Abstract
Rationale
Recent preclinical data has implicated the α7 nicotinic acetylcholine receptor (nAChR) as a target in modulating nicotine reward. However, the role of the channel properties of the α7 nAChR in nicotine withdrawal is unknown.
Objectives
This study aimed to investigate the impact of α7 nAChR pharmacological modulation on mecamylamine-precipitated nicotine withdrawal behaviors in mice by using positive allosteric modulators (PAMs).
Methods
The effect of the orthosteric α7 nAChR full agonist PNU282987 (1, 3, 9 mg/kg, s.c.), type I α7 PAM NS1738 (1 and 10 mg/kg; i.p.) and the type II α7 PAM PNU120596 (3 and 9 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured in mice undergoing mecamylamine-precipitated nicotine withdrawal. Mice were infused with 24 mg/kg/day nicotine or saline for 14 days using s.c. osmotic minipumps. Nicotine withdrawal signs were precipitated upon administration of the non-selective nAChR antagonist mecamylamine (3.5 mg/kg, i.p.).
Results
Anxiety-like behavior in nicotine withdrawn mice was only attenuated by PNU282987 in a dose-related fashion. Somatic signs were reduced by PNU282987 and NS1738. PNU120596 was the only compound that reversed precipitated nicotine withdrawal-induced hyperalgesia.
Conclusions
Taken together, our results suggest that modulation of the α7 nAChR can play important roles in mecamylamine-precipitated nicotine withdrawal behaviors in mice. In addition, the effects of PAMs in this study suggest that endogenous acetylcholine/choline tone is sufficient to attenuate some aspects of precipitated nicotine withdrawal. These findings highlight a beneficial effect of using α7 nAChR PAMs in some aspects of precipitated nicotine withdrawal.
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References
Brioni JD, O’Neill AB, Kim DJ, Decker MW (1993) Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. Eur J Pharmacol 238:1–8
Brunzell DH, McIntosh JM (2012) Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia. Neuropsychopharmacology 37:1134–1143. https://doi.org/10.1038/npp.2011.299
Damaj MI, Kao W, Martin BR (2003) Characterization of spontaneous and precipitated nicotine withdrawal in the mouse. J Pharmacol Exp Ther 307:526–534. https://doi.org/10.1124/jpet.103.054908
Freitas K, Carroll FI, Damaj MI (2013a) The antinociceptive effects of nicotinic receptors α7-positive allosteric modulators in murine acute and tonic pain models. J Pharmacol Exp Ther 344:264–275. https://doi.org/10.1124/jpet.112.197871
Freitas K, Ghosh S, Carroll FI et al (2013b) Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models. Neuropharmacology 65:156–164. https://doi.org/10.1016/j.neuropharm.2012.08.022
Freitas K, Negus S, Carroll FI, Damaj MI (2013c) In vivo pharmacological interactions between a type II positive allosteric modulator of α7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model. Br J Pharmacol 169:567–579. https://doi.org/10.1111/j.1476-5381.2012.02226.x
Grabus SD, Martin BR, Damaj MI (2005) Nicotine physical dependence in the mouse: involvement of the alpha7 nicotinic receptor subtype. Eur J Pharmacol 515:90–93. https://doi.org/10.1016/j.ejphar.2005.03.044
Grønlien JH, Håkerud M, Ween H et al (2007) Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol Pharmacol 72:715–724. https://doi.org/10.1124/mol.107.035410.tamers
Gurley DA, Lanthorn TH (1998) Nicotinic agonists competitively antagonize serotonin at mouse 5-HT3 receptors expressed in Xenopus oocytes. Neurosci Lett 247:107–110. https://doi.org/10.1016/S0304-3940(98)00306-1
Harenza JL, Muldoon PP, De Biasi M et al (2014) Genetic variation within the Chrna7 gene modulates nicotine reward-like phenotypes in mice. Genes Brain Behav 13:213–225. https://doi.org/10.1111/gbb.12113
Higa KK, Grim A, Kamenski ME et al (2017) Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice. Psychopharmology (Berl) 234:1573–1586. https://doi.org/10.1007/s00213-017-4572-2
Horenstein NA, Leonik FM, Papke RL (2008) Multiple pharmacophores for the selective activation of nicotinic alpha 7-type acetylcholine receptors. Mol Pharmacol 74:1496–1511. https://doi.org/10.1124/mol.108.048892
Hughes JR, Gulliver SB, Fenwick JW, Valliere WA, Cruser K, Pepper S, Shea P, Solomon LJ, Flynn BS (1992) Smoking cessation among self-quitters. Health Psychol 11:331–334
Jackson KJ, Martin BR, Changeux JP, Damaj MI (2008) Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther 325:302–312. https://doi.org/10.1124/jpet.107.132977
de Jonge WJ, Ulloa L (2007) The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 151:915–929. doi: https://doi.org/10.1038/sj.bjp.0707264
King JR, Kabbani N (2016) Alpha 7 nicotinic receptor coupling to heterotrimeric G proteins modulates RhoA activation, cytoskeletal motility, and structural growth. J Neurochem 138:532–545. https://doi.org/10.1111/jnc.13660
King JR, Nordman JC, Bridges SP, Lin MK, Kabbani N (2015) Identification and characterization of a G protein-binding cluster in alpha 7 nicotinic acetylcholine receptors. J Biol Chem 290:20060–20070. https://doi.org/10.1074/jbc.M115.647040
Le Foll B, Goldberg SR (2009) Effects of nicotine in experimental animals and humans: an update on addictive properties. Handb Exp Pharmacol:335–367. https://doi.org/10.1007/978-3-540-69248-5_12
Malysz J, Anderson DJ, Grønlien JH et al (2010) In vitro pharmacological characterization of a novel selective alpha 7 neuronal nicotinic acetylcholine receptor agonist ABT-107. J Pharmacol Exp Ther 334:863–874. https://doi.org/10.1124/jpet.110.167072
Markou A, Paterson NE (2001) The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res 3:361–373. https://doi.org/10.1080/14622200110073380
de Moura FB, McMahon LR (2017) The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice. Psychopharmacology 234:781–792. https://doi.org/10.1007/s00213-016-4514-4
Nomikos GG, Hildebrand BE, Panagis G, Svensson TH (1999) Nicotine withdrawal in the rat: role of alpha7 nicotinic receptors in the ventral tegmental area. Neuroreport 10:697–702
Papke RL, Trocme-Thibierge C, Guendisch D, al Rubaiy SAA, Bloom SA (2011) Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists. J Pharmacol Exp Ther 337:367–379. https://doi.org/10.1124/jpet.110.177485
Papke RL, Bagdas D, Kulkarni AR, Gould T, AlSharari SD, Thakur GA, Damaj MI (2015) The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. Neuropharmacology 91:34–42. https://doi.org/10.1016/j.neuropharm.2014.12.002
Papke RL, Stokes C, Damaj MI, Thakur GA, Manther K, Treinin M, Bagdas D, Kulkarni AR, Horenstein NA (2017) Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states. Br J Pharmacol. https://doi.org/10.1111/bph.13851
Paulo J, Brucker W, Hawrot E (2009) Proteomic analysis of an α7 nicotinic acetylcholine receptor interactome. J Proteome Res 8:1849–1858. https://doi.org/10.1021/pr800731z.Proteomic
Salas R, Pieri F, De Biasi M (2004) Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci 24:10035–10039. https://doi.org/10.1523/JNEUROSCI.1939-04.2004
Salas R, Main A, Gangitano D, De Biasi M (2007) Decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit. Neuropharmacology 53:863–869. https://doi.org/10.1016/j.neuropharm.2007.08.017
Séguéla P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW (1993) Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci 13:596–604
Stoker AK, Olivier B, Markou A (2012) Role of α7- and β4-containing nicotinic acetylcholine receptors in the affective and somatic aspects of nicotine withdrawal: studies in knockout mice. Behav Genet 42:423–436. https://doi.org/10.1007/s10519-011-9511-0
Vicens P, Ribes D, Heredia L, Torrente M, Domingo JL (2013) Motor and anxiety effects of PNU-282987, an alpha7 nicotinic receptor agonist, and stress in an animal model of Alzheimer’s disease. Curr Alzheimer Res 10:516–523. https://doi.org/10.2174/15672050113109990130
Williams DK, Wang J, Papke RL (2011a) Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations. Biochem Pharmacol 82:915–930. https://doi.org/10.1016/j.bcp.2011.05.001
Williams DK, Wang J, Papke RL (2011b) Investigation of the molecular mechanism of the alpha 7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states. Mol Pharmacol 80:1013–1032. https://doi.org/10.1124/mol.111.074302.sitized
Williams DK, Peng C, Kimbrell MR, Papke RL (2012) Intrinsically low open probability of α7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures. Mol Pharmacol 82:746–759. https://doi.org/10.1124/mol.112.080317
Yohn NL, Turner JR, Blendy JA (2014) Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors. J Pharmacol Exp Ther 349:348–354. https://doi.org/10.1124/jpet.113.211706
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Experiments were performed during the light cycle and were approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.
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Jackson, A., Papke, R.L. & Damaj, M.I. Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal. Psychopharmacology 235, 1897–1905 (2018). https://doi.org/10.1007/s00213-018-4879-7
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DOI: https://doi.org/10.1007/s00213-018-4879-7