, Volume 219, Issue 4, pp 1153–1164 | Cite as

Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex

  • Paola Devoto
  • Giovanna Flore
  • Pierluigi Saba
  • Roberto Cadeddu
  • Gian Luigi Gessa
Original Investigation



Disulfiram efficacy in treatment of cocaine addiction is attributed to the inhibition of dopamine-β-hydroxylase and reduction in brain noradrenaline (NA)/dopamine (DA) ratio.


Using microdialysis, we investigated if disulfiram causes DA release from noradrenergic terminals and modifies cocaine-induced DA release.


Disulfiram reduced extracellular NA in the medial prefrontal (mPF) cortex, occipital cortex, accumbens and caudate nuclei, while it markedly increased DA not only in mPF but also in the occipital cortex, despite its scanty dopaminergic afferences, and modestly increased DA in the accumbens and caudate nuclei, despite their dense dopaminergic innervation. Disulfiram-induced DA accumulation was reversed in both cortices by tetrodotoxin infusion and by systemic administration of the α2-adrenoceptor agonist clonidine, but was not modified by the α2-adrenoceptor antagonist RS 79948 or the D2-like agonist quinpirole. Disulfiram prevented cocaine-induced NA release in the mPF cortex and nucleus accumbens, potentiated cocaine-induced DA release in the mPF cortex but failed to modify cocaine effect in the nucleus accumbens. DA release induced by disulfiram-cocaine combination in the mPF cortex was prevented by clonidine but not by quinpirole.


We suggested that disulfiram, by removing NA-mediated inhibitory control on noradrenergic terminals, causes an unrestrained cocaine-induced DA release from those terminals in the mPF cortex. In the accumbens and caudate nuclei, “allogenic” DA concentration might be clouded by DA originated from dopaminergic terminals. The possible role of “allogenic” DA in disulfiram ability to prevent stress-induced reinstatement of cocaine seeking is discussed.


Cocaine DBH Disulfiram Dopamine Microdialysis Noradrenaline Prefrontal cortex Nucleus accumbens α2-Autoreceptors 



The authors declare no competing financial interests. This study was supported by the “Guy Everett Laboratory” Foundation. The authors state that the experiments comply with the current Italian laws on laboratory animal use.


  1. Alleweireldt AT, Weber SM, Kirschner KF, Bullock BL, Neisewander JL (2002) Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology 159:284–293PubMedCrossRefGoogle Scholar
  2. Arnsten AFT (1997) Catecholamine regulation of the prefrontal cortex. J Psychopharmacol 11:151–162PubMedCrossRefGoogle Scholar
  3. Bäckström P, Hyytiä P (2007) Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 192:571–580PubMedCrossRefGoogle Scholar
  4. Bourdélat-Parks BN, Anderson GM, Donaldson ZR, Weiss JM, Bonsall RW, Emery MS, Liles LC, Weinshenker D (2005) Effects of dopamine beta-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice. Psychopharmacology 183:72–80PubMedCrossRefGoogle Scholar
  5. Brewer C (1993) Recent developments in disulfiram treatment. Alcohol Alcohol 28:383–395PubMedGoogle Scholar
  6. Carboni E, Tanda GL, Frau R, Di Chiara G (1990) Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 55:1067–1070PubMedCrossRefGoogle Scholar
  7. Carroll KM, Nich C, Ball SA, McCance E, Rounsavile BJ (1998) Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 93:713–727PubMedCrossRefGoogle Scholar
  8. Carroll KM, Nich C, Ball SA, McCance E, Frankforter TL, Rounsaville BJ (2000) One-year follow-up of disulfiram and psychotherapy for cocaine–alcohol users: sustained effects of treatment. Addiction 95:1335–1349PubMedCrossRefGoogle Scholar
  9. Carroll KM, Fenton LR, Ball SA, Nich C, Frankforter TL, Shi J, Rounsaville BJ (2004) Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 61:264–272PubMedCrossRefGoogle Scholar
  10. Darracq L, Drouin C, Blanc G, Glowinski J, Tassin JP (2001) Stimulation of metabotropic but not ionotropic glutamatergic receptors in the nucleus accumbens is required for the D-amphetamine-induced release of functional dopamine. Neuroscience 103:395–403PubMedCrossRefGoogle Scholar
  11. Del Arco A, Mora F (2008) Prefrontal cortex–nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex. Pharmacol Biochem Behav 90:226–235PubMedCrossRefGoogle Scholar
  12. Deutch AY (1992) The regulation of subcortical dopamine system by the prefrontal cortex: interaction of central dopamine systems and the pathogenesis of schizophrenia. J Neural Transm 36:61–89Google Scholar
  13. Devoto P, Flore G (2006) On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr Neuropharmacol 4:115–125PubMedCrossRefGoogle Scholar
  14. Devoto P, Flore G, Longu G, Pira L, Gessa GL (2003a) Origin of extracellular dopamine from dopamine and noradrenaline neurons in the medial prefrontal and occipital cortex. Synapse 50:200–205PubMedCrossRefGoogle Scholar
  15. Devoto P, Flore G, Vacca G, Pira L, Arca A, Casu MA, Pani L, Gessa GL (2003b) Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic. Psychopharmacol 167:79–84Google Scholar
  16. Devoto P, Flore G, Pira L, Longu G, Gessa GL (2004a) Mirtazapine-induced co-release of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex. Eur J Pharmacol 487:105–111PubMedCrossRefGoogle Scholar
  17. Devoto P, Flore G, Longu G, Pira L, Gessa GL (2004b) Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex. J Neurochem 88:1003–1009PubMedCrossRefGoogle Scholar
  18. Gaval-Cruz M, Weinshenker D (2009) Mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv 9:175–187PubMedCrossRefGoogle Scholar
  19. George TP, Chawarski MC, Pakes J, Carroll KM, Kosten TR, Schottenfeld RS (2000) Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. Biol Psychiatry 47:1080–1086PubMedCrossRefGoogle Scholar
  20. Goldman-Rakic PS, Muly EC 3rd, Williams GV (2000) D1 receptors in prefrontal cells and circuits. Brain Res Rev 31:295–301PubMedCrossRefGoogle Scholar
  21. Goldstein M, Nakajima K (1967) The effect of disulfiram on catecholamine levels in the brain. J Pharmacol Exp Ther 157:96–102PubMedGoogle Scholar
  22. Goldstein M, Anagnoste B, Lauber E, Mckeregham MR (1964) Inhibition of dopamine-beta-hydroxylase by disulfiram. Life Sci 3:763–767PubMedCrossRefGoogle Scholar
  23. Grabowski J, Shearer J, Merrill J, Negus SS (2004) Agonist-like replacememnt pharmacotherapy for stimulant abuse and dependence. Addict Behav 29:1439–1464PubMedCrossRefGoogle Scholar
  24. Grenhoff J, Svensson TH (1989) Clonidine modulates dopamine cell firing in the ventral tegmental area. Eur J Pharmacol 165:11–18PubMedCrossRefGoogle Scholar
  25. Gresch PJ, Sved AF, Zigmond MJ, Finlay JM (1995) Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex. J Neurochem 65:111–116PubMedCrossRefGoogle Scholar
  26. Guiard BP, El Mansari M, Blier P (2008) Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus ceruleus, and dorsal hippocampus. Mol Pharmacol 74:1463–1475PubMedCrossRefGoogle Scholar
  27. Haley TJ (1979) Disulfiram (tetraethylthioperoxydicarbonic diamide): a reappraisal of its toxicity and therapeutic application. Drug Metab Rev 9:319–335PubMedCrossRefGoogle Scholar
  28. Han DD, Gu HH (2006) Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 6:6PubMedCrossRefGoogle Scholar
  29. Hart BW, Faiman MD (1992) In vitro and in vivo inhibition of rat liver aldehyde dehydrogenase by S-methyl N, N-diethylthiolcarbamate sulfoxide, a new metabolite of disulfiram. Biochem Pharmacol 43:403–406PubMedCrossRefGoogle Scholar
  30. Heffner TG, Hartman JA, Seiden LS (1980) A rapid method for the regional dissection of the rat brain. Pharmac Biochem Behav 13:453–456CrossRefGoogle Scholar
  31. Hume SP, Ashworth S, Lammertsma AA, Opacka-Juffry J, Law MP, McCarron JA, Clark RD, Nutt DJ, Pike VW (1996) Evaluation in rat of RS-79948-197 as a potential PET ligand for central alpha 2-adrenoceptors. Eur J Pharmacol 317:67–73PubMedCrossRefGoogle Scholar
  32. Ihalainen JA, Tanila H (2002) In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse prefrontal cortex. Eur J Neurosci 15:1789–1794PubMedCrossRefGoogle Scholar
  33. Kalivas PW, McFarland K, Bowers S, Szumlinski K, Xi ZX, Baker D (2003) Glutamate transmission and addiction to cocaine. Ann N Y Acad Sci 1003:169–175PubMedCrossRefGoogle Scholar
  34. Karamanakos PN, Pappas P, Stephanou P, Marselos M (2001) Differentiation of disulfiram effects on central catecholamines and hepatic ethanol metabolism. Pharmacol Toxicol 88:106–110PubMedCrossRefGoogle Scholar
  35. Kawaguchi Y, Shindou T (1998) Noradrenergic excitation and inhibition of GABAergic cell types in rat frontal cortex. J Neurosci 18:6963–6976PubMedGoogle Scholar
  36. Kawahara H, Kawahara Y, Westerink BHC (2001) The noradrenaline–dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis. Eur J Pharmacol 418:177–186PubMedCrossRefGoogle Scholar
  37. Kita JM, Parker LE, Phillips PE, Garris PA, Wightman RM (2007) Paradoxical modulation of short-term facilitation of dopamine release by dopamine autoreceptors. J Neurochem 102:1115–1124PubMedCrossRefGoogle Scholar
  38. Kolachana BS, Saunders RC, Weinberger DR (1995) Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey. Neuroscience 69:859–868PubMedCrossRefGoogle Scholar
  39. Lategan AJ, Marien MR, Colpaert FC (1990) Effects of locus coeruleus lesions on the release of endogenous dopamine in the rat nucleus accumbens and caudate nucleus as determined by intracerebral microdialysis. Brain Res 523:134–138PubMedCrossRefGoogle Scholar
  40. Lindvall O, Björklund A, Divac I (1978) Organization of the catecholamine neurons projecting to the frontal cortex in the rat. Brain Res 142:1–24PubMedCrossRefGoogle Scholar
  41. Lipsky JJ, Shen ML, Naylor S (2001a) In vivo inhibition of aldehyde dehydrogenase by disulfiram. Chem Biol Interact 130–132:93–102PubMedCrossRefGoogle Scholar
  42. Lipsky JJ, Shen ML, Naylor S (2001b) Overview—in vitro inhibition of aldehyde dehydrogenase by disulfiram and metabolites. Chem Biol Interact 130–132:81–91PubMedCrossRefGoogle Scholar
  43. Mateo Y, Budygin EA, John CE, Jones SR (2004) Role of serotonin in cocaine effects in mice with reduced dopamine transporter function. Proc Natl Acad Sci U S A 101:372–377PubMedCrossRefGoogle Scholar
  44. McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663PubMedGoogle Scholar
  45. Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22:389–395PubMedGoogle Scholar
  46. Musacchio JM, Goldstein M, Anagnoste B, Poch G, Kopin IJ (1966) Inhibition of dopamine-beta-hydroxylase by disulfiram in vivo. J Pharmacol Exp Ther 152:56–61PubMedGoogle Scholar
  47. Paladini CA, Beckstead MJ, Weinshenker D (2007) Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse. Neuroscience 144:1067–1074PubMedCrossRefGoogle Scholar
  48. Park WK, Bari AA, Jey AR, Anderson SM, Spealman RD, Rowlett JK, Pierce RC (2002) Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 22:2916–2925PubMedGoogle Scholar
  49. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
  50. Petrakis IL, Carroll KM, Nich C, Gordon LT, McCance-Katz EF, Frankforter T, Rounsaville BJ (2000) Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Addiction 95:219–228PubMedCrossRefGoogle Scholar
  51. Pirot S, Godbout R, Mantz J, Tassin JP, Glowinski J, Thierry AM (1992) Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components. Neuroscience 49:857–865PubMedCrossRefGoogle Scholar
  52. Pitts DK, Marwah J (1987) Electrophysiological actions of cocaine on noradrenergic neurons in rat locus ceruleus. J Pharmacol Exp Ther 240:345–351PubMedGoogle Scholar
  53. Pozzi L, Invernizzi R, Cervo L, Vallebuona F, Samanin R (1994) Evidence that extracellular concentrations of dopamine are regulated by noradrenergic neurons in the frontal cortex of rats. J Neurochem 63:195–200PubMedCrossRefGoogle Scholar
  54. Sanchez CJ, Bailie TM, Wu WR, Li N, Sorg BA (2003) Manipulation of dopamine D1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior. Neuroscience 119:497–505PubMedCrossRefGoogle Scholar
  55. Schank JR, Ventura R, Puglisi-Allegra S, Alcaro A, Cole CD, Liles LC, Seeman P, Weinshenker D (2006) Dopamine-β-hydroxylase knock-out mice have alterations in dopamine signalling and are hypersensitive to cocaine. Neuropsychopharmacology 31:2221–2230PubMedGoogle Scholar
  56. Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase. Neuropsychopharmacology 35:2440–2449PubMedCrossRefGoogle Scholar
  57. Skirboll LR, Grace AA, Bunney BS (1979) Dopamine auto- and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists. Science 206:80–82PubMedCrossRefGoogle Scholar
  58. Sofuoglu M, Kosten TR (2006) Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opin Emerg Drugs 11:91–98PubMedCrossRefGoogle Scholar
  59. Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, Walker K, Martinez G, Eglen RM, Whiting RL, Hegde SS (1997) Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase. Br J Pharmacol 121:1803–1809PubMedCrossRefGoogle Scholar
  60. Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63:348–365PubMedCrossRefGoogle Scholar
  61. Svensson TH, Bunney BS, Aghajanian GK (1975) Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine. Brain Res 92:291–306PubMedCrossRefGoogle Scholar
  62. Tanaka S (2006) Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective. Neuroscience 139:153–171PubMedCrossRefGoogle Scholar
  63. Thompson TL, Moss RL (1995) In vivo stimulated dopamine release in the nucleus accumbens: modulation by prefrontal cortex. Brain Res 686:93–98PubMedCrossRefGoogle Scholar
  64. Ventura R, Cabib S, Puglisi-Allegra S (2002) Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioural “despair” in a mouse model of depression. Neuroscience 115:999–1007PubMedCrossRefGoogle Scholar
  65. Ventura R, Cabib S, Alcaro A, Orsini C, Puglisi-Allegra S (2003) Norepinehrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release. J Neurosci 23:1879–1885PubMedGoogle Scholar
  66. Weinshenker D, Ferrucci M, Busceti CL, Biagioni F, Lazzeri G, Liles LC, Lenzi P, Pasquali L, Murri L, Paparelli A, Fornai F (2008) Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine. J Neurochem 105:471–483PubMedCrossRefGoogle Scholar
  67. White FJ, Wang RY (1984) Pharmacological characterization of dopamine autoreceptors in the rat ventral tegmental area: microiontophoretic studies. J Pharmacol Exp Ther 231:275–280PubMedGoogle Scholar
  68. Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575PubMedCrossRefGoogle Scholar
  69. Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I (2010) Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis. Nat Med 16:1024–1028PubMedCrossRefGoogle Scholar
  70. Zhang W-P, Ouyang M, Thomas SA (2004) Potency of catecholamines and other L-tyrosine derivatives at the cloned mouse adrenergic receptors. Neuropharmacology 47:438–449PubMedCrossRefGoogle Scholar
  71. Zoli M, Jansson A, Sykovà E, Agnati LF, Fuxe K (1999) Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol Sci 20:142–150PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Paola Devoto
    • 1
    • 2
    • 4
    • 5
  • Giovanna Flore
    • 2
    • 3
  • Pierluigi Saba
    • 1
  • Roberto Cadeddu
    • 1
  • Gian Luigi Gessa
    • 1
    • 4
  1. 1.Department of NeuroscienceUniversity of CagliariMonserratoItaly
  2. 2.Tourette Syndrome CentreUniversity of CagliariMonserratoItaly
  3. 3.Department of Cardiovascular and Neurological SciencesUniversity of CagliariMonserratoItaly
  4. 4.“Guy Everett Laboratory”University of CagliariMonserratoItaly
  5. 5.“B.B. Brodie” Department of NeuroscienceCittadella UniversitariaMonserratoItaly

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