While it is well-known that nicotine exerts its rewarding effects by attaching to nicotine receptors in the brain, the mechanisms underlying nicotine withdrawal remain poorly understood.
To gain a better understanding of these mechanisms, researchers funded by NIDA studied nicotine withdrawal in normal mice, as well as mice lacking the alpha-2 and alpha-5 nicotinic receptor subunits. In the experiments, all mice were chronically provided with nicotine, and then injected with mecamylamine—a drug that blocks nicotine receptors—to precipitate withdrawal.
Researchers found that mice lacking the alpha-2 and alpha-5 nicotine subunits showed a decrease in typical withdrawal symptoms, including shaking and repetitive grooming or scratching. In a separate experiment, blockade of nicotinic activity, via direct injections of mecamylamine into the medial habenula and interpeduncular nuclear brain regions (but not to the cortex, hippocampus or ventral tegmental area), of normal mice precipitated signs of nicotine withdrawal. These results suggest that the medial habenula and the interpeduncular nucleus and alpha-2 and alpha-5 nicotinic receptor subunits are key mediators of withdrawal.
The authors conclude that these brain regions and receptor subtypes are potentially relevant targets for the development of new medications and smoking cessation therapies.
Salas R, Sturm R, Boulter J, De Biasi M. Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice. J Neurosci. 2009 Mar 11;29(10):3014-8.