, Volume 184, Issue 3–4, pp 435–446 | Cite as

Preferential increase of extracellular dopamine in the rat nucleus accumbens shell as compared to that in the core during acquisition and maintenance of intravenous nicotine self-administration

  • Daniele Lecca
  • Fabio Cacciapaglia
  • Valentina Valentini
  • Janne Gronli
  • Saturnino Spiga
  • Gaetano Di ChiaraEmail author
Original Investigation



It has been reported that passive administration of nicotine increases preferentially extracellular dopamine (DA) release in the shell as compared to that in the core of the nucleus accumbens (NAc). To date, no information is available if this also applies to active, response-contingent nicotine administration.


This study was aimed to monitor the changes of extracellular DA in the NAc shell and core during active intravenous nicotine self-administration (SA).


Rats were bilaterally implanted with chronic cannulae and were trained to self-administer nicotine (0.03 mg/kg, i.v.) in single daily 1-h session for 6 weeks, with an initial fixed ratio (FR) 1 schedule increased to FR 2. Dialysate DA from the NAc shell and core was monitored before and for 90 min after the start of SA.


Significant increases of active nose-pokes over inactive ones were found starting from the 16th SA session. No differences were found in basal extracellular DA in the NAc subdivisions. Data analysis showed (1) significant increases over basal of dialysate DA in the NAc subdivisions during nicotine SA, starting from the first week in the shell and from the second week in the core, (2) preferential increase of extracellular DA during nicotine SA in the shell (24–43%) compared to that in the core (10–23%) and (3) no change in dialysate DA in NAc subdivisions during extinction.


Response-contingent nicotine SA preferentially increases the DA output in the NAc shell as compared to that in the core, independently from the duration of the nicotine exposure. Increase in NAc DA is strictly related to nicotine action since is not observed during extinction in spite of active responding.


Self-administration Microdialysis Nicotine Dopamine Nucleus accumbens shell Nucleus accumbens core 



The authors gratefully acknowledge the supply of the self-administration cages by Dr. Steve Goldberg and Dr. Gianluigi Tanda. This study was supported by funds from Ministero dell’Università e della Ricerca, progetti di Ricerca Nazionale Bando 2003, from the Centre of Excellence for Studies on Dependence and from the European Commission, NIDE project.


  1. Acquas E, Carboni E, Leone P, Di Chiara G (1989) SCH 23390 blocks drug-conditioned place–preference and place–aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade? Psychopharmacology (Berl) 99:151–155CrossRefGoogle Scholar
  2. Alheid GF (2003) Extended amygdala and basal forebrain. Ann N Y Acad Sci 985:185–205PubMedCrossRefGoogle Scholar
  3. Balfour DJ (2002) Neuroplasticity within the mesoaccumbens dopamine system and its role in tobacco dependence. Curr Drug Targets CNS Neurol Disord 1:413–421CrossRefPubMedGoogle Scholar
  4. Balfour DJ, Benwell ME, Birrell CE, Kelly RJ, Al Aloul M (1998) Sensitization of the mesoaccumbens dopamine response to nicotine. Pharmacol Biochem Behav 59:1021–1030CrossRefPubMedGoogle Scholar
  5. Bassareo V, Di Chiara G (1997) Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum. J Neurosci 17:851–861PubMedGoogle Scholar
  6. Bassareo V, Di Chiara G (1999) Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments. Neuroscience 89:637–641CrossRefPubMedGoogle Scholar
  7. Benwell ME, Balfour DJ (1992) The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br J Pharmacol 105:849–856PubMedGoogle Scholar
  8. Brazell MP, Mitchell SN, Joseph MH, Gray JA (1990) Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate–putamen. Neuropharmacology 29:1177–1185CrossRefPubMedGoogle Scholar
  9. Cadoni C, Solinas M, Di Chiara G (2000) Psychostimulant sensitization: differential changes in accumbal shell and core dopamine. Eur J Pharmacol 388:69–76CrossRefPubMedGoogle Scholar
  10. Cadoni C, Solinas M, Valentini V, Di Chiara G (2003) Selective psychostimulant sensitization by food restriction: differential changes in accumbens shell and core dopamine. Eur J Neurosci 18:2326–2334CrossRefPubMedGoogle Scholar
  11. Caine SB, Koob GF (1993) Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260:1814–1816PubMedCrossRefGoogle Scholar
  12. Calabresi P, Lacey MG, North RA (1989) Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording. Br J Pharmacol 98:135–140PubMedGoogle Scholar
  13. Camp DM, Robinson TE (1992) On the use of multiple probe insertions at the same site for repeated intracerebral microdialysis experiments in the nigrostriatal dopamine system of rats. J Neurochem 58:1706–1715PubMedCrossRefGoogle Scholar
  14. Carboni E, Acquas E, Leone P, Perezzani L, Di Chiara G (1988) 5-HT3 receptor antagonists block morphine- and nicotine-induced place–preference conditioning. Eur J Pharmacol 151:159–160CrossRefPubMedGoogle Scholar
  15. Carboni E, Bortone L, Giua C, Di Chiara G (2000) Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats. Drug Alcohol Depend 58:93–102CrossRefPubMedGoogle Scholar
  16. Clarke PB (1990) Mesolimbic dopamine activation—the key to nicotine reinforcement? Ciba Found Symp 152:153–162PubMedGoogle Scholar
  17. Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99:473–478CrossRefGoogle Scholar
  18. Corrigall WA, Coen KM (1991) Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology (Berl) 104:171–176CrossRefGoogle Scholar
  19. Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107:285–289CrossRefGoogle Scholar
  20. Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284CrossRefPubMedGoogle Scholar
  21. Damsma G, Day J, Fibiger HC (1989) Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens. Eur J Pharmacol 168:363–368CrossRefPubMedGoogle Scholar
  22. Dani JA (2003) Roles of dopamine signaling in nicotine addiction. Mol Psychiatry 8:255–256CrossRefPubMedGoogle Scholar
  23. Datla KP, Ahier RG, Young AM, Gray JA, Joseph MH (2002) Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat. Eur J Neurosci 16:1987–1993CrossRefPubMedGoogle Scholar
  24. Deroche V, Marinelli M, Maccari S, Le Moal M, Simon H, Piazza PV (1995) Stress-induced sensitization and glucocorticoids. I. Sensitization of dopamine-dependent locomotor effects of amphetamine and morphine depends on stress-induced corticosterone secretion. J Neurosci 15:7181–7188PubMedGoogle Scholar
  25. Di Chiara G (1998) A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use. J Psychopharmacol 12:54–67PubMedCrossRefGoogle Scholar
  26. Di Chiara G (2000a) Behavioural pharmacology and neurobiology of nicotine reward and dependence. In: Clementi F, Fornasari D, Gotti C (eds) Handbook of experimental pharmacology. Springer, Berlin Heidelberg New York, pp 603–750Google Scholar
  27. Di Chiara G (2000b) Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393:295–314CrossRefPubMedGoogle Scholar
  28. Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114CrossRefPubMedGoogle Scholar
  29. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278PubMedCrossRefGoogle Scholar
  30. Di Chiara G, Tanda G, Carboni E (1996) Estimation of in-vivo neurotransmitter release by brain microdialysis: the issue of validity. Behav Pharmacol 7:640–657PubMedCrossRefGoogle Scholar
  31. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47(Suppl 1):227–241CrossRefPubMedGoogle Scholar
  32. Donny EC, Caggiula AR, Knopf S, Brown C (1995) Nicotine self-administration in rats. Psychopharmacology (Berl) 122:390–394CrossRefGoogle Scholar
  33. Donny EC, Caggiula AR, Mielke MM, Jacobs KS, Rose C, Sved AF (1998) Acquisition of nicotine self-administration in rats: the effects of dose, feeding schedule, and drug contingency. Psychopharmacology (Berl) 136:83–90CrossRefGoogle Scholar
  34. Donny EC, Lanza ST, Balster RL, Collins LM, Caggiula A, Rowell PP (2004) Using growth models to relate acquisition of nicotine self-administration to break point and nicotinic receptor binding. Drug Alcohol Depend 75:23–35CrossRefPubMedGoogle Scholar
  35. Fu Y, Matta SG, Gao W, Brower VG, Sharp BM (2000) Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-d-aspartate receptors in the ventral tegmental area. J Pharmacol Exp Ther 294:458–465PubMedGoogle Scholar
  36. Fumero B, Guadalupe T, Valladares F, Mora F, O’Neill RD, Mas M, Gonzalez-Mora JL (1994) Fixed versus removable microdialysis probes for in vivo neurochemical analysis: implications for behavioral studies. J Neurochem 63:1407–1415PubMedCrossRefGoogle Scholar
  37. Georgieva J, Luthman J, Mohringe B, Magnusson O (1993) Tissue and microdialysate changes after repeated and permanent probe implantation in the striatum of freely moving rats. Brain Res Bull 31:463–470CrossRefPubMedGoogle Scholar
  38. Grenhoff J, Aston-Jones G, Svensson TH (1986) Nicotinic effects on the firing pattern of midbrain dopamine neurons. Acta Physiol Scand 128:351–358PubMedCrossRefGoogle Scholar
  39. Heimer L, Alheid GF, de Olmos JS, Groenewegen HJ, Haber SN, Harlan RE, Zahm DS (1997) The accumbens: beyond the core–shell dichotomy. J Neuropsychiatry Clin Neurosci 9:354–381PubMedGoogle Scholar
  40. Imperato A, Mulas A, Di Chiara G (1986) Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur J Pharmacol 132:337–338CrossRefPubMedGoogle Scholar
  41. Ito R, Dalley JW, Howes SR, Robbins TW, Everitt BJ (2000) Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J Neurosci 20:7489–7495PubMedGoogle Scholar
  42. Mereu G, Yoon KW, Boi V, Gessa GL, Naes L, Westfall TC (1987) Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. Eur J Pharmacol 141:395–399CrossRefPubMedGoogle Scholar
  43. Moore H, Stuckman S, Sarter M, Bruno JP (1995) Stimulation of cortical acetylcholine efflux by FG 7142 measured with repeated microdialysis sampling. Synapse 21:324–331CrossRefPubMedGoogle Scholar
  44. 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 16:36–44CrossRefPubMedGoogle Scholar
  45. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, SydneyGoogle Scholar
  46. Picciotto MR, Corrigall WA (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci 22:3338–3341PubMedGoogle Scholar
  47. Picciotto MR, Caldarone BJ, Brunzell DH, Zachariou V, Stevens TR, King SL (2001) Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications. Pharmacol Ther 92:89–108CrossRefPubMedGoogle Scholar
  48. Pidoplichko VI, Noguchi J, Areola OO, Liang Y, Peterson J, Zhang T, Dani JA (2004) Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn Mem 11:60–69CrossRefPubMedGoogle Scholar
  49. Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci U S A 92:12304–12308PubMedCrossRefGoogle Scholar
  50. Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257CrossRefPubMedGoogle Scholar
  51. Pothos EN, Creese I, Hoebel G (1995) Restricted eating with weight loss selectively decreases extracellular dopamine in the nucleus accumbens and alters dopamine response to amphetamine, morphine and food intake. J Neurosci 15:6640–6650PubMedGoogle Scholar
  52. Rahman S, Zhang J, Engleman EA, Corrigall WA (2004) Neuroadaptive changes in the mesoaccumbens dopamine system after chronic nicotine self-administration: a microdialysis study. Neuroscience 129:415–424CrossRefPubMedGoogle Scholar
  53. Robinson TE, Camp DM (1991) The feasibility of repeated microdialysis for within-subjects design experiments: studies on mesostriatal dopamine system. In: Robins TE, Justice JB (eds) Microdialysis in the neurosciences. Elsevier, Amsterdam, pp 189–234Google Scholar
  54. Shoaib M, Schindler CW, Goldberg SR (1997) Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology (Berl) 129:35–43CrossRefGoogle Scholar
  55. Spina L, Fenu S, Longoni R, Rivas E, Di Chiara G (2005) Nicotine-conditioned single-trial place preference: selective role of nucleus accumbens shell dopamine D1 receptors in acquisition. Psychopharmacology (Berl) 10:1–9CrossRefGoogle Scholar
  56. Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048–2050CrossRefPubMedGoogle Scholar
  57. Watkins SS, Koob GF, Markou A (2000) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res 2:19–37CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Daniele Lecca
    • 1
  • Fabio Cacciapaglia
    • 1
  • Valentina Valentini
    • 1
    • 2
  • Janne Gronli
    • 1
  • Saturnino Spiga
    • 3
  • Gaetano Di Chiara
    • 1
    • 2
    • 4
    Email author
  1. 1.Department of ToxicologyUniversity of CagliariCagliariItaly
  2. 2.Centre of Excellence for Neurobiology of AddictionUniversity of CagliariCagliariItaly
  3. 3.Department of Animal Biology and EcologyUniversity of CagliariCagliariItaly
  4. 4.Institute of Neuroscience, Section of CagliariConsiglio Nazionale delle Ricerche (CNR)CagliariItaly

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