Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum.

Nicotine use can lead to dependence through complex processes that are regulated by both its rewarding and aversive effects. Recent studies show that aversive nicotine doses activate excitatory inputs to the interpeduncular nucleus (IPN) from the medial habenula (MHb), but the downstream targets of the IPN that mediate aversion are unknown. Here we show that IPN projections to the laterodorsal tegmentum (LDTg) are GABAergic using optogenetics in tissue slices from mouse brain. Selective stimulation of these IPN axon terminals in LDTg in vivo elicits avoidance behavior, suggesting that these projections contribute to aversion. Nicotine modulates these synapses in a concentration-dependent manner, with strong enhancement only seen at higher concentrations that elicit aversive responses in behavioral tests. Optogenetic inhibition of the IPN-LDTg connection blocks nicotine conditioned place aversion, suggesting that the IPN-LDTg connection is a critical part of the circuitry that mediates the aversive effects of nicotine.

A Cooperative Mechanism Involving Ca2+-Permeable AMPA Receptors and Retrograde Activation of GABAB Receptors in Interpeduncular Nucleus Plasticity.

The medial habenula-interpeduncular nucleus (MHb-IPN) pathway, which connects the limbic forebrain to the midbrain, has recently been implicated in aversive behaviors. The MHb-IPN circuit is characterized by a unique topographical organization, an excitatory role of GABA, and a prominent co-release of neurotransmitters and neuropeptides. However, little is known about synaptic plasticity in this pathway. An application of a high-frequency stimulation resulted in a long-lasting potentiation of glutamate release in IPN neurons. Our experiments reveal that a Ca2+-permeable AMPA receptor (CPAR)-dependent release of GABA from IPN neurons and a retrograde activation of GABAB receptors on MHb terminals result in a long-lasting enhancement of glutamate release. Strikingly, adolescent IPN neurons lacked CPARs and exhibited an inability to undergo plasticity. In addition, fear conditioning suppressed an activity-dependent potentiation of MHb-IPN synapses, whereas fear extinction reversed this plasticity deficit, suggesting a role of the MHb-IPN synaptic plasticity in the regulation of aversive behaviors.

Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei.

The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR) and caudal dorsal raphe nucleus (DRC), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions or the MnR and additionally examined the transmitter phenotype of major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques. Besides receiving inputs from MHb and also LHb, we found that IP is reciprocally interconnected mainly with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and laterodorsal tegmental nucleus. The bidirectional connections between IP and MnR proved to be primarily GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas major ascending projections, including focal projections to ventral hippocampus, ventrolateral septum, and LHb originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures that modulate hippocampal theta activity and forms a node linking MHb and LHb with this network, and the hippocampus. Moreover, they support a cardinal role of GABAergic IP/MnR interconnections in the behavioral response to nicotine.

The habenulo-interpeduncular pathway in nicotine aversion and withdrawal.

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 ß4 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'.