Chemogenetic control of GABAergic neurons within the interpeduncular nucleus reveals dissociable behavioral components of the nicotine withdrawal phenotype

Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The interpeduncular nucleus (IPN) contains a high concentration of nicotinic acetylcholine receptors (nAChRs) and has been identified as a key brain region involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Withdrawal was induced in mice by implantation of osmotic pumps containing nicotine, followed by precipitation by intraperitoneal injections of mecamylamine. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naïve mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naïve mice elicits opposite effects on affective and somatic behaviors. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.