The habenulo-interpeduncular pathway in nicotine aversion and withdrawal

Abstract

Progress has been made over the last decade in our understanding of the brain areas and circuits involved in nicotine reward and withdrawal, leading to models of addiction that assign different addictive behaviors to distinct, yet overlapping, neural circuits (Koob and Volkow, 2010; Lobo and Nestler, 2011; Tuesta et al., 2011; Volkow et al., 2011). Recently the habenulo-interpeduncular (Hb-IPN) midbrain pathway has re-emerged as a new critical crossroad that influences the brain response to nicotine. This brain area is particularly enriched in nicotinic acetylcholine receptor (nAChR) subunits α5, α3 and β4 encoded by the CHRNA5-A3-B4 gene cluster, which has been associated with vulnerability to tobacco dependence in human genetics studies. This finding, together with studies in mice involving deletion and replacement of nAChR subunits, and investigations of the circuitry, cell types and electrophysiological properties, have begun to identify the molecular mechanisms that take place in the MHb-IPN which underlie critical aspects of nicotine dependence. In the current review we describe the anatomical and functional connections of the MHb-IPN system, as well as the contribution of specific nAChRs subtypes in nicotine-mediated behaviors. Finally, we discuss the specific electrophysiological properties of MHb-IPN neuronal populations and how nicotine exposure alters their cellular physiology, highlighting the unique role of the MHb-IPN in the context of nicotine aversion and withdrawal. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

Keywords: Habenula; Interpeduncular nucleus; Nicotine; Pacemaking; nAChR.

Figure 1. MHb-IPN connectivity

Schematic sagittal view of a mouse brain showing known MHb afferents (blue), MHb efferents (red), IPN afferents (purple) and IPN efferents (orange). The thickness of the arrows reflects the strength of the connection. 3V, third ventricle; 4V, fourth ventricle; DR, dorsal raphe; DTg, dorsal tegmental nucleus; EC, entorhinal cortex; HC, hippocampus; Hyp, hypothalamus; IPN, interpeduncular nucleus; LC, locus coeruleus; LDTg, laterodorsal tegmental nucleus; LHb, lateral habenula; LV, lateral ventricle; MHb, medial habenula; MnR, median raphe; NI, nucleus incertus; PAG, periaqueductal gray; Thal, thalamus; VTA, ventral tegmental area.

Figure 2. Subnuclei of the MHb and IPN

(A) Schematic representation of the MHb subnuclei indicating expression of different markers based on (Aizawa et al., 2012) and (Shih et al., 2014). (B–C) Expression of α3β4-eGFP and ChAT in the ventral two-thirds of the MHb and of Substance P (SP) in the dorsal MHb in sagittal (B) and coronal (C) brain sections of Tabac mice expressing the CHRNB4-A3-eGFP-A5 gene cluster. (D) Schematic representation of the IPN subnuclei indicating expression of different makers localized to cell bodies within the IPN. The panel on the left is a coronal schematic. The right panel is a sagittal schematic. (E) Coronal sections at the level of the IPN showing α3β4-eGFP immunoreactivity (green) and SP immunoreactivity (red) in the habenular terminals of Tabac mice. (Scale bar: 100 μm.) ChAT, choline acetyltransferase; IPA, apical subnucleus of the IPN; IPC, central subnucleus of the IPN; IPDL, dorsolateral subnucleus of the IPN; IPDM, dorsomedial subnucleus of the IPN; IPI, intermediate subnucleus of the IPN; IPL, lateral subnucleus of the IPN; IPN, interpeduncular nucleus; IPR, rostral subnucleus of the IPN; LHb, lateral habenula; MHb, medial habenula; MHbD, dorsal part of the MHb, MHbS, superior part of the MHb; MHbVc, ventro-central part of the MHb; MHbVl, ventro-lateral part of the MHb; MHbVm, ventro-medial part of the MHb; SP, substance P.

Figure 3. The MHb-IPN α5 and β4 nAChRs subunits mediate nicotine aversion

(A) α5^−/− mice self-administer more nicotine than wildtype mice. Data are presented as mean (± SEM) number of nicotine infusions earned across different nicotine doses. Modified with permission from (Fowler et al., 2011) (B) Total nicotine intake at each dose analyzed in A. Modified with permission from (Fowler et al., 2011). (C) Tabac mice, which overexpress β4 in the MHb, display strong aversion to nicotine in the two-bottle choice paradigm at increasing concentrations of nicotine. Data is expressed as percent of the volume of nicotine solution consumed divided by the total fluid intake per day. Modified with permission from (Frahm et al., 2011). (D) Tabac mice stereotactically injected in the MHb with a lentivirus encoding the most frequent variant associated to heavy smoking, α5 D398N, do not display nicotine aversion at 25 μg/ml in the two-bottle choice paradigm compared to Tabac mice injected with control lentivirus. Data is expressed as percent of the volume of nicotine solution consumed divided by the total fluid intake per day. Two-way ANOVA, p<0.05 Modified with permission from (Frahm et al., 2011).

Figure 4. Neurotransmitter systems in the MHb-IPN

Schematic illustration showing the neurotransmitter inputs to the MHb: GABAergic input from the medial septum (M. Septum) and nucleus of the diagonal band (NDB), glutamatergic and ATP-ergic input from the triangular septum (T. Septum) and cholinergic input from the posterior septum. MHb terminals in the IPN co-release glutamate and acetylcholine. Nicotinic acetylcholine receptors (nAChRs) are located in the somatodendritic compartment of MHb neurons, presynaptically in MHb axon terminals and postsynaptically in IPN neurons.