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

Overview

Journal Curr Biol

Publisher Cell Press

Specialty Biology

Date 2013 Nov 19

PMID 24239118

Citations 79

Authors

Rubing Zhao-Shea

Liwang Liu

Xueyan Pang

Paul D Gardner

Andrew R Tapper

Affiliations

Soon will be listed here.

Abstract

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 channelrhodopsin elicited physical withdrawal symptoms in both nicotine-naive and chronic-nicotine-exposed mice. Dampening excitability of GABAergic neurons during nicotine withdrawal through IPN-selective infusion of an NMDA receptor antagonist or through blockade of 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-naive mice and activated nonsomatostatin 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.

Citing Articles

GABA receptor-mediated potentiation of ventral medial habenula glutamatergic transmission in GABAergic and glutamatergic interpeduncular nucleus neurons.

Stinson H, Ninan I bioRxiv. 2025; .

PMID: 39803438 PMC: 11722340. DOI: 10.1101/2025.01.03.631193.

Effects of E-Cigs on Physiological Pathways and Proposed Therapeutic Intervention with Bixin.

Claymore S, Allen-Gipson D Biomedicines. 2025; 12(12.

PMID: 39767612 PMC: 11673039. DOI: 10.3390/biomedicines12122705.

Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling.

Kim B, Kim H, Woo J, Lee H, Kim T, Min H Adv Sci (Weinh). 2024; 11(47):e2402274.

PMID: 39491887 PMC: 11653618. DOI: 10.1002/advs.202402274.

The influence of ovarian hormones on the putative mechanisms that promote female nicotine use.

Giner P, Ortegon S, Bagdas D, ODell L Curr Opin Neurobiol. 2024; 88:102900.

PMID: 39153250 PMC: 11560049. DOI: 10.1016/j.conb.2024.102900.

Abundant extrasynaptic expression of α3β4-containing nicotinic acetylcholine receptors in the medial habenula-interpeduncular nucleus pathway in mice.

Tsuzuki A, Yamasaki M, Konno K, Miyazaki T, Takei N, Tomita S Sci Rep. 2024; 14(1):14193.

PMID: 38902419 PMC: 11189931. DOI: 10.1038/s41598-024-65076-3.

References

Salas R, Pieri F, De Biasi M . Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci. 2004; 24(45):10035-9. PMC: 6730195. DOI: 10.1523/JNEUROSCI.1939-04.2004. View

Kenny P, Markou A . Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav. 2002; 70(4):531-49. DOI: 10.1016/s0091-3057(01)00651-7. View

Grabus S, Martin B, Batman A, Tyndale R, Sellers E, Damaj M . Nicotine physical dependence and tolerance in the mouse following chronic oral administration. Psychopharmacology (Berl). 2004; 178(2-3):183-92. DOI: 10.1007/s00213-004-2007-3. View

Hikosaka O . The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci. 2010; 11(7):503-13. PMC: 3447364. DOI: 10.1038/nrn2866. View

Jackson K, Martin B, Changeux J, Damaj M . Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther. 2008; 325(1):302-12. PMC: 3821841. DOI: 10.1124/jpet.107.132977. View

Tye K, Mirzabekov J, Warden M, Ferenczi E, Tsai H, Finkelstein J . Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2012; 493(7433):537-541. PMC: 4160519. DOI: 10.1038/nature11740. View

Plaza-Zabala A, Flores A, Maldonado R, Berrendero F . Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal. Biol Psychiatry. 2011; 71(3):214-23. DOI: 10.1016/j.biopsych.2011.06.025. View

Watkins S, Stinus L, Koob G, Markou A . Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J Pharmacol Exp Ther. 2000; 292(3):1053-64. View

Hamill G, Jacobowitz D . A study of afferent projections to the rat interpeduncular nucleus. Brain Res Bull. 1984; 13(4):527-39. DOI: 10.1016/0361-9230(84)90035-2. View

10.

Kawaja M, Flumerfelt B, Hrycyshyn A . Glutamate decarboxylase immunoreactivity in the rat interpeduncular nucleus: a light and electron microscope investigation. Neuroscience. 1989; 30(3):741-53. DOI: 10.1016/0306-4522(89)90166-8. View

11.

Hemmendinger L, Moore R . Interpeduncular nucleus organization in the rat: cytoarchitecture and histochemical analysis. Brain Res Bull. 1984; 13(1):163-79. DOI: 10.1016/0361-9230(84)90018-2. View

12.

Grady S, Moretti M, Zoli M, Marks M, Zanardi A, Pucci L . Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release. J Neurosci. 2009; 29(7):2272-82. PMC: 2680386. DOI: 10.1523/JNEUROSCI.5121-08.2009. View

13.

Salas R, Main A, Gangitano D, De Biasi M . Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit. Neuropharmacology. 2007; 53(7):863-9. PMC: 2149846. DOI: 10.1016/j.neuropharm.2007.08.017. View

14.

Picciotto M, Kenny P . Molecular mechanisms underlying behaviors related to nicotine addiction. Cold Spring Harb Perspect Med. 2012; 3(1):a012112. PMC: 3530035. DOI: 10.1101/cshperspect.a012112. View

15.

Hendrickson L, Zhao-Shea R, Pang X, Gardner P, Tapper A . Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption. J Neurosci. 2010; 30(30):10169-76. PMC: 2941435. DOI: 10.1523/JNEUROSCI.2601-10.2010. View

16.

Zaveri N, Jiang F, Olsen C, Polgar W, Toll L . Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation. J Med Chem. 2010; 53(22):8187-91. PMC: 2997436. DOI: 10.1021/jm1006148. View

17.

Fowler C, Lu Q, Johnson P, Marks M, Kenny P . Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011; 471(7340):597-601. PMC: 3079537. DOI: 10.1038/nature09797. View

18.

Cole A, Saffen D, Baraban J, Worley P . Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature. 1989; 340(6233):474-6. DOI: 10.1038/340474a0. View

19.

Tsai H, Zhang F, Adamantidis A, Stuber G, Bonci A, De Lecea L . Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science. 2009; 324(5930):1080-4. PMC: 5262197. DOI: 10.1126/science.1168878. View

20.

Boehm S, Betz H . Somatostatin inhibits excitatory transmission at rat hippocampal synapses via presynaptic receptors. J Neurosci. 1997; 17(11):4066-75. PMC: 6573526. View