Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Jul;6(1):4-16.

Neuronal Mechanisms Underlying Development of Nicotine Dependence: Implications for Novel Smoking-Cessation Treatments

Affiliations
Free PMC article
Review

Neuronal Mechanisms Underlying Development of Nicotine Dependence: Implications for Novel Smoking-Cessation Treatments

Manoranjan S D'Souza et al. Addict Sci Clin Pract. .
Free PMC article

Abstract

Tobacco smoking causes high rates of mortality and morbidity throughout the world. Despite the availability of smoking-cessation medications, maintenance of long-term abstinence is difficult, and most individuals who attempt to quit smoking relapse. Although tobacco smoke contains many substances, researchers and policymakers agree that nicotine is a major cause of tobacco dependence. Understanding the neural substrates of nicotine dependence is essential for the development of more effective antismoking medications than those currently available. This article focuses on the neural substrates, especially nicotinic acetylcholine receptors, that mediate the reinforcing effects of nicotine and the development of nicotine dependence. Neuroadaptations in the function of the neurotransmitters dopamine, glutamate, and gamma-aminobutyric acid (GABA), which have been shown to be critically involved in nicotine dependence, are also reviewed. Finally, the article discusses progress in the discovery and development of smoking-cessation medications.

Figures

FIGURE 1
FIGURE 1
Nicotine Acetylcholine Receptor (A) Side view of the α7 nAChR showing binding sites for acetylcholine or nicotine. (B) Top view of the α7 nAChR showing binding sites. (C) Schematic top views of four nAChR subtypes, showing their subunit composition: α7 (homomeric); α4β2 (heteromeric); α3β4 (heteromeric); α4α6β2β3 (heteromeric). Reproduced with permission from Changeux and Taly, 2008.
FIGURE 1
FIGURE 1
Nicotine Acetylcholine Receptor (A) Side view of the α7 nAChR showing binding sites for acetylcholine or nicotine. (B) Top view of the α7 nAChR showing binding sites. (C) Schematic top views of four nAChR subtypes, showing their subunit composition: α7 (homomeric); α4β2 (heteromeric); α3β4 (heteromeric); α4α6β2β3 (heteromeric). Reproduced with permission from Changeux and Taly, 2008.
FIGURE 1
FIGURE 1
Nicotine Acetylcholine Receptor (A) Side view of the α7 nAChR showing binding sites for acetylcholine or nicotine. (B) Top view of the α7 nAChR showing binding sites. (C) Schematic top views of four nAChR subtypes, showing their subunit composition: α7 (homomeric); α4β2 (heteromeric); α3β4 (heteromeric); α4α6β2β3 (heteromeric). Reproduced with permission from Changeux and Taly, 2008.
FIGURE 2
FIGURE 2
Pharmacological Strategies to Attenuate Nicotine Reinforcement and Alleviate Withdrawal A) Potential targets in the mesolimbic reward system can promote smoking cessation by attenuating the reinforcing effects of nicotine. The reinforcing effects of nicotine are partly mediated by the activation of dopamine neurons in the ventral tegmental area (VTA) and the release of dopamine (DA) in the nucleus accumbens (NAc). The activity of dopamine neurons in the VTA is regulated by glutamatergic and GABAergic inputs from different brain regions. Pharmacological strategies that attenuate the reinforcing effects of nicotine and cue-induced reinstatement of nicotine seeking in animals include compounds that block nicotine and acetylcholine from stimulating nACh receptors on glutamate- and dopamine-releasing neurons, such as nicotinic receptor antagonists and partial agonists; compounds that reduce excitatory glutamatergic neurotransmission in the VTA, such as the presynaptic mGlu2/3 receptor agonists/positive modulators, postsynaptic mGlu5 antagonists/negative modulators, and N-methyl-d-aspartate (NMDA) receptor antagonists; and compounds that increase the influence of the inhibitory neurotransmitter GABA at receptors on dopamine neurons such as GABA enhancers and GABAB positive modulators. Compounds that reduce dopaminergic neurotransmission, such as DA receptor antagonists, also attenuate nicotine reinforcement and reinstatement in animal models. B) Potential targets in the mesolimbic reward system may help to alleviate the negative affective symptoms seen in smokers who quit smoking. Chronic nicotine exposure results in decreased dopamine and glutamate neurotransmission in the VTA and NAc. Pharmacological compounds that facilitate dopamine and/or glutamate release in the VTA and/or NAc alleviate the negative affective effects of nicotine withdrawal in animals. Such compounds/strategies include nicotine replacement therapy, nicotine receptor partial agonists, mGlu2/3 receptor antagonists/negative modulators, and dopamine uptake blockers.

Comment in

  • Response: a quest and a wager.
    Bevins R, Kenny P, Rose J. Bevins R, et al. Addict Sci Clin Pract. 2011 Jul;6(1):16-7. Addict Sci Clin Pract. 2011. PMID: 22003418 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by 38 articles

See all "Cited by" articles

References

    1. Balfour DJK. The neuronal pathways mediating the behavioral and addictive properties of nicotine. Handbook of Experimental Pharmacology. 2009;192:209–233. - PubMed
    1. Barrett SP, et al. The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [11C]raclopride. Synapse. 2004;54(2):65–71. - PubMed
    1. Changeux JP, Taly A. Nicotinic receptors, allosteric proteins and medicine. Trends in Molecular Medicine. 2008;14(3):93–102. - PubMed
    1. Conn PJ, Jones CK. Promise of mGluR2/3 activators in psychiatry. Neuropsychopharmacology. 2009;34(1):248–249. - PMC - PubMed
    1. Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annual Review of Pharmacology and Toxicology. 2007;47:699–729. - PubMed

Publication types

MeSH terms

LinkOut - more resources

Feedback