The Role of the Habenula in Nicotine Addiction

Philip R Baldwin, Raul Alanis, Ramiro Salas
2012 Journal of Addiction Research & Therapy  
The habenula is a small brain structure that has elicited great interest lately. The name habenula (latin for "little rein") comes from the shape that resembles a rein, located by the third ventricle. The habenula is divided into two structures termed medial and lateral habenula, that are anatomically and transcriptionally very different [1] . Ramon y Cajal recognized the possible importance of the habenula, based mainly on the prevalence of its connectivity [2] . Among the major axon bundles
more » ... the rodent brain are the stria medullaris (habenular input) and the fasciculus retroflexus (habenular output). The stria medullaris brings input to the habenula from several areas including the septum and hippocampus, the ventral pallidum, the lateral hypothalamus, the globus pallidus, and other basal ganglia structures [1] . The fasciculus retroflexus is a major axon bundle that brings habenular input to midbrain structures. It is divided into a core region that originates in the medial habenula and ends at the interpeduncular nucleus, and an outer region that originates in the lateral habenula and ends at the rostromedial tegmental nucleus (RMTg). The RMTg (which was sometimes called the "tail" of the ventral tegmental area (VTA)) is a small nucleus that contains mainly inhibitory gabaergic cells. These cells are activated by glutamate released by the lateral habenula via the fasciculus retroflexus and in turn release GABA onto dopaminergic cells in the VTA and substantia nigra pars compacta (SNc). Therefore, lateral habenular activity indirectly inhibits dopaminergic cells in the VTA/SNc. This results in a decrease in dopamine being released in striatal areas ( Figure 1 ) [3, 4] . Less is known about the medial than the lateral habenula. The medial habenula receives input mainly from the septum (the stria medullaris brings inputs to both the lateral and medial habenule), and projects to the interpeduncular nucleus [5, 6] . The function of the medial habenula is not as clear as for the lateral. Since the interpeduncular nucleus projects to dopaminergic areas, it is possible that the medial habenula is also involved in prediction error as the lateral habenula has been shown to be [7] . Throughout this review, we mention "lateral" or "medial" habenula when the data allows for that distinction and simply "habenula" when the original data leaves that question unresolved. An example of "habenula" happens in functional magnetic resonance experiments, where spatial resolution does not permit the distinction between medial and lateral habenula. In contrast, in electrophysiology the position of the electrodes can be carefully studied and the results can be ascribed to the medial or lateral habenula. The study of the habenula had a first "golden age" several years ago, when a series of elegant and thoughtful reports where released [5, 6, [8] [9] [10] [11] [12] [13] . Probably because of its small size, the complexity and subtlety of its role, and the lack of suitable pharmacological agents, the study of the habenula has been much slower than that of many other brain regions. There are several reasons why the habenula is currently the object of intense study. The main reasons related to drug abuse are discussed below. Mouse work points to the medial habenula as a critical region for nicotine withdrawal Work on several lines of mutant mice pointed to the medial habenula as a critical mediator of nicotine withdrawal signs and several other effects of nicotine. Several groups have created and Abstract To thrive in any given environment, mobile creatures must be able to learn from the outcomes of both successful and disappointing events. To learn from success, the brain relies on signals originating in the ventral tegmental area and substantia nigra that result in increased release of dopamine in the striatum. Recently, it was shown that to learn from disappointment the brain relies on signals originating in the lateral habenula, which indirectly inhibit dopaminergic activity. The habenula is a small brain region that has been shown in mice to be critical for the appearance of nicotine withdrawal symptoms. The nicotinic acetylcholine receptor subunits expressed in the medial habenula are necessary to observe withdrawal symptoms in mice, and blocking nicotinic activity in the medial habenula only is sufficient to precipitate withdrawal in dependent mice. In addition, recent genome wide association studies have shown that in humans, genetic variants in the same nicotinic receptor subunits are at least partially responsible for the genetic predisposition to become a smoker. The habenula is linked not only to nicotine, but also to the effects of several other drugs. We postulate that the continuous use of drugs of abuse results in habenular hyperactivity as a compensatory mechanism for artificially elevated dopamine release. Drug withdrawal would then result in non-compensated habenular hyperactivity, and could be thought of as a state of continuous disappointment (or a negative emotional state), driving repeated drug use. We believe that drugs that alter habenular activity may be effective therapies against tobacco smoke and drug addiction in general.
doi:10.4172/2155-6105.s1-002 pmid:22493758 pmcid:PMC3321348 fatcat:2u2oyujasbc2thxsfluvtctjha