Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep 6:6:32937.
doi: 10.1038/srep32937.

Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms

Wanhong Zuo  1 , Cheng Xiao  1 , Ming Gao  2 , F Woodward Hopf  3 , Krešimir Krnjević  4 , J Michael McIntosh  5 , Rao Fu  1 , Jie Wu  2 , Alex Bekker  1 , Jiang-Hong Ye  1
Affiliations

Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms

Wanhong Zuo et al. Sci Rep. .

Abstract

There is much interest in brain regions that drive nicotine intake in smokers. Interestingly, both the rewarding and aversive effects of nicotine are probably critical for sustaining nicotine addiction. The medial and lateral habenular (LHb) nuclei play important roles in processing aversion, and recent work has focused on the critical involvement of the LHb in encoding and responding to aversive stimuli. Several neurotransmitter systems are implicated in nicotine's actions, but very little is known about how nicotinic acetylcholine receptors (nAChRs) regulate LHb activity. Here we report in brain slices that activation of nAChRs depolarizes LHb cells and robustly increases firing, and also potentiates glutamate release in LHb. These effects were blocked by selective antagonists of α6-containing (α6*) nAChRs, and were absent in α6*-nAChR knockout mice. In addition, nicotine activates GABAergic inputs to LHb via α4β2-nAChRs, at lower concentrations but with more rapid desensitization relative to α6*-nAChRs. These results demonstrate the existence of diverse functional nAChR subtypes at presynaptic and postsynaptic sites in LHb, through which nicotine could facilitate or inhibit LHb neuronal activity and thus contribute to nicotine aversion or reward.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Nicotine regulates LHb activity.
(A) Brain atlas diagram for approximate location of MHb and LHb (A1). Representative images of coronal slices containing the LHb with (A2) and without MHb (A3). (B–D) Nicotine first slowed and then accelerated LHb firing. Red arrow: initial firing reduction; (E) Concentration-response of nicotine-induced % increase of firing rate, recorded in cell-attached mode, in brain slices containing both LHb and MHb (●). Nicotine (1 μM and 10 μM) caused similar increases in firing rate of LHb neurons in brain slices with removed MHb (∆). ns = no significance, with MHb vs without MHb. Number of neurons is indicated. Nicotine depolarization of LHb neurons (F), even in presence of TTX (G,H). (I,J) Nicotine-induced inward currents at a holding potential of −70 mV, and in the presence of Inhibitor Cocktail. *p < 0.05, **p < 0.01, ***p < 0.001, one-way ANOVA.
Figure 2
Figure 2. nAChR subtypes mediating nicotine effects in LHb.
(A) Nicotine-induced inward currents were blocked by MEC, α-CTx-MII, MII[H9A; L15A] and DHβE, but not MLA. (B) Nicotine-induced increases in firing rate was prominently reduced by MEC, and MII [H9A; L15A], and weakly but significantly reduced by MLA. (C,D) Summary of above data. (E) Local ACh application induced an MII [H9A; L15A]-sensitive inward current. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 3
Figure 3. Nicotine enhances IPSCs and EPSCs in LHb neurons.
(A,B) Nicotine action on paired evoked IPSCs (eIPSCs) (A) and evoked EPSCs (eEPSCs) (B). eIPSCs (recorded at VH = +40 mV) were abolished by gabazine (10 μM), a GABAA receptor antagonist; eEPSCs (at VH = −70 mV) were abolished by DNQX (20 μM), an AMPA receptor blocker. (C) Nicotine (10 μM) enhanced the first of PSC pairs. (D) % change in amplitude (AMP) of first PSCs and paired pulse ratio (PPR = PSC2/PSC1). (E–J) Nicotine increased spontaneous sIPSC frequency and amplitude (E–G) as well as sEPSC frequency (H–J). (K,L) Simultaneous recording of sIPSC/sIPSPs and sEPSC/sEPSPs at −40 mV under voltage-(K) and current-clamp (L). (M) Different time course of nicotine action on the frequency of sIPSC/Ps and sEPSC/Ps (n = 9). (N,O) Concentration-dependence of increased sEPSC and sIPSC frequency (N) and amplitude (O). *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 4
Figure 4
Nicotine causes a smaller but significant increase in the frequency of spontaneous EPSCs (A1–3) and IPSCs (B1–3) in 0.5 μM TTX, in calcium free ACSF (extracellular Ca2+ was replaced with Mg2+), and in 100 μM CdCl2 (calcium channel blocker). (C,D) % increases in sEPSC and sIPSC frequency (C) and amplitude (D) induced by nicotine in the absence (ACSF) and presence of TTX, or calcium free ACSF, or CdCl2. ##p < 0.01, ###p < 0.001, Student’s paired t-test for nicotine application vs pre-nicotine control. *p < 0.05, **p < 0.01, ***p < 0.001, One-way ANOVA followed by Tukey’s multiple comparison test for nicotine application vs nicotine plus TTX/calcium free ACSF/CdCl2.
Figure 5
Figure 5. nAChR subtypes mediating nicotine effects on sIPSCs and sEPSCs.
(A,B) Effects of various nAChR blockers on nicotine-induced acceleration of sIPSCs (A) and sEPSCs (B). (C) Summary of above data. *p < 0.05, **p < 0.01, ***p < 0.001. (D) Proposed schematic of nAChR subtype distribution in the LHb. (E,F) Nicotine enhanced firing (E) and mEPSC frequency (F) recorded in brain slices from wild-type (WT) but not α6-nAChR knock out (α6 KO) mice. *p < 0.05, #p < 0.05, ##p < 0.01. (G) Summary of above data.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fowler C. D. & Kenny P. J. Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability. Neuropharmacology 76 Pt B, 533–544, 10.1016/j.neuropharm.2013.09.008 (2014). - DOI - PMC - PubMed
    1. Kenny P. J. & Markou A. Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav 70, 531–549 (2001). - PubMed
    1. Kenny P. J. & Markou A. Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31, 1203–1211, 10.1038/sj.npp.1300905 (2006). - DOI - PubMed
    1. Sun N., Laviolette S. R. & Addiction Research G. Dopamine receptor blockade modulates the rewarding and aversive properties of nicotine via dissociable neuronal activity patterns in the nucleus accumbens. Neuropsychopharmacology 39, 2799–2815, 10.1038/npp.2014.130 (2014). - DOI - PMC - PubMed
    1. Sellings L. H., Baharnouri G., McQuade L. E. & Clarke P. B. Rewarding and aversive effects of nicotine are segregated within the nucleus accumbens. Eur J Neurosci 28, 342–352, 10.1111/j.1460-9568.2008.06341.x (2008). - DOI - PubMed

Publication types

LinkOut - more resources