Abstract
β2 subunit containing nicotinic acetylcholine receptors (β2*nAChRs; asterisk (*) denotes assembly with other subunits) are critical for nicotine self-administration and nicotine-associated dopamine (DA) release that supports nicotine reinforcement. The α6 subunit assembles with β2 on DA neurons where α6β2*nAChRs regulate nicotine-stimulated DA release at neuron terminals. Using local infusion of α-conotoxin MII (α-CTX MII), an antagonist with selectivity for α6β2*nAChRs, the purpose of these experiments was to determine if α6β2*nAChRs in the nucleus accumbens (NAc) shell are required for motivation to self-administer nicotine. Long-Evans rats lever-pressed for 0.03 mg/kg, i.v., nicotine accompanied by light+tone cues (NIC) or for light+tone cues unaccompanied by nicotine (CUEonly). Following extensive training, animals were tested under a progressive ratio (PR) schedule that required an increasing number of lever presses for each nicotine infusion and/or cue delivery. Immediately before each PR session, rats received microinfusions of α-CTX MII (0, 1, 5, or 10 pmol per side) into the NAc shell or the overlying anterior cingulate cortex. α-CTX MII dose dependently decreased break points and number of infusions earned by NIC rats following infusion into the NAc shell but not the anterior cingulate cortex. Concentrations of α-CTX MII that were capable of attenuating nicotine self-administration did not disrupt locomotor activity. There was no effect of infusion on lever pressing in CUEonly animals and NAc infusion α-CTX MII did not affect locomotor activity in an open field. These data suggest that α6β2*nAChRs in the NAc shell regulate motivational aspects of nicotine reinforcement but not nicotine-associated locomotor activation.
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References
Arnold JM, Roberts DC (1997). A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57: 441–447.
Boye SM, Grant RJ, Clarke PB (2001). Disruption of dopaminergic neurotransmission in nucleus accumbens core inhibits the locomotor stimulant effects of nicotine and D-amphetamine in rats. Neuropharmacology 40: 792–805.
Brunzell DH, Chang JR, Schneider B, Olausson P, Taylor JR, Picciotto MR (2006). beta2-Subunit-containing nicotinic acetylcholine receptors are involved in nicotine-induced increases in conditioned reinforcement but not progressive ratio responding for food in C57BL/6 mice. Psychopharmacology (Berl) 184: 328–338.
Brunzell DH, Picciotto MR (2009). Molecular mechanisms underlying the motivational effects of nicotine. Nebr Symp Motiv 55: 17–30.
Cadoni C, Di Chiara G (2000). Differential changes in accumbens shell and core dopamine in behavioral sensitization to nicotine. Eur J Pharmacol 387: R23–R25.
Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF (2002). Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77: 683–687.
Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA et al (2001). Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav 70: 515–530.
Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM (1996). A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem 271: 7522–7528.
Champtiaux N, Gotti C, Cordero-Erausquin M, David DJ, Przybylski C, Lena C et al (2003). Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. J Neurosci 23: 7820–7829.
Champtiaux N, Han ZY, Bessis A, Rossi FM, Zoli M, Marubio L et al (2002). Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J Neurosci 22: 1208–1217.
Christian MS, Hoberman AM, Johnson MD, Brown WR, Bucci TJ (1998). Effect of dietary optimization on growth, survival, tumor incidences and clinical pathology parameters in CD Sprague–Dawley and Fischer-344 rats: a 104-week study. Drug Chem Toxicol 21: 97–117.
Cohen C, Perrault G, Griebel G, Soubrie P (2005). Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 30: 145–155.
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.
Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992). The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107: 285–289.
Cui C, Booker TK, Allen RS, Grady SR, Whiteaker P, Marks MJ et al (2003). The beta3 nicotinic receptor subunit: a component of alpha-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. J Neurosci 23: 11045–11053.
Donny EC, Caggiula AR, Rowell PP, Gharib MA, Maldovan V, Booth S et al (2000). Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology (Berl) 151: 392–405.
Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA et al (2003). Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology (Berl) 169: 68–76.
Donny EC, Houtsmuller E, Stitzer ML (2007). Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days. Addiction 102: 324–334.
Drenan RM, Grady SR, Whiteaker P, McClure-Begley T, McKinney S, Miwa JM et al (2008). In vivo activation of midbrain dopamine neurons via sensitized, high-affinity alpha 6 nicotinic acetylcholine receptors. Neuron 60: 123–136.
Due DL, Huettel SA, Hall WG, Rubin DC (2002). Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging. Am J Psychiatry 159: 954–960.
Dwoskin LP, Wooters TE, Sumithran SP, Siripurapu KB, Joyce BM, Lockman PR et al (2008). N,N′-Alkane-diyl-bis-3-picoliniums as nicotinic receptor antagonists: inhibition of nicotine-evoked dopamine release and hyperactivity. J Pharmacol Exp Ther 326: 563–576.
Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ (2008). Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology 33: 2158–2166.
Exley R, Cragg SJ (2008). Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission. Br J Pharmacol 153 (Suppl 1): S283–S297.
Ferrari R, Le Novere N, Picciotto MR, Changeux JP, Zoli M (2002). Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur J Neurosci 15: 1810–1818.
Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB et al (2006). Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296: 47–55.
Grady SR, Murphy KL, Cao J, Marks MJ, McIntosh JM, Collins AC (2002). Characterization of nicotinic agonist-induced [(3)H]dopamine release from synaptosomes prepared from four mouse brain regions. J Pharmacol Exp Ther 301: 651–660.
Grady SR, Salminen O, Laverty DC, Whiteaker P, McIntosh JM, Collins AC et al (2007). The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem Pharmacol 74: 1235–1246.
Iyaniwura TT, Wright AE, Balfour DJ (2001). Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain. Psychopharmacology (Berl) 158: 73–79.
Kelsey JE, Gerety LP, Guerriero RM (2009). Electrolytic lesions of the nucleus accumbens core (but not the medial shell) and the basolateral amygdala enhance context-specific locomotor sensitization to nicotine in rats. Behav Neurosci 123: 577–588.
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.
Kulak JM, Nguyen TA, Olivera BM, McIntosh JM (1997). Alpha-conotoxin MII blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J Neurosci 17: 5263–5270.
Kuryatov A, Olale F, Cooper J, Choi C, Lindstrom J (2000). Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology 39: 2570–2590.
Kuzmin A, Jerlhag E, Liljequist S, Engel J (2009). Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior. Psychopharmacology (Berl) 203: 99–108.
Le Novere N, Zoli M, Changeux JP (1996). Neuronal nicotinic receptor alpha 6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. Eur J Neurosci 8: 2428–2439.
le Novere N, Zoli M, Lena C, Ferrari R, Picciotto MR, Merlo-Pich E et al (1999). Involvement of alpha6 nicotinic receptor subunit in nicotine-elicited locomotion, demonstrated by in vivo antisense oligonucleotide infusion. NeuroReport 10: 2497–2501.
Levin ED, McClernon FJ, Rezvani AH (2006). Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184: 523–539.
Lof E, Olausson P, deBejczy A, Stomberg R, McIntosh JM, Taylor JR et al (2007). Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology (Berl) 195: 333–343.
Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP et al (2005). Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436: 103–107.
McIntosh JM, Azam L, Staheli S, Dowell C, Lindstrom J, Kuryatov A et al (2004). Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol 65: 944–952.
Mineur YS, Brunzell DH, Grady SR, Lindstrom JM, McIntosh JM, Marks MJ et al (2009). Localized low-level re-expression of high-affinity mesolimbic nicotinic acetylcholine receptors restores nicotine-induced locomotion but not place conditioning. Genes Brain Behav 8: 257–266.
Olsen CM, Winder DG (2009). Operant sensation seeking engages similar neural substrates to operant drug seeking in C57 mice. Neuropsychopharmacology 34: 1685–1694.
Perez XA, Bordia T, McIntosh JM, Grady SR, Quik M (2008). Long-term nicotine treatment differentially regulates striatal alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR expression and function. Mol Pharmacol 74: 844–853.
Perez XA, O'Leary KT, Parameswaran N, McIntosh JM, Quik M (2009). Prominent role of alpha3/alpha6beta2*nAChRs in regulating evoked dopamine release in primate putamen: effect of long-term nicotine treatment. Mol Pharmacol 75: 938–946.
Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM et al (1998). Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391: 173–177.
Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM et al (2008). Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28: 12318–12327.
Rice ME, Cragg SJ (2004). Nicotine amplifies reward-related dopamine signals in striatum. Nat Neurosci 7: 583–584.
Robinson TE, Berridge KC (2003). Addiction. Annu Rev Psychol 54: 25–53.
Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA et al (2007). Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52: 985–994.
Salminen O, Drapeau JA, McIntosh JM, Collins AC, Marks MJ, Grady SR (2007). Pharmacology of alpha-conotoxin MII-sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Mol Pharmacol 71: 1563–1571.
Salminen O, Murphy KL, McIntosh JM, Drago J, Marks MJ, Collins AC et al (2004). Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol Pharmacol 65: 1526–1535.
Salminen O, Whiteaker P, Grady SR, Collins AC, McIntosh JM, Marks MJ (2005). The subunit composition and pharmacology of alpha-conotoxin MII-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay. Neuropharmacology 48: 696–705.
Schroeder BE, Binzak JM, Kelley AE (2001). A common profile of prefrontal cortical activation following exposure to nicotine- or chocolate-associated contextual cues. Neuroscience 105: 535–545.
Stein EA, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, Hoffmann RG et al (1998). Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 155: 1009–1015.
Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C et al (2004). Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science 306: 1029–1032.
Tiffany ST, Carter BL (1998). Is craving the source of compulsive drug use? J Psychopharmacol 12: 23–30.
Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007). Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol 64: 1575–1579.
Whiteaker P, Peterson CG, Xu W, McIntosh JM, Paylor R, Beaudet AL et al (2002). Involvement of the alpha3 subunit in central nicotinic binding populations. J Neurosci 22: 2522–2529.
WHO (2008). MPOWER: A policy package to reverse the tobacco epidemic. WHO Perss, World Health Organization: Geneva, Switzerland.
Zhang H, Sulzer D (2004). Frequency-dependent modulation of dopamine release by nicotine. Nat Neurosci 7: 581–582.
Acknowledgements
We thank the AH Lichtman laboratory for generously providing us with use of their tracking equipment for the locomotor studies in this manuscript. We also thank Patrick Taylor, Ayn Buttner, Derrick Bullock, and Yun Ding for their technical assistance. This work was supported by NIH grants MH53631 and GM48677 to JM McIntosh and NIH grant DA023114 to DH Brunzell.
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The authors have no financial conflicts of interest with any data or original ideas presented in this paper. DH Brunzell has received financial support from the National Institutes of Health (NIH) for this work. JMM has served as a consultant and received grant funding from Memory Pharmaceuticals, Targacept, Pfizer, Metabolic Inc., the Ben B and Iris M Margolis Foundation, and the University of Utah Research Foundation for other projects.
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Brunzell, D., Boschen, K., Hendrick, E. et al. α-Conotoxin MII-Sensitive Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Shell Regulate Progressive Ratio Responding Maintained by Nicotine. Neuropsychopharmacol 35, 665–673 (2010). https://doi.org/10.1038/npp.2009.171
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DOI: https://doi.org/10.1038/npp.2009.171
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