The Role of Nicotinic Receptors in the Habenula in Mediating Addiction


Numerous genome-wide association studies have found that SNPs in the alpha3-beta4-alpha5 nicotinic receptor cluster on chromosome 15q24 are associated with nicotine dependence. Although it is reasonable to presume that this association is mediated by the reward system centered on the mesolimbic dopamine pathway, recent work suggests that the effects of alpha3-beta4-alpha5 nicotinic receptors on drug-seeking behavior are mediated, instead, by actions centered on the habenula and interpeduncular nucleus. In this symposium, speakers presented the unique neurobiological properties and anatomy of this system, and its relation to drug abuse and addiction. When combined with the results of previous genome-wide association studies, the presentations provided new insights into the biological basis of individual vulnerability to drug addiction.


Dr. Jonathan Pollack
National Institute on Drug Abuse

Representation of Negative and Positive Motivational Values in the Monkey Lateral Habenula

Okihide Hikosaka, M.D., Ph.D.

This presentation focuses on the relationship between the lateral habenula and the basal ganglia, a group of nuclei in the brain associated with a variety of functions, including voluntary muscle movement, reasoning, emotional responses, and procedural learning related to habits. Many studies suggest that the basal ganglia facilitate behaviors leading to larger rewards and suppress behaviors leading to smaller rewards. A key factor in this behavior change is the release of dopamine in the basal ganglia, as most dopamine neurons are excited by a larger-than-expected reward (or its predictor) and inhibited by a smaller-than-expected reward (or its predictor).

However, previous studies have not determined how or why dopamine affects learning and causes the brain to predict the anticipated amount of reward accurately. Dr. Hikosaka and his team of researchers recently learned that the lateral habenula, a small area in the thalamus, inhibits dopamine neurons in the basal ganglia and thereby controls motor and cognitive behaviors. A majority of lateral habenula neurons were excited by a visual stimulus predicting a small reward and inhibited by a stimulus predicting a large reward, a pattern opposite to that seen in dopamine neurons. Microstimulation of the lateral habenula caused a clear inhibition in most of the dopamine neurons. Therefore, lateral habenula neurons send reward-related signals to dopamine neurons while converting it from negative reward signals to positive reward signals. Researchers also found that aversive events (or their predictors) excite lateral habenula neurons and inhibit a group of dopamine neurons. These results demonstrate that the basal ganglia are under critical control of neural circuits outside the basal ganglia involving the lateral habenula.

The Habenula and Nicotine Withdrawal: From Mouse to Human

Ramiro Salas, Ph.D.

Nicotine has an addictive effect on the brain because it binds nicotinic acetylcholine receptors. These receptors are ion channels modulated by nicotine. The role of each receptor in normal physiological and pathological states has been extensively debated. Using mice that lack different subunits of the nicotinic receptors, Dr. Salas and his research team were able to define a group of subunits—alpha2, alpha5, and beta4—as directly influencing nicotine withdrawal.

To illustrate and analyze symptoms of withdrawal, mice were delivered saline or nicotine continuously for 2 weeks. They were then injected with mecamylamine, a chemical that blocks nicotinic receptors, which caused withdrawal signs such as scratching, grooming, and shaking. These signs were monitored for 20 minutes. Using knockout mice that lack each subunit, the research team found that nicotinic receptors made up of the alpha2, alpha5, and beta4 subunits play a critical role in nicotine withdrawal in mice. Also, blocking nicotinic activity only in the habenula or its main target, the interpeduncular nucleus (but not in other areas), results in withdrawal signs in nicotine-treated mice.

Since these subunits are expressed mainly in the habenula, the researchers decided to study habenular activity in humans using functional Magnetic Resonance Imaging (fMRI), a type of specialized MRI scan that measures changes in blood flow related to neural activity in the brain. Using this technology, they demonstrated that when the brain experiences a smaller-than-expected reward, the habenula is activated. Volunteers viewed cues on a computer screen and received small squirts of sweet juice in their mouth to experience reward. Later, the cue-juice timing was manipulated to produce disappointment (juice expected but not delivered). The fMRI illustrated an activated habenula when a reward was expected but not delivered. This insight will allow researchers to study habenular activity during smoking and tobacco abstinence. The researchers hypothesize that habenular hyperactivation may be the mechanism that triggers tobacco withdrawal in humans, which is in agreement with enhanced negative feelings during attempts to quit smoking.