L-cysteine Prevents Ethanol-Induced Stimulation of Mesolimbic Dopamine Transmission

Alcoholism: Clinical and Experimental Research

Volumn 35, Issue 5, 2011, Pages 862-869

  Sirca, Donatella ^a   Enrico, Paolo ^a   Mereu, Maddalena ^a,b   Peana, Alessandra Tiziana ^a   Diana, Marco ^a  

^a UNIVERSITY OF SASSARI   (Italy)

^b NATIONAL INSTITUTE ON DRUG ABUSE   (United States)

Author keywords

Acetaldehyde; Ethanol; Mesolimbic dopamine system; Microdialysis; Rat

Indexed keywords

ACETALDEHYDE; ALCOHOL; CYSTEINE; MORPHINE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DOPAMINE RELEASE; DOPAMINERGIC TRANSMISSION; MALE; MESOLIMBIC DOPAMINERGIC SYSTEM; MICRODIALYSIS; NONHUMAN; NUCLEUS ACCUMBENS; PRIORITY JOURNAL; RAT;

ANIMALS; CYSTEINE; DOPAMINE; ETHANOL; LIMBIC SYSTEM; MALE; MICRODIALYSIS; RATS; RATS, WISTAR; SYNAPTIC TRANSMISSION;

RATTUS; RATTUS NORVEGICUS;

EID: 79955477261     PISSN: 01456008     EISSN: 15300277     Source Type: Journal    
DOI: 10.1111/j.1530-0277.2010.01416.x     Document Type: Article

References (64)

1. Acquas E, Ibba F, Vinci S, Spiga S, Assaretti AR, Peana AT, Longoni R, Spina L (2008) Effect of ethanol-derived acetaldehyde on extracellular signal Regulated Kinase in the rat nucleus accumbens and extended amygdala. Immunohistochemical and place conditioning study. Neuroscience, 2008, Program/Poster: 659.2/GG7. Available at:
2. Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW (2002) The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 22:9134-9141.
3. Bannai S, Tateishi N (1986) Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol 89:1-8.
4. Brown ZW, Amit Z, Smith BR, Sutherland EA, Selvaggi N (1983) Alcohol-induced euphoria enhanced by disulfiram and calcium carbimide. Alcohol Clin Exp Res 7:276-278.
5. Chen Y, Swanson RA (2003) The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures. J Neurochem 84:1332-1339.
6. Chevens LCF (1953) Antabuse addiction. Br J Med 1:1450-1451.
7. Correa M, Manrique HM, Font L, Escrig MA, Aragon CM (2008) Reduction in the anxiolytic effects of ethanol by centrally formed acetaldehyde: the role of catalase inhibitors and acetaldehyde-sequestering agents. Psychopharmacology (Berl) 200:455-464.
8. Croucher MJ, Thomas LS, Ahmadi H, Lawrence V, Harris JH (2001) Endogenous sulfur-containing amino acids: potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system. Br J Pharmacol 133:815-824.
9. Deng C, Li KY, Zhou C, Ye JH (2009) Ethanol enhances glutamate transmission by retrograde dopamine signaling in a postsynaptic neuron/synaptic bouton preparation from the ventral tegmental area. Neuropsychopharmacology 34:1233-1244.
10. Dood S, Dean O, Copolov DL, Malhi GS, Berk M (2008) N-acetylcysteine for antioxidant theraphy: pharmacology and clinical utility. Exp Opin Biol Ther 8:1955-1962.
11. Edenberg HJ (2007) The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 30:5-13.
12. Enrico P, Sirca D, Mereu M, Peana AT, Lintas A, Golosio A, Diana M (2009) Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission. Drug Alcohol Depend 100:265-271.
13. Ericson M, Molander A, Lof E, Engel JA, Soderpalm B (2003) Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors. Eur J Pharmacol 467:85-93.
14. Foddai M, Dosia G, Spiga S, Diana M (2004) Acetaldehyde increases dopaminergic neuronal activity in the VTA. Neuropsychopharmacology 29:530-536.
15. Font L, Aragon CM, Miquel M (2006a) Ethanol-induced conditioned place preference, but not aversion, is blocked by treatment with D-penicillamine, an inactivation agent for acetaldehyde. Psychopharmacology (Berl) 184:56-64.
16. Font L, Aragon CM, Miquel M (2006b) Voluntary ethanol consumption decreases after the inactivation of central acetaldehyde by d-penicillamine. Behav Brain Res 171:78-86.
17. Font L, Miquel M, Aragon CM (2005) Prevention of ethanol-induced behavioral stimulation by D-penicillamine: a sequestration agent for acetaldehyde. Alcohol Clin Exp Res 29:1156-1164.
18. Hansson T, Tindberg N, Ingelman-Sundberg M, Kohler C (1990) Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience 34:451-463.
19. Hayes D, Wiessner M, Rauen T, McBean GJ (2005) Transport of L-[14C]cystine and L-[14C]cysteine by subtypes of high affinity glutamate transporters over-expressed in HEK cells. Neurochem Int 46:585-594.
20. Hill VA, Seymour CA, Mortimer PS (2000) Penicillamine-induced elastosis perforans serpiginosa and cutis laxa in Wilson's disease. Br J Dermatol 142:560-591.
21. Jamal M, Ameno K, Uekita I, Kumihashi M, Wang W, Ijiri I (2007) Catalase mediates acetaldehyde formation in the striatum of free-moving rats. Neurotoxicology 28:1245-124.
22. Kartal A, Hietala J, Laakso I, Kaihovaara P, Salaspuro V, Sakkinen M, Salaspuro M, Marvola M (2007) Formulation and in-vivo evaluation of L-cysteine chewing gums for binding carcinogenic acetaldehyde in the saliva during smoking. J Pharm Pharmacol 59:1353-1358.
23. Kera Y, Kiriyama T, Komura S (1985) Conjugation of acetaldehyde with cysteinylglycine, the first metabolite in glutathione breakdown by gamma-glutamyltranspeptidase. Agents Actions 17:48-52.
24. Koechling UM, Amit Z (1994) Effects of 3-amino-1, 2, 4-triazole on brain catalase in the mediation of ethanol consumption in mice. Alcohol 11:235-239.
25. Manrique HM, Miquel M, Aragon CM (2005) Brain catalase mediates potentiation of social recognition memory produced by ethanol in mice. Drug Alcohol Depend 79:343-350.
26. McBean GJ (2002) Cerebral cystine uptake: a tale of two transporters. Trends Pharmacol Sci 23:299-302.
27. Melis M, Enrico P, Peana AT, Diana M (2007) Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system. Eur J Neurosci 26:2824-2833.
28. Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK (2005) Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci 25:6389-6393.
29. Nagasawa HT, Elberling JE, Roberts JC (1987) Beta-substituted cysteines as sequestering agents for ethanol-derived acetaldehyde in vivo. J Med Chem 30:1373-1378.
30. Nagasawa HT, Goon DJ, DeMaster EG (1978) 2, 5, 5-Trimethylthiazolidine-4-carboxylic acid, a D(-)-penicillamine-directed pseudometabolite of ethanol. Detoxication mechanism for acetaldehyde. J Med Chem 21:1274-1279.
31. Nagasawa HT, Goon DJ, Muldoon WP, Zera RT (1984) 2-Substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity. J Med Chem 27:591-596.
32. National Research Council (1996) Guide for the care and use of laboratory animals. Institute of Laboratory Animal Resources. Commission on the Life Sciences National Academy Press, Washington D.C.
33. Okamoto T, Harnett MT, Morikawa H (2006) Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice. J Neurophysiol 95:619-626.
34. Pastor R, Sanchis-Segura C, Aragon CM (2002) Ethanol-stimulated behaviour in mice is modulated by brain catalase activity and H2O2 rate of production. Psychopharmacology (Berl) 165:51-59.
35. Paxinos G, Watson C (2006) The Rat Brain in Stereotaxic Coordinates. Elsevier Academic Press, Amsterdam.
36. Peana AT, Assaretti AR, Muggironi G, Enrico P, Diana M (2008b) The peripheral competitive inhibitor of alcohol dehydrogenase, 4-methylpyrazole, reduces oral ethanol self-administration. ESBRA2008 Nordmann Award Meeting-Animal Models in Alcohol Research. Sept. 26-27, 2008 Cagliari, Sardinia, Italy.
37. Peana AT, Assaretti AR, Muggironi G, Enrico P, Diana M (2009) Reduction of ethanol-derived acetaldehyde induced motivational properties by L-cysteine. Alcohol Clin Exp Res 33:43-48.
38. Peana AT, Enrico P, Assaretti AR, Pulighe E, Muggironi G, Nieddu M, Piga A, Lintas A, Diana M (2008a) Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat. Alcohol Clin Exp Res 32:249-258.
39. Peana AT, Muggironi G, Calvisi G, Enrico P, Mereu M, Nieddu M, Boatto G, Diana M (2010) l-Cysteine reduces oral ethanol self-administration and reinstatement of ethanol-drinking behavior in rats. Pharmacol Biochem Behav 94:431-437.
40. Poon E, Mason GH, Oh C (2002) Clinical and histological spectrum of elastotic changes induced by penicillamine. Australas J Dermatol 43:147-150.
41. Quertemont E (2003) Discriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution. Behav Pharmacol 14:343-350.
42. Quertemont E, De Witte P (2001) Conditioned stimulus preference after acetaldehyde but not ethanol injections. Pharmacol Biochem Behav 68: 449-454.
43. Quertemont E, Didone V (2006) Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol. Alcohol Res Health 29:258-265.
44. Quertemont E, Eriksson CJ, Zimatkin SM, Pronko PS, Diana M, Pisano M, Rodd ZA, Bell RR, Ward RJ (2005a) Is ethanol a pro-drug? Acetaldehyde contribution to brain ethanol effects. Alcohol Clin Exp Res 29:1514-1521.
45. Quertemont E, Tambour S, Tirelli E (2005b) The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies. Prog Neurobiol 75:247-274.
46. Ramchandani VA, Bosron WF, Li TK (2001) Research advances in ethanol metabolism. Pathol Biol (Paris) 49:676-682.
47. Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li TK (2002) The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem Behav 72:55-64.
48. Rosner S, Leucht S, Lehert P, Soyka M (2008) Acamprosate supports abstinence, naltrexone prevents excessive drinking: evidence from a meta-analysis with unreported outcomes. J Psychopharmacol 22:11-23.
49. Salaspuro V (2007) Pharmacological treatments and strategies for reducing oral and intestinal acetaldehyde. Novartis Found Symp 285:145-153; discussion 153-157, 198-199.
50. Salaspuro V, Hietala J, Kaihovaara P, Pihlajarinne L, Marvola M, Salaspuro M (2002) Removal of acetaldehyde from saliva by a slow-release buccal tablet of L-cysteine. Int J Cancer 97:361-364.
51. Salaspuro VJ, Hietala JM, Marvola ML, Salaspuro MP (2006) Eliminating carcinogenic acetaldehyde by cysteine from saliva during smoking. Cancer Epidemiol Biomarkers Prev 15:146-149.
52. Sanchez-Catalan MJ, Hipolito L, Guerri C, Granero L, Polache A (2008) Distribution and differential induction of CYP2E1 by ethanol and acetone in the mesocorticolimbic system of rat. Alcohol Alcohol 43:401-407.
53. Serrano E, Pozo OJ, Beltran J, Hernandez F, Font L, Miquel M, Aragon CM (2007) Liquid chromatography/tandem mass spectrometry determination of (4S, 2RS)-2, 5, 5-trimethylthiazolidine-4-carboxylic acid, a stable adduct formed between D-(-)-penicillamine and acetaldehyde (main biological metabolite of ethanol), in plasma, liver and brain rat tissues. Rapid Commun Mass Spectrom 21:1221-1229.
54. Shih AY, Erb H, Sun X, Toda S, Kalivas PW, Murphy TH (2006) Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci 26:10514-10523.
55. Sprince H (1985) Protective action of sulfur compounds against aldehyde toxicants of cigarette smoke. Eur J Respir Dis Suppl 139:102-112.
56. Sprince H, Parker CM, Smith GG, Gonzales LJ (1974) Protection against acetaldehyde toxicity in the rat by L-cysteine, thiamin and L-2-methylthiazolidine-4-carboxylic acid. Agents Actions 4:125-130.
57. Takahashi M, Billups B, Rossi D, Sarantis M, Hamann M, Attwell D (1997) The role of glutamate transporters in glutamate homeostasis in the brain. J Exp Biol 200:401-409.
58. Valjent E, Pages C, Herve D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826-1836.
59. Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299-315.
60. Waller MB, McBride WJ, Lumeng L, Li TK (1982) Effects of intravenous ethanol and of 4-methylpyrazole on alcohol drinking in alcohol-preferring rats. Pharmacol Biochem Behav 17:763-768.
61. Xi ZX, Ramamoorthy S, Baker DA, Shen H, Samuvel DJ, Kalivas PW (2002) Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J Pharmacol Exp Ther 303:608-615.
62. Xiao C, Shao XM, Olive MF, Griffin WC 3rd, Li KY, Krnjevic K, Zhou C, Ye JH (2009) Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area. Neuropsychopharmacology 34:307-318.
63. Zimatkin SM, Liopo AV, Deitrich RA (1998) Distribution and kinetics of ethanol metabolism in rat brain. Alcohol Clin Exp Res 22:1623-1627.
64. Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ, Deitrich RA (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500-1505.