Activation of GABAergic neurons in the interpeduncular nucleus triggers physical nicotine withdrawal symptoms.
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.
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
Rubing
R
Zhao-Shea
Liwang
L
Liu
Xueyan
X
Pang
Paul D
PD
Gardner
Andrew R
AR
Tapper
D000818:Animals; D059330:GABAergic Neurons / Q000378:metabolism* / Q000528:radiation effects; D018698:Glutamic Acid / Q000378:metabolism; D008027:Light; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010789:Phototherapy / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000096:biosynthesis; D012243:Rhodopsin / Q000096:biosynthesis / Q000235:genetics; D013004:Somatostatin; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D009435:Synaptic Transmission / Q000502:physiology
D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D018698:Glutamic Acid; D013004:Somatostatin; D008464:Mecamylamine; D009538:Nicotine; D012243:Rhodopsin