title: Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation.
abstract: Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder.
authors.affiliation: Department of Psychology, Neuroscience Program, Weiss Hall, Temple University, Philadelphia, PA, USA. Electronic address: munir.kutlu@temple.edu.
authors.forename: Munir Gunes
authors.initials: MG
authors.lastname: Kutlu
authors.affiliation: Department of Psychology, Neuroscience Program, Weiss Hall, Temple University, Philadelphia, PA, USA.
authors.forename: Chicora
authors.initials: C
authors.lastname: Oliver
authors.affiliation: Department of Pharmacology, Temple University Medical School, Philadelphia, PA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Temple University Medical School, Philadelphia, PA, USA.
authors.forename: Lee-Yuan
authors.initials: LY
authors.lastname: Liu-Chen
authors.affiliation: Department of Psychology, Neuroscience Program, Weiss Hall, Temple University, Philadelphia, PA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
mesh_terms: D000818:Animals; D004334:Drug Administration Schedule; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology* / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000008:administration & dosage* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: Extinction; Nicotine; Nicotinic receptors; PTSD