Abstract
Rationale
Nicotine is the main addictive component of tobacco and modifies brain function via its action on neuronal acetylcholine nicotinic receptors (nAChRs). The mesolimbic dopamine (DA) system, where neurons of the ventral tegmental area (VTA) project to the nucleus accumbens (ACb), is considered a core site for the processing of nicotine’s reinforcing properties. However, the precise subtypes of nAChRs that mediate the rewarding properties of nicotine and that contribute to the development of addiction remain to be identified.
Objectives
We investigated the role of the nAChRs containing the α7 nicotinic subunit (α7*nAChRs) in the reinforcing properties of nicotine within the VTA and in the nicotine-induced changes in ACb DA outflow in vivo.
Methods
We performed intra-VTA self-administration and microdialysis experiments in genetically modified mice lacking the α7 nicotinic subunit or after pharmacological blockade of α7*nAChRs in wild-type mice.
Results
We show that the reinforcing properties of nicotine within the VTA are lower in the absence or after pharmacological blockade of α7*nAChRs. We also report that nicotine-induced increases in ACb DA extracellular levels last longer in the absence of these receptors, suggesting that α7*nAChRs regulate the action of nicotine on DA levels over time.
Conclusions
The present results reveal new insights for the role of α7*nAChRs in modulating the action of nicotine within the mesolimbic circuit. These receptors appear to potentiate the reinforcing action of nicotine administered into the VTA while regulating its action over time on DA outflow in the ACb.
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References
Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ (2009) Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res 199:89–102
Belluardo N, Mudò G, Blum M, Fuxe K (2000) Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res 113:21–34
Benwell ME, Balfour DJ, Birrell CE (1995) Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine. Br J Pharmacol 114:454–460
Bespalov A, Lebedev A, Panchenko G, Zvartau E (1999) Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur Neuropsychopharmacology 9:377–383
Besson M, David V, Suarez S, Cormier A, Cazala P, Changeux JP, Granon S (2006) Genetic dissociation of two behaviors associated with nicotine addiction: beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome. Psychopharmacology (Berl) 187:189–199
Besson M, Granon S, Mameli-Engvall M, Cloëz-Tayarani I, Maubourguet N, Cormier A, Cazala P, David V, Changeux JP, Faure P (2007) Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc Natl Acad Sci U S A 104:8155–8160
Bilkei-Gorzo A, Rácz I, Michel K, Darvas M, Maldonado R, Zimmer A (2008) A common genetic predisposition to stress sensitivity and stress-induced nicotine craving. Biol Psychiatry 63:164–171
Brody AL, Mandelkern MA, London ED et al (2006) Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arch Gen Psychiatry 63:907–915
Brown RW, Kolb B (2001) Nicotine sensitization increases dendritic length and spine density in the nucleus accumbens and cingulate cortex. Brain Res 899:94–100
Carr KD (2002) Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms. Physiol Behav 76:353–364
Champtiaux N, Gotti C, Cordero-Erausquin M, David DJ, Przybylski C, Léna C, Clementi F, Moretti M, Rossi FM, Le Novère N, McIntosh JM, Gardier AM, Changeux JP (2003) Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. J Neurosci 23:7820–7829
Changeux JP (2010) Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci 11:389–401
Changeux JP, Edelstein SJ (2005) Allosteric mechanisms of signal transduction. Science 308:1424–1428
Chistyakov V, Patkina N, Tammimäki A, Talka R, Salminen O, Belozertseva I, Galankin T, Tuominen R, Zvartau E (2010) Nicotine exposure throughout early development promotes nicotine self-administration in adolescent mice and induces long-lasting behavioural changes. Eur J Pharmacol 640:87–93
Contet C, Whisler KN, Jarrell H, Kenny PJ, Markou A (2010) Patterns of responding differentiate intravenous nicotine self-administration from responding for a visual stimulus in C57BL/6 J mice. Psychopharmacology 212:283–299
Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284
David V, Besson M, Changeux JP, Granon S, Cazala P (2006) Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: dependence on cholinergic nicotinic and dopaminergic D1 receptors. Neuropharmacology 50:1030–1040
Di Chiara G (2000) Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393:295–314
Gäddnäs H, Piepponen TP, Ahtee L (2002) Mecamylamine decreases accumbal dopamine output in mice treated chronically with nicotine. Neurosci Lett 330:219–222
Galeote L, Berrendero F, Bura SA, Zimmer A, Maldonado R (2009) Prodynorphin gene disruption increases the sensitivity to nicotine self-administration in mice. Int J Neuropsychopharmacol 12:615–625
Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 27:482–491
Grabus SD, Martin BR, Brown SE, Damaj MI (2006) Nicotine place preference in the mouse: influences of prior handling, dose and strain and attenuation by nicotinic receptor antagonists. Psychopharmacology (Berl) 184:456–463
Grenhoff J, Svensson TH (1988) Selective stimulation of limbic dopamine activity by nicotine. Acta Physiol Scand 133:595–596
Grenhoff J, Aston-Jones G, Svensson TH (1986) Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol Scand 128:351–358
Grottick AJ, Trube G, Corrigall WA, Huwyler J, Malherbe P, Wyler R, Higgins GA (2000) Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine. J Pharmacol Exp Ther 294:1112–1119
Hemby SE, Co C, Koves TR, Smith JE, Dworkin SI (1997) Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat. Psychopharmacology 133:7–16
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
Ikemoto S, Qin M, Liu ZH (2006) Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci 18:723–730
Imperato A, Mulas A, Di Chiara G (1986) Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur J Pharmacol 132:337–338
Jones IW, Wonnacott S (2004) Precise localization of alpha7 nicotinic acetylcholine receptors on glutamatergic axon terminals in the rat ventral tegmental area. J Neurosci 24:11244–11252
Kenny PJ, Markou A (2006) Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31:1203–1211
Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 21:1452–1463
Koob GF (2006) The neurobiology of addiction: a neuroadaptational view relevant for diagnosis. Addiction 101:23–30
Koob G, Volkow N (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35 :217–238.
Laviolette SR, van der Kooy D (2003a) Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol Psychiatry 8:50–59
Laviolette SR, van der Kooy D (2003b) The motivational valence of nicotine in the rat ventral tegmental area is switched from rewarding to aversive following blockade of the alpha7-subunit-containing nicotinic acetylcholine receptor. Psychopharmacology (Berl) 166:306–313
Laviolette SR, van der Kooy D (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5:55–65
Malagié I, Trillat AC, Bourin M, Jacquot C, Hen R, Gardier AM (2001) 5-HT1B Autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex. J Neurochem 76:865–871
Mameli-Engvall M, Evrard A, Pons S, Maskos U, Svensson TH, Changeux JP, Faure P (2006) Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron 50:911–921
Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33:905–919
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
Marubio LM, Gardier AM, Durier S, David D, Klink R, Arroyo-Jimenez MM, McIntosh JM, Rossi F, Champtiaux N, Zoli M, Changeux JP (2003) Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur J Neurosci 17:1329–1337
Maskos U, Molles BE, Pons S et al (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436:103–107
Mason PA, Milner PM, Miousse R (1985) Preference paradigm: provides better self-stimulation reward discrimination than a rate-dependent paradigm. Behav Neural Biol 44:521–529
Metaxas A, Bailey A, Barbano MF, Galeote L, Maldonado R, Kitchen I (2010) Differential region-specific regulation of α4β2* nAChRs by self-administered and non-contingent nicotine in C57BL/6 J mice. Addict Biol 15:464–479
Mogg AJ, Whiteaker P, McIntosh JM, Marks M, Collins AC, Wonnacott S (2002) Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. J Pharmacol Exp Ther 302:197–204
Nisell M, Nomikos GG, Svensson TH (1994) Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16:36–44
Oades RD, Halliday GM (1987) Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res 434:117–165
Orr-Urtreger A, Göldner FM, Saeki M, Lorenzo I, Goldberg L, De Biasi M, Dani JA, Patrick JW, Beaudet AL (1997) Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci 17:9165–9171
Panagis G, Kastellakis A, Spyraki C, Nomikos G (2000) Effects of methyllycaconitine (MLA), an alpha 7 nicotinic receptor antagonist, on nicotine- and cocaine-induced potentiation of brain stimulation reward. Psychopharmacology (Berl) 149:388–396
Paxinos G, Franklin KB (2004) The mouse brain in stereotaxic coordinates. Academic/Elsevier Science, San Diego
Peto R, Lopez AD, Boreham J, Thun M, Heath C Jr, Doll R (1996) Mortality from smoking worldwide. Br Med Bull 52:12–21
Picciotto MR, Zoli M, Lena C, Bessis A, Lallemand Y, Le Novere N, Vincent P, Pich EM, Brulet P, Changeux JP (1995) Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374:65–67
Picciotto MR, Zoli M, Rimondini R, Léna C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177
Pich EM, Pagliusi SR, Tessari M, Talabot-Ayer D, Hooft van Huijsduijnen R, Chiamulera C (1997) Common neural substrates for the addictive properties of nicotine and cocaine. Science 275:83–86
Pidoplichko VI, DeBiasi M, Williams JT, Dani JA (1997) Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401–404
Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effects of drugs of abuse? Neurosci Biobehav Rev 30:215–238
Plaza-Zabala A, Martín-García E, de Lecea L, Maldonado R, Berrendero F (2010) Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 30:2300–2310
Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM, Changeux JP, Maskos U, Fratta W (2008) Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28:12318–12327
Quarta D, Naylor CG, Barik J, Fernandes C, Wonnacott S, Stolerman IP (2009) Drug discrimination and neurochemical studies in alpha7 null mutant mice: tests for the role of nicotinic alpha7 receptors in dopamine release. Psychopharmacology (Berl) 203:399–410
Rada P, Jensen K, Hoebel BG (2001) Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens. Psychopharmacology (Berl) 157:105–110
Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, Garg S, Garg PK (2010) Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11 C-nicotine. Proc Natl Acad Sci U S A 107:5190–5195
Schilström B, Fagerquist MV, Zhang X, Hertel P, Panagis G, Nomikos GG, Svensson TH (2000) Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38:375–383
Sellings LH, Baharnouri G, McQuade LE, Clarke PB (2008) Rewarding and aversive effects of nicotine are segregated within the nucleus accumbens. Eur J Neurosci 28:342–352
Shim I, Javaid JI, Wirtshafter D, Jang SY, Shin KH, Lee HJ, Chung YC, Chun BG (2001) Nicotine-induced behavioral sensitization is associated with extracellular dopamine release and expression of c-Fos in the striatum and nucleus accumbens of the rat. Behav Brain Res 121:137–147
Stefanski R, Ladenheim B, Lee SH, Cadet JL, Goldberg SR (1999) Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur J Pharmacol 371:123–135
Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berl) 117:2–10
Suarez SV, Amadon A, Giacomini E, Wiklund A, Changeux JP, Le Bihan D, Granon S (2009) Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study. Psychopharmacology (Berl) 202:599–610
Visanji NP, Mitchell SN, O'Neill MJ, Duty S (2006) Chronic pre-treatment with nicotine enhances nicotine-evoked striatal dopamine release and alpha6 and beta3 nicotinic acetylcholine receptor subunit mRNA in the substantia nigra pars compacta of the rat. Neuropharmacology 50:36–46
Walters CL, Brown S, Changeux JP, Martin B, Damaj MI (2006) The beta2 but not alpha7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice. Psychopharmacology (Berl) 184:339–344
Wonnacott S, Sidhpura N, Balfour DJ (2005) Nicotine: from molecular mechanisms to behaviour. Curr Opin Pharmacol 5:53–59
Zhou FM, Wilson CJ, Dani JA (2002) Cholinergic interneuron characteristics and nicotinic properties in the striatum. J Neurobiol 53:590–605
Acknowledgements
This work was supported by Institut Pasteur and Centre National de la Recherche Scientifique. MB was supported by Fondation pour la Recherche Médicale. The authors would like to thank Uwe Maskos, Philippe Faure and David Belin for valuable discussion. The authors would like to thank Ruth McNamara for the correction of English.
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M. Besson and V. David equally contributed to the work.
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Besson, M., David, V., Baudonnat, M. et al. Alpha7-nicotinic receptors modulate nicotine-induced reinforcement and extracellular dopamine outflow in the mesolimbic system in mice. Psychopharmacology 220, 1–14 (2012). https://doi.org/10.1007/s00213-011-2422-1
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DOI: https://doi.org/10.1007/s00213-011-2422-1