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Role of the Glutamatergic System in Nicotine Dependence

Implications for the Discovery and Development of New Pharmacological Smoking Cessation Therapies

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Abstract

Preclinical research findings in laboratory animals indicate that the glutamatergic system is critically involved in nicotine dependence. In animals, compounds that decrease glutamatergic neurotransmission, such as antagonists at postsynaptic NMDA receptors, antagonists at excitatory postsynaptic metabotropic glutamate (mGlu) 5 receptors, or agonists at inhibitory presynaptic mGlu2 and mGlu3 receptors, decreased nicotine self-administration or reinstatement of nicotine-seeking behaviour. These findings suggest that medications that decrease glutamatergic transmission overall may reduce the reinforcing effects of tobacco smoking and prevent relapse to tobacco smoking in humans. Furthermore, compounds that increase glutamate release, such as antagonists at mGlu2 and mGlu3 receptors, ameliorated reward deficits associated with nicotine withdrawal in animals, and thus may alleviate the depression-like symptoms associated with nicotine withdrawal in humans. Animal studies also showed that α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors did not appear to be involved in mediating the primary reinforcing effects of nicotine but that they may be involved in the development of nicotine dependence and withdrawal.

Taken together, the preclinical data indicate that different glutamatergic receptors are involved in the mediation of different aspects of nicotine dependence. These findings have implications for the discovery and development of new pharmacotherapies that target the glutamatergic system to aid in smoking cessation. At present, very few clinical studies have addressed the effects of glutamatergic compounds on cigarette smoking. Clinical studies involving compounds that have actions at ionotropic glutamate receptors are briefly discussed in this review and suggest the potential of glutamatergic compounds as pharmacotherapies to aid in smoking cessation. Medications that target mGlu receptors have recently been tested in human phase II trials for various indications; however, the potential of these mGlu compounds as medications for nicotine dependence remains to be evaluated in humans. The preclinical data evaluated in this review indicate that such clinical trials for smoking cessation with mGlu compounds are clearly warranted and may reveal novel treatments for nicotine dependence.

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Acknowledgements

This work was supported by National Institute on Drug Abuse grants DA11946 and DA023209, and Tobacco-Related Disease Research Program grant 15RT-0022 awarded to Athina Markou. Athina Markou’s laboratory was a recipient of a research grant from Novartis Pharma AG on metabotropic glutamate receptors. Athina Markou and colleagues have submitted a patent application regarding the use of metabotropic glutamate receptor compounds for smoking cessation. Matthias Liechti was supported by fellowship awards from the Swiss National Science Foundation (SNF-PBZHB-108501, SSMBS 1246 and F. Hofmann-La Roche Ltd, Basel, Switzerland). He has no other conflicts of interest to declare that are directly relevant to the content of this review. The authors would like to thank Mr Mike Arends for his editorial assistance.

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  1. Division of Clinical Pharmacology and Toxicology, University Hospital of Basel, Basel, Switzerland

    Matthias E. Liechti

  2. Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0603, USA

    Athina Markou

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Correspondence to Athina Markou.

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Liechti, M.E., Markou, A. Role of the Glutamatergic System in Nicotine Dependence. CNS Drugs 22, 705–724 (2008). https://doi.org/10.2165/00023210-200822090-00001

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