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The Journal of Neuroscience, March 11, 2009, 29(10):3014-3018; doi:10.1523/JNEUROSCI.4934-08.2009

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Brief Communications
Nicotinic Receptors in the Habenulo-Interpeduncular System Are Necessary for Nicotine Withdrawal in Mice

Ramiro Salas,^1 * Renea Sturm,^1 * Jim Boulter,² and Mariella De Biasi¹

¹Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and ²Department of Psychiatry and Biobehavioral Sciences, Hatos Research Center for Neuropharmacology, Brain Research and Molecular Biology Institutes, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Mariella De Biasi, Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030. Email: debiasi{at}bcm.tmc.edu

In humans, tobacco withdrawal produces symptoms that contribute to the difficulty associated with smoking cessation. Nicotine withdrawal symptoms can also be observed in rodents. A major standing question is which nicotinic receptor subtypes and which areas of the brain are necessary for nicotine withdrawal to occur. Using knock-out mice, we previously showed that the β4, but not the β2 subunit of nicotinic acetylcholine receptors, is necessary for the somatic manifestations of nicotine withdrawal. Since the β4 subunit is highly expressed in the medial habenula, we focused our studies on the medial habenula and its primary target, the interpeduncular nucleus. In particular, we studied nicotine withdrawal in mice lacking the 2 or the 5 nicotinic receptor subunits, which are highly expressed in the interpeduncular nucleus. We precipitated withdrawal by systemically injecting the nicotinic antagonist mecamylamine in mice chronically treated with nicotine. Both the 2 and the 5 null mutations abolished the somatic manifestations of nicotine withdrawal. In addition, in wild-type mice chronically treated with nicotine, mecamylamine precipitated withdrawal when microinjected into the habenula or the interpeduncular nucleus, but not into the cortex, ventral tegmental area or hippocampus. Our results demonstrate a major role for the habenulo-interpeduncular system and the nicotinic receptor subunits expressed therein, in nicotine withdrawal symptoms. Our data suggest that the efforts to develop new smoking cessation therapies should concentrate on these areas and receptor types.

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Received Oct. 13, 2008; revised Dec. 22, 2008; accepted Jan. 10, 2009.

Correspondence should be addressed to Mariella De Biasi, Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030. Email: debiasi{at}bcm.tmc.edu

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