Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry

Abstract

Antagonism of nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb) or interpeduncular nucleus (IPN) triggerswithdrawal-like behaviors in mice chronically exposed to nicotine, implying that nicotine dependence involves the sensitization of nicotinic signaling. Identification of receptor and/or neurophysiological mechanisms underlying this sensitization is important, as it could promote novel therapeutic strategies to reduce tobacco use. Using an approach involving photoactivatable nicotine, we previously demonstrated that chronic nicotine (cNIC) potently enhances nAChR function in dendrites of MHb neurons. However, whether cNIC modulates downstream components of the habenulo-interpeduncular (Hb-IP) circuit is unknown. In this study, cNIC-mediated changes to Hb-IP nAChR function were examined in mouse (male and female) brain slices using molecular, electrophysiological, and optical techniques. cNIC enhanced action potential firing and modified spike waveform characteristics in MHb neurons. Nicotine uncaging revealed nAChR functional enhancement by cNIC on proximal axonal membranes. Similarly, nAChR-driven glutamate release from MHb axons was enhanced by cNIC. In IPN, the target structure of MHb axons, neuronal morphology, and nAChR expression is complex, with stronger nAChR function in the rostral subnucleus [rostral IPN (IPR)]. As in MHb, cNIC induced strong upregulation of nAChR function in IPN neurons. This, coupled with cNIC-enhanced nicotine-stimulated glutamate release, was associated with stronger depolarization responses to brief (1 ms) nicotine uncaging adjacent to IPR neurons. Together, these results indicate that chronic exposure to nicotine dramatically alters nicotinic cholinergic signaling and cell excitability in Hb-IP circuits, a key pathway involved in nicotine dependence.This study uncovers several neuropharmacological alterations following chronic exposure to nicotine in a key brain circuit involved in nicotine dependence. These results suggest that smokers or regular users of electronic nicotine delivery systems (i.e., "e-cigarettes") likely undergo sensitization of cholinergic circuitry in the Hb-IP system. Reducing the activity of Hb-IP nAChRs, either volitionally during smoking cessation or inadvertently via receptor desensitization during nicotine intake, may be a key trigger of withdrawal in nicotine dependence. Escalation of nicotine intake in smokers, or tolerance, may involve stimulation of these sensitized cholinergic pathways. Smoking cessation therapeutics are only marginally effective, and by identifying cellular/ receptor mechanisms of nicotine dependence, our results take a step toward improved therapeutic approaches for this disorder. Arvin et al. • Habenulo-Interpeduncular Circuits Modified by Nicotine

β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement

“…In the present study, nicotine infusions were restricted to the VTA, thus raising an important question about the relevance of this ACh-dependent negative feedback mechanism in smokers. Chronic nicotine upregulates nAChRs in rodent and human brain and sensitize the MHb-IPN pathway (Marks et al, 1992;Mamede et al, 2007;Arvin et al, 2019). The behavioral consequences of this sensitization are not fully understood, and it is unclear whether direct effects of nicotine on this circuit and/or chronic treatment are necessary (Görlich et al, 2013).…”

Nicotine Self-Administration Induces Plastic Changes to Nicotinic Receptors in Medial Habenula

“…PA-Nic photolysis was performed as previously described (Arvin et al, 2019a;Arvin et al, 2019b;Banala et al, 2018;Yan et al, 2018). A modified Olympus BX51 upright microscope and a 60x (1.0 NA) water-dipping (2 mm working distance) objective was used to visualize cells.…”

“…For example, radioligand binding (Huang and Winzer-Serhan, 2006) and immunohistochemical (Nashmi et al, 2007) approaches failed to detect nAChR upregulation in medial habenula (MHb), a small brain region critical for nicotine dependence (Fowler et al, 2011;Zhao-Shea et al, 2013). Subsequently, we used electrophysiological measurements to demonstrate robust MHb nAChR functional upregulation in two different non-contingent exposure paradigms (Arvin et al, 2019a;Banala et al, 2018;Shih et al, 2015). Blockade of ongoing MHb nAChR activity is sufficient to trigger withdrawal behavior in mice exposed chronically to nicotine but not saline (Salas et al, 2009), which strongly implicates MHb nAChR upregulation.…”

Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models

“…Interestingly, all of these subunits exhibit selectively dense expression in the MHb-IPN pathway, which has also been specifically implicated in somatic aspects of nicotine withdrawal. Administration of the general nAChR antagonist mecamylamine into the MHb-IPN pathway is sufficient to precipitate withdrawal, whereas injections into the cortex, VTA or hippocampus are ineffective (Salas et al 2009), and re-exposure to nicotine during withdrawal results in increased activity of MHb and IPN neurons (Arvin et al 2019;Gorlich et al 2013). Further, injections of antagonists for a4b2* or a6b2*, but not a3b4*, nAChRs in the MHb decrease the expression of anxiety-related behavior under conditions of nicotine withdrawal in mice (Pang et al 2016).…”