Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling

Abstract

The medial habenula (MHb) densely expresses nicotinic acetylcholine receptors (nAChRs) and participates in nicotine-related behaviors such as nicotine withdrawal and regulating nicotine intake. Although specific nAChR subunits are identified as being involved in withdrawal behavior, the cellular mechanisms through which nicotine acts to cause this aversive experience is unclear. Here, we demonstrate an interaction between the nicotinic and neurokinin signaling systems that may form the basis for some symptoms experienced during nicotine withdrawal. Using patch-clamp electrophysiology in mouse brain slices, we show that nicotine (1 M) increases intrinsic excitability in MHb neurons. This nicotine-induced phenomenon requires ␣5-containing nAChRs and depends on intact neurokinin signaling. The effect is blocked by preincubation with neurokinin 1 (NK1; L-732138, 10 M) and NK3 (SB222200, 2 M) antagonists and mimicked by NK1 (substance P, 100 nM) and NK3 (neurokinin B [NKB], 100 nM) agonists. Microinjections (1 l) of L-732138 (50 nM) and SB222200 (100 nM) into the MHb induces withdrawal behavior in chronic nicotine-treated (8.4 mg/kg/d, 2 weeks) mice. Conversely, withdrawal behavior is absent with analogous microinjections into the lateral habenula of nicotine-treated mice or in mice chronically treated with a vehicle solution. Further, chronic nicotine reduces nicotine's acute modulation of intrinsic excitability while sparing modulation by NKB. Our work elucidates the interplay between two neuromodulatory signaling systems in the brain through which nicotine acts to influence intrinsic excitability. More importantly, we document a neuroadaptation of this mechanism to chronic nicotine exposure and implicate these mechanisms collectively in the emergence of nicotine withdrawal behavior.

Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

“…This is particularly important given that our pharmacological experiments suggest that nAChRs containing a6 subunits are a minority, although of high sensitivity, subtype in MHbVI. These results demonstrate the importance of considering MHb subregions independently when studying nAChRs and chronic nicotine, as several recent studies did not identify changes in the response of MHb neurons to nicotine when the MHb was analyzed without considering subregions (Gorlich et al, 2013;Hsu et al, 2013;Dao et al, 2014).…”

“…MHb neurons fire spontaneous action potentials in slice preparation (Gorlich et al, 2013;Dao et al, 2014;Shih et al, 2014). To examine the effects of short-term nicotine exposure on MHbVL and MHbVI neuron firing rates, we recorded baseline and nicotine-elicited action potential firing.…”

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

“…Lentivirus-mediated gene delivery to the MHb restored β4 nAChR subunit expression on a β4KO background, forming putative a3β4* nAChRs in MHb soma and terminals innervating the IPN. MHb β4* nAChRs are required for nicotine-evoked excitatory responses (Dao et al, 2014;Görlich et al, 2013;Hsu et al, 2013), and β4* nAChRs on MHb terminals are required for nicotine-evoked acetylcholine release (Beiranvand et al, 2014;Grady et al, 2009). We found that partial re-expression of β4* nAChRs along the length of MHb neurons (mean: 26.0%) did not rescue nicotine IVSA.…”

Diversity of native nicotinic receptor subtypes in mammalian brain

“…Fowler et al (2011) have shown that habenular nAChRs containing the a5 subunit regulate the consumption of nicotine at normally aversive high doses. Dao et al (2014) used patch-clamp electrophysiology in mouse brain slices to show that acute nicotine administration increases the intrinsic excitability of MHb neurons, and that this increase is due to the presence of a5b2*-containing receptors. By activating a5* receptors, acute nicotine exposure facilitates the release of neurokinins on MHb neurons expressing neurokinin receptors type 1 and 3, whose activation increases intrinsic MHb neuron excitability whereas chronic nicotine exposure reduces the responsiveness of a5* nAChRs and the neuromodulatory effect of nicotine on intrinsic excitability probably as a result of nAChR desensitisation, and this may contribute to aversive experiences during nicotine withdrawal.…”