Nicotinic acetylcholine receptors along the habenulo-interpeduncular pathway: Roles in nicotine withdrawal and other aversive aspects

Abstract

Addiction to tobacco smoking is a deadly disease that consumes millions of lives each year. However, the neurobiology underlying the disease remains an enigma. One reason for this is the relative complexity of nicotine's effects on the brain, with a multitude of targets throughout many different brain regions, each subserving individual components of the disease. Still, a handful of brain circuits mediate particularly signifi cant roles in the disease. The epithalamic habenulointerpeduncular (Hb-IPN) pathway participates in the aversive aspects of nicotine dependence, including the aversive experience of nicotine withdrawal. Many hypotheses regarding the exact mechanisms for these behavioral roles exist, but the convergent feature of those hypotheses is that nicotine acts at populations of nicotinic acetylcholine receptors (nAChRs) across the brain, including the Hb-IPN pathway. Of note, the Hb-IPN pathway is one of the brain regions with the highest density of nAChRs, including both heteromeric (e.g., α3β4 and α4β2) and homomeric (i.e., α7) receptors. As nAChR subtypes that subserve multiple aspects of affective and reinforcement behaviors are expressed along this pathway, it is of no surprise that the Hb-IPN pathway participates in similar affective behaviors. This chapter will discuss the roles of nAChRs along the Hb-IPN in aversive nicotine- associated behaviors, as well as touch upon the innate roles of those populations of nAChRs over biology and behavior in healthy animals.