay and Benowitz, 1997, Rose et al., 1999. Initially, the brain is free of nicotine, and the nAChRs should be responding normally to cholinergic synaptic activity. When the nicotine first arrives, nAChRs are activated, causing the neurons to depolarize and fire action potentials. This process occurs throughout the brain, with

Acknowledgements

Work from our laboratories is supported by US NIH grants from the National Institute of Neurological Disorders and Stroke (NS21229) and the National Institute on Drug Abuse (DA09411 and DA12661).

References (103)

  • JP Changeux et al.

    Brain nicotinic receptors: structure and regulation, role in learning and reinforcement

    Brain Res Brain Res Rev

    (1998)
  • PB Clarke

    Dopaminergic mechanisms in the locomotor stimulant effects of nicotine

    Biochem Pharmacol

    (1990)
  • JA Dani

    Overview of nicotinic receptors and their roles in the central nervous system

    Biol Psychiatry

    (2001)
  • JA Dani et al.

    Molecular and cellular aspects of nicotine abuse

    Neuron

    (1996)
  • JA Dani et al.

    Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas

    Eur J Pharmacol

    (2000)
  • JA Dani et al.

    Synaptic plasticity and nicotine addiction

    Neuron

    (2001)
  • G Di Chiara

    Drug addiction as dopamine-dependent associative learning disorder

    Eur J Pharmacol

    (1999)
  • G Di Chiara

    Role of dopamine in the behavioural actions of nicotine related to addiction

    Eur J Pharmacol

    (2000)
  • SR Goldberg et al.

    Reinforcing effects of nicotine in humans and experimental animals responding under intermittent schedules of iv drug injection

    Pharmacol, Biochem Behav

    (1988)
  • JE Henningfield et al.

    Higher levels of nicotine in arterial than in venous blood after cigarette smoking

    Drug Alcohol Depend

    (1993)
  • ME Jarvik et al.

    Nicotine blood levels and subjective craving for cigarettes

    Pharmacol, Biochem Behav

    (2000)
  • D Ji et al.

    Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity

    Neuron

    (2001)
  • S Jones et al.

    Nicotinic receptors in the brain: correlating physiology with function

    Trends Neurosci

    (1999)
  • P Kasa

    The cholinergic systems in brain and spinal cord

    Prog Neurobiol

    (1986)
  • GF Koob

    Drugs of abuse: anatomy, pharmacology and function of reward pathways

    Trends Pharmacol Sci

    (1992)
  • C Lena et al.

    Allosteric nicotinic receptors, human pathologies

    J Physiol (Paris)

    (1998)
  • RA Lester et al.

    Time-dependent changes in central nicotinic acetylcholine channel kinetics in excised patches

    Neuropharmacology

    (1994)
  • J Lindstrom et al.

    Structure and function of neuronal nicotinic acetylcholine receptors

    Prog Brain Res

    (1996)
  • HD Mansvelder et al.

    Long-term potentiation of excitatory inputs to brain reward areas by nicotine

    Neuron

    (2000)
  • JD Oh et al.

    Cholinergic neurons in the rat central nervous system demonstrated by in situ hybridization of choline acetyltransferase mRNA

    Neuroscience

    (1992)
  • RL Papke et al.

    An evaluation of neuronal nicotinic acetylcholine receptor activation by quaternary nitrogen compounds indicates that choline is selective for the α7 subtype

    Neurosci Lett

    (1996)
  • D Paterson et al.

    Neuronal nicotinic receptors in the human brain

    Prog Neurobiol

    (2000)
  • LW Role et al.

    Nicotinic receptors in the development and modulation of CNS synapses

    Neuron

    (1996)
  • JE Rose et al.

    Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction

    Drug Alcohol Depend

    (1999)
  • MA Russell

    Subjective and behavioural effects of nicotine in humans: some sources of individual variation

    Prog Brain Res

    (1989)
  • R Spanagel et al.

    The dopamine hypothesis of reward: past and current status

    Trends Neurosci

    (1999)
  • IP Stolerman et al.

    The neurobiology of tobacco addiction

    Trends Pharmacol Sci

    (1991)
  • TM Tzschentke

    Pharmacology and behavioral pharmacology of the mesocortical dopamine system

    Prog Neurobiol

    (2001)
  • F Wang et al.

    Chronic nicotine treatment up-regulates human α3β2 nut not α3β4 acetylcholine receptors stably transfected in human embryonic kidney cells

    J Biol Chem

    (1998)
  • RA Wise

    Addiction becomes a brain disease

    Neuron

    (2000)
  • S Wonnacott

    Presynaptic nicotinic ACh receptors

    Trends Neurosci

    (1997)
  • EX Albuquerque et al.

    Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function

    J Pharmacol Exp Ther

    (1997)
  • M Alkondon et al.

    Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices

    J Pharmacol Exp Ther

    (1997)
  • M Alkondon et al.

    Choline is a selective agonist of alpha7 nicotinic acetylcholine receptors in the rat brain neurons

    Eur J Neurosci

    (1997)
  • ME Benwell et al.

    The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity

    Br J Pharmacol

    (1992)
  • RS Broide et al.

    The α7 nicotinic acetylcholine receptor in neuronal plasticity

    Mol Neurobiol

    (1999)
  • B Buisson et al.

    Chronic exposure to nicotine upregulates the human (α)4(β)2 nicotinic acetylcholine receptor function

    J Neurosci

    (2001)
  • P Calabresi et al.

    Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording

    Br J Pharmacol

    (1989)
  • PB Clarke

    Nicotinic receptor blockade therapy and smoking cessation

    Br J Addict

    (1991)
  • E Cooper et al.

    Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor

    Nature

    (1991)
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