Abstract
Rationale
Recent studies have revealed the participation of the endogenous opioid system in several behavioural responses induced by nicotine including antinociception, rewarding properties, and physical drug dependence.
Objectives
The present study was designed to examine the possible involvement of the various opioid receptors in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice.
Methods
The acute administration of low (0.05) or high (0.8 mg/kg) doses of nicotine subcutaneously produced opposite effects in the elevated plus maze, i.e. anxiolytic- and anxiogenic-like responses, respectively. Animals were only exposed once to nicotine. The effects of the pretreatment with the μ-opioid receptor antagonist, β-funaltrexamine (5 mg/kg), the δ-opioid antagonist, naltrindole (2.5 mg/kg) and the κ-opioid antagonist, nor-binaltorphimine (2.5 mg/kg) intraperitoneally were evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine.
Results
β-funaltrexamine, but not nor-binaltorphimine or naltrindole, abolished nicotine-induced anxiolytic-like effects, suggesting an involvement of μ-opioid receptors in this behavioural response. On the other hand, naltrindole, but not nor-binaltorphimine or β-funaltrexamine, increased the anxiogenic-like responses of nicotine, suggesting an involvement of δ-receptors in this behavioural effect.
Conclusions
These results demonstrate that the endogenous opioid system is involved in the effects induced by nicotine on anxiety-like behaviour and provide new findings to further clarify the interaction between these two neurochemical systems.
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References
Balfour DJ (1982) The effects of nicotine on brain neurotransmitter systems. Pharmacol Ther 16:269–282
Berrendero F, Maldonado R (2002) Involvement of the opioid system in the anxiolytic-like effects induced by Delta(9)-tetrahydrocannabinol. Psychopharmacology 163:111–117
Berrendero F, Kieffer BL, Maldonado R (2002) Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor knock-out mice. J Neurosci 22:10935–10940
Berrendero F, Mendizabal V, Robledo P, Galeote L, Bilkei-Gorzo A, Zimmer A, Maldonado R (2005) Nicotine-induced antinociception, rewarding effects and physical dependence are decreased in mice lacking the pre–proenkephalin gene. J Neurosci 25:1103–1112
Brazell MP, Mitchell SN, Gray JA (1991) Effect of acute administration of nicotine on in vivo release of noradrenaline in the hippocampus of freely moving rats: a dose–response and antagonist study. Neuropharmacology 30:823–833
Bremner JD, Krystal JH, Southwick SM, Charney DS (1996) Noradrenergic mechanisms in stress and anxiety. I. Preclinical studies. Synapse 23:28–38
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
Brioni JD, O’Neill AB, Kim DJ, Buckley MJ, Decker MW, Arneric SP (1994) Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. Pharmacol Exp Ther 271:353–361
Cao W, Burkholder T, Wilkins L, Collins AC (1993) A genetic comparison of behavioral actions of ethanol and nicotine in the mirrored chamber. Pharmacol Biochem Behav 45:803–809
Cheeta S, Irvine EE, File SE (2000a) The dorsal raphe nucleus is involved in nicotine tolerance and withdrawal responses in the social interaction test. J Psychopharmacol 14:A75
Cheeta S, Kenny PJ, File SE (2000b) Hippocampal and septal injections of nicotine and 8-OH-DPAT distinguish among different animal tests of anxiety. Prog Neuropsychopharmacol Biol Psychiatry 24:1053–1067
Cheeta S, Irvine E, File SE (2001) Social isolation modifies nicotine’s effects in animal tests of anxiety. Br J Pharmacol 132:1389–1395
Corrigall WA, Coen KM (1991) Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology 104:171–176
Costall B, Kelly ME, Naylor RJ, Onaivi ES (1989) The actions of nicotine and cocaine in a mouse model of anxiety. Pharmacol Biochem Behav 33:197–203
Dani JA (2001) Overview of nicotinic receptors and their roles in the central nervous system. Biol Psychiatry 49:166–174
Decker MW, Meyer MD (1999) Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics. Biochem Pharmacol 58:917–923
Decker MW, Brioni JD, Bannon AW, Arneric SP (1995) Diversity of neuronal nicotinic acetylcholine receptors: lessons from behavior and implications for CNS therapeutics. Life Sci 56:545–570
Dhatt RK, Gudehithlu KP, Wemlinger TA, Tejwani GA, Neff NH, Hadjiconstantinou M (1995) Preproenkephalin mRNA and methionine-enkephalin content are increased in mouse striatum after treatment with nicotine. J Neurochem 64:1878–1883
Endoh T, Matsuura H, Tanaka C, Nagase H (1992) Nor-binaltorphimine: a potent and selective kappa-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn Ther 316:30–42
File SE (1992) Behavioural detection of anxiolytic action. In: Elliot JM, Heal DJ, Marsden CA (eds) Experimental approaches to anxiety and depression. Wiley, London, pp 25–44
File SE, Kenny PJ, Ouagazzal AM (1998) Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus. Behav Neurosci 112:1423–1429
File SE, Cheeta S, Kenny PJ, Ouagazzal A-M (1999) Roles of the dorsal raphe nucleus, lateral septum and dorsal hippocampus in nicotine’s effects on anxiety. Soc Neurosci Abstr 24:1981
File SE, Kenny PJ, Cheeta S (2000) The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety. Pharmacol Biochem Behav 66:65–72
Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gaveriaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kieffer BL (2000) Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25:195–200
Fu Y, Matta SG, James TJ, Sharp BM (1998) Nicotine-induced norepinephrine release in the rat amygdala and hippocampus is mediated through brainstem nicotinic cholinergic receptors. J Pharmacol Exp Ther 284:1188–1196
Gilbert DG, Robinson JH, Chamberlin CL, Spielberger CD (1989) Effects of smoking/nicotine on anxiety, heart rate, and lateralization of EEG during a stressful movie. Psychophysiology 26:311–320
Gray JA, Mitchell SN, Joseph MH, Grogoryan G, Daws S, Hodges H (1994) Neurochemical mechanisms mediating the behavioural and cognitive effects of nicotine. Drug Dev Res 31:3–17
Guimaraes S, Carobrez PP, De Aguiar JC, Graeff FG (1991) Anxiolytic effect in the elevated plus-maze of the NMDA receptor antagonist AP7 microinjected into the dorsal periaqueductal grey. Psychopharmacology 103:91–94
Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary–adrenocortical axis. Trends Neurosci 20:78–84
Hildebrand BE, Panagis G, Svensson TH, Nomikos GG (1999) Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area. Neuropsychopharmacology 21:560–574
Houdi AA, Pierzchala K, Marson L, Palkovits M, Van Loon GR (1991) Nicotine-induced alteration in Tyr–Gly–Gly and Met-enkephalin in discrete brain nuclei reflects altered enkephalin neuron activity. Peptides 12:161–166
Jackson HC, Ripley TL, Nutt DJ (1989) Exploring delta-receptor function using the selective opioid antagonist naltrindole. Neuropharmacology 28:1427–1430
Jessa M, Nazar M, Plaznik A (1995) Anxiolytic-like action of intra-hippocampally administered NMDA antagonists in rats. Pol J Pharmacol 47:81–84
Karras A, Kane JM (1980) Naloxone reduces cigarette smoking. Life Sci 27:1541–1545
Kenny PJ, Cheeta S, File SE (2000) Anxiogenic effects of nicotine in the dorsal hippocampus are mediated by 5-HT1A and not by muscarinic M1 receptors. Neuropharmacology 39:300–307
König M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, Brownstein MJ, Zimmer A (1996) Pain responses, anxiety and aggression in mice deficient in pre–proenkephalin. Nature 383:535–538
Mansour A, Fox CA, Akil H, Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18:22–29
Mathieu-Kia AM, Kellogg SH, Butelman ER, Kreek MJ (2002) Nicotine addiction: insights from recent animal studies. Psychopharmacology 162:102–118
Newman MB, Manresa JJ, Sanberg PR, Shytle RD (2002) Anxiolytic effects of mecamylamine in two animal models of anxiety. Exp Clin Psychopharmacol 10:18–25
Okuda H, Shioda S, Nakai Y, Nakayama H, Okamoto M, Nakashima T (1993) The presence of corticotropin-releasing factor-like immunoreactive synaptic vesicles in axon terminals with nicotinic acetylcholine receptor-like immunoreactivity in the median eminence of the rat. Neurosci Lett 161:183–186
Olausson P, Akesson P, Engel JA, Soderpalm B (2001) Effects of 5-HT1A and 5-HT2 receptor agonists on the behavioral and neurochemical consequences of repeated nicotine treatment. Eur J Pharmacol 420:45–54
Onaka T, Palmer JR, Yagi K (1996) Norepinephrine depletion impairs neuroendocrine responses to fear but not novel environmental stimuli in the rat. Brain Res 713:261–268
Ouagazzal AM, Kenny PJ, File SE (1999a) Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine. Psychopharmacology 144:54–60
Ouagazzal AM, Kenny PJ, File SE (1999b) Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety. Eur J Neurosci 11:3957–3962
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Pierzchala K, Houdi AA, Van Loon GR (1987) Nicotine-induced alterations in brain regional concentrations of native and cryptic Met- and Leu-enkephalin. Peptides 8:1035–1043
Pomerleau OF (1986) Nicotine as a psychoactive drug: anxiety and pain reduction. Psychopharmacol Bull 22:865–869
Pomerleau OF, Fertig JB, Seyler LE, Jaffe J (1983) Neuroendocrine reactivity to nicotine in smokers. Psychopharmacology 81:61–67
Portoghese PS, Sultana M, Takemori AE (1988) Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist. Eur J Pharmacol 146:185–186
Seth P, Cheeta S, Tucci S, File SE (2002) Nicotinic–serotonergic interactions in brain and behaviour. Pharmacol Biochem Behav 71:795–805
Sharp BM, Matta SG (1993) Detection by in vivo microdialysis of nicotine-induced norepinephrine secretion from the hypothalamic paraventricular nucleus of freely moving rats: dose-dependency and desensitization. Endocrinology 133:11–19
Thompson RC, Mansour A, Akil H, Watson SJ (1993) Cloning and pharmacological characterization of a rat mu opioid receptor. Neuron 11:903–913
Toth E, Sershen H, Hashim A, Vizi ES, Lajtha A (1992) Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid. Neurochem Res 17:265–271
Tsuda M, Suzuki T, Misawa M, Nagase H (1996) Involvement of the opioid system in the anxiolytic effect of diazepam in mice. Eur J Pharmacol 307:7–14
Vale AL, Green S (1986) Effects of chlordiazepoxide, nicotine and d-amphetamine in the rat potentiated startle model of anxiety. Behav Pharmacol 7:138–143
Ward SJ, Portoghese PS, Takemori AE (1982) Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine. J Pharmacol Exp Ther 220:494–498
Ward SJ, Fries DS, Larson DL, Portoghese PS, Takemori AE (1985) Opioid receptor binding characteristics of the non-equilibrium mu antagonist, beta-funaltrexamine (beta-FNA). Eur J Pharmacol 107:323–330
Watkins SS, Stinus L, Koob GF, Markou A (2000) Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J Pharmacol Exp Ther 292:1053–1064
Wewers ME, Dhatt R, Tejwani GA (1998) Naltrexone administration affects ad libitum smoking behavior. Psychopharmacology 140:185–190
Acknowledgements
This work has been supported by grants from National Institutes of Health (1R01-DA016768-0111), Human Frontier Science Program Organisation (RG0077/2000-B), Marató TV3, Redes de Centros y Grupos del Instituto de Salud Carlos III (C03/06 and G03/005), Generalitat de Catalunya (Research Distinction and 2002 SGR00193), and the European Commission (Quality of Life and Management of Living Resources QLRT-2001-01691). Graciela Balerio is a postdoctoral fellow supported by “Fundación Carolina”. We thank the helpful assistance of Ms. Kaja Beate Nyquist and Ms. Núria Gresa.
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Balerio, G.N., Aso, E. & Maldonado, R. Involvement of the opioid system in the effects induced by nicotine on anxiety-like behaviour in mice. Psychopharmacology 181, 260–269 (2005). https://doi.org/10.1007/s00213-005-2238-y
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DOI: https://doi.org/10.1007/s00213-005-2238-y