Activation of GABAergic Neurons in the Interpeduncular Nucleus Triggers Physical Nicotine Withdrawal Symptoms

Abstract

Summary Background Chronic exposure to nicotine elicits physical dependence in smokers, yet the mechanism and neuroanatomical bases for withdrawal symptoms are unclear. As in humans, rodents undergo physical withdrawal symptoms after cessation from chronic nicotine characterized by increased scratching, head nods, and body shakes. Results Here we show that induction of physical nicotine withdrawal symptoms activates GABAergic neurons within the interpeduncular nucleus (IPN). Optical activation of IPN GABAergic neurons via light stimulation of channel rhodopsin elicited physical withdrawal symptoms in both nicotine-naïve and chronic nicotine-exposed mice. Dampening excitability of GABAergic neurons during nicotine withdrawal through IPN-selective infusion of an NMDA receptor antagonist or through blocking IPN neurotransmission from the medial habenula reduced IPN neuronal activation and alleviated withdrawal symptoms. During chronic nicotine exposure, nicotinic acetylcholine receptors containing the β4 subunit were upregulated in somatostatin interneurons clustered in the dorsal region of the IPN. Blockade of these receptors induced withdrawal signs more dramatically in nicotine-dependent compared to nicotine-naïve mice and activated non-somatostatin neurons in the IPN. Conclusions Together, our data indicate that therapeutic strategies to reduce IPN GABAergic neuron excitability during nicotine withdrawal, for example, by activating nicotinic receptors on somatostatin interneurons, may be beneficial for alleviating withdrawal symptoms and facilitating smoking cessation.

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

“…In summary, by using a stratified approach to investigate β4* nAChR function, we have demonstrated for the first time that these receptors located post-synaptically in the IPN are critical for nicotine reinforcement, and do not exclusively modulate nicotine aversion and withdrawal, as has been reported previously (Salas et al, 2009;Zhao-Shea et al, 2013). We also provide evidence for the role of β4* nAChRs in the IPN for modulating meso-accumbal DA responses to nicotine.…”

“…The role of β4* nAChRs has been investigated in certain nicotine-mediated behaviors, including nicotine-elicited seizures (Salas et al, 2004), aversion (Frahm et al, 2013;Slimak et al, 2014), anxiety (Salas et al, 2003), and withdrawal (Salas et al, 2004;Zhao-Shea et al, 2013), supporting the involvement of this subunit in regulating the aversive properties of nicotine (Fowler and Kenny, 2014). However, recent findings provide evidence for their role in the habenulo-interpeduncular pathway in nicotine reinforcement.…”

“…IPN neurons project to the raphe nucleus and dorsal tegmentum (Hsu et al, 2013), which provide neurological input to the ventral tegmental area (VTA) (Geisler and Zahm, 2005). Thus far, the MHb and IPN have been linked to anxiety, impulsivity, nicotine withdrawal, and primary reinforcement (Hsu et al, 2014;Kobayashi et al, 2013;Zhao-Shea et al, 2013).…”

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…Although both the nicotinic antagonist mecamylamine and the low efficacy partial agonist cytisine can decrease c-fos activity in the amygdala (Mineur et al, 2007), it is not known where in the brain nAChRs are required to alter behaviors relevant to stress and depression. Many brain areas that receive significant ACh innervation, including hippocampus, prefrontal cortex, habenuala, IPN, ventral tegmental area, and nucleus accumbens/striatum (Leao et al, 2015;Mineur et al, 2013Mineur et al, , 2015Picciotto and Mineur, 2014;Polter and Kauer, 2014;Zhao-Shea et al, 2013 could be involved in nAChR-related mood regulation. We demonstrate here that the non-selective nAChR antagonist mecamylamine can induce antidepressant-like effects when infused locally into the amygdala, suggesting that nAChR signaling is critical for baseline neuronal activity in this brain region, and that decreasing nAChR activity in amygdala is sufficient for an antidepressant-like response.…”

miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family

“…At the molecular level, nicotine, the addictive component of tobacco, initiates dependence by binding to and activating neuronal nicotinic acetylcholine receptors (nAChRs), which are normally activated by the endogenous neurotransmitter acetylcholine (ACh) (Albuquerque et al 2009;Improgo et al 2010). Activation of the receptors in the dopaminergic mesocorticolimbic reward pathway is thought to underlie the initiation of dependence whereas signaling through nAChRs in the habenulo-interpeduncular pathway that feeds into the reward pathway is thought to play a key role in eliciting nicotine-associated withdrawal symptoms (Albuquerque et al 2009;Salas et al 2009;Zhao-Shea et al 2013). Neuronal nAChRs are a family of ligand-gated cation channels signaling through which underlies a variety of fundamental physiological processes (Dani 1993(Dani , 2001).…”