Differential effects of α4β2 nicotinic receptor antagonists and partial-agonists on contextual fear extinction in male C57BL/6 mice
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Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction
In the present study, we examined the effects of inhibition and desensitization of α4β2 nAChRs via a full antagonist (Dihydro-beta-erythroidine (DhβE)) and two α4β2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice.
We trained and tested the subjects in a contextual fear extinction as well as an open field paradigm and spontaneous recovery following injections of DhβE, varenicline, and sazetidine-A.
Our results demonstrated that lower doses of DhβE (1 mg/kg) and sazetidine-A (0.01 mg/kg) enhanced contextual fear extinction whereas higher doses of varenicline (0.1 mg/kg) and sazetidine-A (0.1 mg/kg) resulted in impaired contextual fear extinction. However, the higher dose of sazetidine-A (0.1 mg/kg) decreased locomotor activity, which may contribute to increased freezing response observed during fear extinction. Finally, we found that the low dose of DhβE, but not sazetidine-A, also decreased spontaneous recovery of contextual fear following fear extinction.
Overall, these results suggest that inhibition and desensitization of α4β2 nAChRs enhance extinction of contextual fear memories. This suggests that modulation of α4β2 nAChRs may be employed as an alternative pharmacological strategy to aid exposure therapies associated with PTSD by augmenting contextual fear extinction processes.
KeywordsNicotinic receptors Fear extinction Spontaneous recovery PTSD
This work was funded with grant support from the National Institute on Drug Abuse (T.J.G., DA017949; 1U01DA041632), Jean Phillips Shibley Endowment, and Penn State Biobehavioral Health Department. We declare no potential conflict of interest.
- Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, … Shrikhande A (2005). Varenicline: an α4β2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48(10):3474–3477. doi: https://doi.org/10.1021/jm050069n
- Craske MG, Mystkowski J (2006) Exposure therapy and extinction: clinical studies. In: Craske M, Hermans D (Eds) Fear and learning: contemporary perspectives. American Psychological Association, Washington, DCGoogle Scholar
- Faessel HM, Smith BJ, Gibbs MA, Gobey JS, Clark DJ, Burstein AH (2006) Single-dose pharmacokinetics of varenicline, a selective nicotinic receptor partial agonist, in healthy smokers and nonsmokers. J Clin Pharmacol 46(9):991–998. https://doi.org/10.1177/0091270006290669 CrossRefPubMedGoogle Scholar
- Koenen KC, Hitsman B, Lyons MJ, Niaura R, McCaffery J, Goldberg J, … Tsuang M (2005) A twin registry study of the relationship between posttraumatic stress disorder and nicotine dependence in men. Arch Gen Psychiatry 62(11):1258–1265. doi: https://doi.org/10.1001/archpsyc.62.11.1258
- Krystal JH, Davis LL, Neylan TC, Raskind MA, Schnurr PP, Stein MB, … Huang GD (2017) It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: a consensus statement of the PTSD psychopharmacology working group. Biol Psychiatry 82(7): e51–e59. doi: https://doi.org/10.1016/j.biopsych.2017.03.007
- Kutlu MG, Tumolo JM, Holliday E, Garrett B, Gould TJ (2016b) Acute nicotine enhances spontaneous recovery of contextual fear and changes c-fos early gene expression in infralimbic cortex, hippocampus, and amygdala. Learn Mem 23(8):405–414. https://doi.org/10.1101/lm.042655.116 CrossRefPubMedPubMedCentralGoogle Scholar
- Kutlu MG, Zeid D, Tumolo JM, Gould TJ (2017b) Pre-adolescent and adolescent mice are less sensitive to the effects of acute nicotine on extinction and spontaneous recovery. Brain Res Bull. https://doi.org/10.1016/j.brainresbull.2017.06.010 PubMedGoogle Scholar
- Luetje CW, Wada K, Rogers S, Abramson SN, Tsuji K, Heinemann S, Patrick J (1990) Neurotoxins distinguish between different neuronal nicotinic acetylcholine receptor subunit combinations. J Neurochem 55(2):632–640. https://doi.org/10.1111/j.1471-4159.1990.tb04180.x CrossRefPubMedGoogle Scholar
- Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, … Sands SB (2007). Pharmacological profile of the α 4 β 2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52(3):985–994. doi: https://doi.org/10.1016/j.neuropharm.2006.10.016
- Tian S, Gao J, Han L, Fu J, Li C, Li Z (2008) Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats. Neuroscience 153(4):935–943. https://doi.org/10.1016/j.neuroscience.2008.03.005 CrossRefPubMedGoogle Scholar
- Wada E, Wada K, Boulter JIM, Deneris E, Heinemann S, Patrick JIM, Swanson LW (1989) Distribution of alpha2, alpha3, alpha4, and beta2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol 284(2):314–335. https://doi.org/10.1002/cne.902840212 CrossRefPubMedGoogle Scholar
- Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, … Calhoun PS (2008). Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 10(12):1691–1715. doi: https://doi.org/10.1080/14622200802443569
- Zwart R, Carbone AL, Moroni M, Bermudez I, Mogg AJ, Folly EA, … Heinz BA (2008) Sazetidine-A is a potent and selective agonist at native and recombinant α4β2 nicotinic acetylcholine receptors. Mol Pharmacol 73(6):1838–1843. doi: https://doi.org/10.1124/mol.108.045104