Complications from tobacco addiction are the number one cause of preventable death in America. In mice, the alpha 2, alpha 5 and beta 4 (but not the beta 2) subunits of the nicotinic acetylcholine receptors (nAChR) are necessary for nicotine withdrawal. In humans, genetic variants in the alpha 3, alpha 5 and beta 4 subunits are associated with tobacco addiction risk. In the brain, these subunits are expressed mainly in the habenula (Hb) and its main target, the interpeduncular nucleus (ipn). Microinjection of nicotinic blockers into the Hb or the ipn, but not in other areas, precipitates withdrawal in nicotine treated mice. If the same is true in humans, the design of new pharmacotherapies to help people quit smoking should radically change focus. We propose to study the activation of the Hb in humans under different smoking conditions, by using fMRI. Our hypothesis is that habenular activation is a critical mediator of nicotine withdrawal. We will specifically study the Hb using a very unique region of interest analysis and high resolution images because this area is too small to be readily visible using the techniques usually applied to the rest of the brain. We will also study activation in other areas important for addiction such as the putamen. Thus, we will study how activity in areas known to be important for addiction, is related to activity in the Hb during tobacco withdrawal. Our preliminary data showed that in a control population, the human habenula is active at moments of negative reward prediction error (i.e. the outcome is worst than predicted) which is in agreement with data from experiments is monkeys. We will use two paradigms to activate habenular activity in sated, abstinent, and nonsmokers: passive learning using juice as reward, and a market task in which subjects gain and lose money.
Tobacco abuse is a behavioral pattern that is very difficult to break, mainly because of withdrawal symptoms. To help design better anti-tobacco abuse therapies, we will study which parts of the brain are involved in tobacco abuse behavior and withdrawal symptoms.
