Neurocircuitry Involved in the Development of Alcohol Addiction: The Dopamine System and its Access Points

  • Bo SöderpalmEmail author
  • Mia Ericson
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 13)


The brain reward system, and especially the mesolimbic dopamine pathway, plays a major role in drug reinforcement and is most likely involved in the development of drug addiction. All major drugs of abuse, including ethanol, acutely activate the mesolimbic dopamine system. Both this acute drug-induced dopamine elevation, the dopamine elevations observed after presentations of drug-associated stimuli and alterations of dopamine function induced by chronic drug administration are of importance. Whereas the mechanisms of actions for central stimulants, opioids and nicotine in their dopamine activating effects are fairly well established, the corresponding mechanisms with respect to ethanol have been elusive. Here we review the actions of ethanol in the mesolimbic dopamine system, focusing on ethanol’s interaction with ligand-gated ion-channel receptors, opiate receptors, the ghrelin system and the possible involvement of acetaldehyde. Preclinical studies have provided the opportunity to dissect these interactions in some detail and although we do not fully comprehend the actions of ethanol there have been some great advances resulting in increased knowledge of the complexity of ethanol’s mechanism of action in this system.


Dopamine Ethanol Ligand-gated ion-channels Opiate receptors Ghrelin 





Adrenocorticotrophic hormone


Attention-Deficit/Hyperactivity Disorder


2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid


Gamma-aminobutyric acid


Growth hormone secretagogue receptor


Glycine receptor


Nucleus accumbens


Nicotinic acetylcholine receptor




NMDA receptor one/two


Reverse transcriptase polymerase chain reaction


Ventral tegmental area


  1. Acquas E, Meloni M, Di Chiara G (1993) Blockade of delta-opioid receptors in the nucleus accumbens prevents ethanol-induced stimulation of dopamine release. Eur J Pharmacol 230(2):239–241PubMedGoogle Scholar
  2. Addolorato G, Capristo E, Leggio L, Ferrulli A, Abenavoli L, Malandrino N, Farnetti S, Domenicali M, D’Angelo C, Vonghia L, Mirijello A, Cardone S, Gasbarrini G (2006) Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients. Alcohol Clin Exp Res 30(11):1933–1937PubMedGoogle Scholar
  3. Adermark L, Clarke RBC, Olsson T, Hansson E, Söderpalm B, Ericson M (2011) Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens. Addict Biol 16(1):43–54PubMedGoogle Scholar
  4. Aguayo LG, Pancetti FC (1994) Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons. J Pharmacol Exp Ther 270(1):61–69PubMedGoogle Scholar
  5. Aguayo LG, Tapia JC, Pancetti FC (1996) Potentiation of the glycine-activated Cl- current by ethanol in cultured mouse spinal neurons. J Pharmacol Exp Ther 279(3):1116–1122PubMedGoogle Scholar
  6. Ahlenius S, Carlsson A, Engel J, Svensson T, Sodersten P (1973) Antagonism by alpha methyltyrosine of the ethanol-induced stimulation and euphoria in man. Clin Pharmacol Ther 14(4):586–591PubMedGoogle Scholar
  7. Ahmed SH, Koob GF (2005) Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology (Berl) 180(3):473–490Google Scholar
  8. Aistrup GL, Marszalec W, Narahashi T (1999) Ethanol modulation of nicotinic acetylcholine receptor currents in cultured cortical neurons. Mol Pharmacol 55(1):39–49PubMedGoogle Scholar
  9. Altshuler HL, Phillips PE, Feinhandler DA (1980) Alteration of ethanol self-administration by naltrexone. Life Sci 26(9):679–688PubMedGoogle Scholar
  10. Amit Z, Brown ZW, Rockman GE (1977) Possible involvement of acetaldehyde, norepinephrine and their tetrahydroisoquinoline derivatives in the regulation of ethanol seld-administration. Drug Alcohol Depend 2:495–500PubMedGoogle Scholar
  11. Benjamin D, Grant ER, Pohorecky LA (1993) Naltrexone reverses ethanol-induced dopamine release in the nucleus accumbens in awake, freely moving rats. Brain Res 621(1):137–140PubMedGoogle Scholar
  12. Betz H (1992) Structure and function of inhibitory glycine receptors. Q Rev Biophys 25(4):381–394PubMedGoogle Scholar
  13. Blaha CD, Yang CR, Floresco SB, Barr AM, Phillips AG (1997) Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efflux in the rat nucleus accumbens. Eur J Neurosci 9(5):902–911PubMedGoogle Scholar
  14. Blomqvist O, Engel JA, Nissbrandt H, Soderpalm B (1993) The mesolimbic dopamine-activating properties of ethanol are antagonized by mecamylamine. Eur J Pharmacol 249(2):207–213PubMedGoogle Scholar
  15. Blomqvist O, Ericson M, Engel JA, Söderpalm B (1997) Accumbal dopamine overflow after ethanol: localization of the antagonizing effect of mecamylamine. Eur J Pharmacol 334(2–3):149–156PubMedGoogle Scholar
  16. Blomqvist O, Ericson M, Johnson DH, Engel JA, Söderpalm B (1996) Voluntary ethanol intake in the rat: effects of nicotinic acetylcholine receptor blockade or subchronic nicotine treatment. Eur J Pharmacol 314:257–267PubMedGoogle Scholar
  17. Blomqvist O, Hernandez-Avila CA, Van Kirk J, Rose JE, Kranzler HR (2002) Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol. Alcohol Clin Exp Res 26:326–331PubMedGoogle Scholar
  18. Blomqvist O, Söderpalm B, Engel JA (1992) Ethanol-induced locomotor activity: involvement of central nicotinic acetylcholine receptors? Brain Res Bull 29(2):173–178PubMedGoogle Scholar
  19. Boileau I, Assaad JM, Pihl RO, Benkelfat C, Leyton M, Diksic M, Tremblay RE, Dagher A (2003) Alcohol promotes dopamine release in the human nucleus accumbens. Synapse 49:226–231PubMedGoogle Scholar
  20. Boismare F, Daoust M, Moore N, Saligaut C, Lhuintre JP, Chretien P, Durlach J (1984) A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved? Pharmacol Biochem Behav 21(5):787–789PubMedGoogle Scholar
  21. Borghese CM, Henderson LA, Bleck V, Trudell JR, Harris RA (2003a) Sites of excitatory and inhibitory actions of alcohols on neuronal alpha2beta4 nicotinic acetylcholine receptors. J Pharmacol Exp Ther 307(1):42–52PubMedGoogle Scholar
  22. Borghese CM, Wang L, Bleck V, Harris RA (2003b) Mutation in neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes blocks ethanol action. Addict Biol 8(3):313–318PubMedGoogle Scholar
  23. Bourdélat-Parks BN, Anderson GM, Donaldson ZR, Weiss JM, Bonsall RW, Emery MS et al (2005) Effects of dopamine beta-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice. Psychopharmacology 183:72–80PubMedGoogle Scholar
  24. Brackmann M, Zhao C, Schmieden V, Braunewell KH (2004) Cellular and subcellular localization of the inhibitory glycine receptor in hippocampal neurons. Biochem Biophys Res Commun 324(3):1137–1142PubMedGoogle Scholar
  25. Bradley RJ, Peper K, Sterz R (1980) Postsynaptic effects of ethanol at the frog neuromuscular junction. Nature 284:60–62PubMedGoogle Scholar
  26. 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(3–4):328–338Google Scholar
  27. Burch JB, de Fiebre CM, Marks MJ, Collins AC (1988) Chronic ethanol or nicotine treatment results in partial cross-tolerance between these agents. Psychopharmacology (Berl) 95(4):452–458Google Scholar
  28. Calissendorff J, Danielsson O, Brismar K, Röjdmark S (2005) Inhibitory effect of alcohol on ghrelin secretion in normal man. Eur J Endocrinol 152(5):743–747PubMedGoogle Scholar
  29. Campbell AD, McBride WJ (1995) Serotonin-3 receptor and ethanol-stimulated dopamine release in the nucleus accumbens. Pharmacol Biochem Behav 51:835–842PubMedGoogle Scholar
  30. Carboni E, Acquas E, Frau R, Di Chiara G (1989) Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release. Eur J Pharmacol 164:515–519PubMedGoogle Scholar
  31. Cardoso RA, Brozowski SJ, Chavez-Noriega LE, Harpold M, Valenzuela CF, Harris RA (1999) Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 289(2):774–780PubMedGoogle Scholar
  32. Carlsson A, Engel J, Svensson TH (1972) Inhibition of ethanol-induced excitation in mice and rats by α-methyl-p-tyrosine. Psychopharmacological 26(3):307–312Google Scholar
  33. Carlsson A, Lindqvist M (1973) Effect of ethanol on the hydroxylation of tyrosine and tryptophan in rat brain in vivo. J Pharm Pharmacol 25:437–440PubMedGoogle Scholar
  34. Carlsson A, Lindqvist M, Magnusson T (1957) 3, 4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180:1200PubMedGoogle Scholar
  35. Carlsson A, Lindqvist M, Magnusson T, Waldeck B (1958) On the presence of 3-hydroxytyramine in brain. Science 127(3296):471PubMedGoogle Scholar
  36. Celentano JJ, Gibbs TT, Farb DH (1988) Ethanol potentiates GABA- and glycine-induced chloride currents in chick spinal cord neurons. Brain Res 455(2):377–380PubMedGoogle Scholar
  37. Chandler LJ, Sumners C, Crews FT (1993) Ethanol inhibits NMDA receptor-mediated excitotoxicity in rat primary neuronal cultures. Alcohol Clin Exp Res 17:54–60PubMedGoogle Scholar
  38. Chattipakorn SC, McMahon LL (2003) Strychnine-sensitive glycine receptors depress hyperexcitability in rat dentate gyrus. J Neurophysiol 89(3):1339–1342PubMedGoogle Scholar
  39. Chau P, Lidö HH, Söderpalm B, Ericson M (2010a) Glycine receptors in the nucleus accumbens involved in the ethanol intake-reducing effect of acamprosate. Alcohol Clin Exp Res 34(1):39–45PubMedGoogle Scholar
  40. Chau P, Stomberg R, Löf E, Söderpalm B, Ericson M (2010b) Glycine receptors involved in acamprosate’s modulation of accumbal dopamine levels: an in vivo microdialysis study. Alcohol Clin Exp Res 34(1):32–28PubMedGoogle Scholar
  41. Chen JP, van Praag HM, Gardner EL (1991) Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens. Brain Res 543:354–357PubMedGoogle Scholar
  42. Chesnoy-Marchais D (1996) Potentiation of chloride responses to glycine by three 5-HT3 antagonists in rat spinal neurones. Br J Pharmacol 118:2115–2125PubMedGoogle Scholar
  43. Chesnoy-Marchais D, Lévi S, Acher F (2000) Glycinergic potentiation by some 5-HT(3) receptor antagonists: insight into selectivity. Eur J Pharmacol 402:205–213PubMedGoogle Scholar
  44. Chi H, de Wit H (2003) Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers. Alcohol Clin Exp Res 27:780–786PubMedGoogle Scholar
  45. Collins AC, Burch JB, de Fiebre CM, Marks MJ (1988) Tolerance to and cross tolerance between ethanol and nicotine. Pharmacol Biochem Behav 29(2):365–373PubMedGoogle Scholar
  46. Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653(1–2):278–284PubMedGoogle Scholar
  47. Corrodi H, Fuxe K, Hökfelt T (1966) The effect of ethanol on the activity of central catecholamine neurones in rat brain. J Pharm Pharmacol 18:821–823PubMedGoogle Scholar
  48. Covernton PJ, Connolly JG (1997) Differential modulation of rat neuronal nicotinic receptor subtypes by acute application of ethanol. Br J Pharmacol 122(8):1661–1668PubMedGoogle Scholar
  49. Criswell HE, Simson PE, Duncan GE, McCown TJ, Herbert JS, Morrow AL, Breese GE (1993) Molecular basis for regionally specific action of ethanol on g-aminobutyric acidA receptors: generalization to other ligand-gated ion channels. J Pharmacol Exp Ther 267:522–537PubMedGoogle Scholar
  50. Czachowski CL, Chappell AM, Samson HH (2001) Effects of raclopride in the nucleus accumbens on ethanol seeking and consumption. Alcohol Clin Exp Res 25:1431–1440PubMedGoogle Scholar
  51. Dahchour A, De Witte P, Bolo N, Nédélec JF, Muzet M, Durbin P, Macher JP (1998) Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats. Psychiatry Res 82(2):107–114Google Scholar
  52. Dahchour A, Quertemont E, De Witte P (1996) Taurine increases in the nucleus accumbens microdialysate after acute ethanol administration to naive and chronically alcoholised rats. Brain Res 735(1):9–19PubMedGoogle Scholar
  53. Dahlström A, Fuxe K (1964) Localization of monoamines in the lower brain stem. Experientia 20:398–399PubMedGoogle Scholar
  54. Davidson M, Wilce PA, Shanley BC (1993) Chronic ethanol administration sensitizes hippocampal neurons to neurotoxicity of N-methyl-D-aspartic acid. Alcohol Alcohol Suppl 2:365–369PubMedGoogle Scholar
  55. Deitrich RA (2004) Acetaldehyde: deja vu du jour. J Stud Alcohol 65:557–572PubMedGoogle Scholar
  56. 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(5):1233–1244PubMedCentralPubMedGoogle Scholar
  57. Diana M, Pistis M, Carboni S, Gessa GL, Rossetti ZL (1993) Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence. Proc Natl Acad Sci U S A 90(17):7966–7969PubMedCentralPubMedGoogle Scholar
  58. DiChiara 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 85:5274–5278Google Scholar
  59. DiChiara G, Imperato A (1985) Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. Eur J Pharmacol 115(1):131–132Google Scholar
  60. Dyr W, Koros E, Bienkowski P, Kostowski W (1999) Involvement of nicotinic acetylcholine receptors in the regulation of alcohol dringking in Wistar rats. Alcohol Alcohol 34(1):43–47PubMedGoogle Scholar
  61. Edenberg HJ (2007) The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 30:5–13PubMedGoogle Scholar
  62. Ei-Fakahany EF, Miller ER, Abbassy MA, Eldefrawi AT, Eldefrawi ME (1983) Alcohol modulation of drug binding to the channel sites of the nicotinic acetylcholine receptor. J Pharmacol Exp Ther 224(2):289–296PubMedGoogle Scholar
  63. Engblom AC, Akerman KE (1991) Effect of ethanol on gamma-aminobutyric acid and glycine receptor-coupled Cl- fluxes in rat brain synaptoneurosomes. J Neurochem 57(2):384–390PubMedGoogle Scholar
  64. Engel J, Carlsson A (1977) Catecholamines and behavior. In: Valzelli L, Essman WB (eds) Current developments in psychopharmacology, vol 4. Spectrum Publishing, New York, pp 1–32Google Scholar
  65. Engel J (1977) Neurochemical aspects of the euphoria induced by dependence-producing drugs. In: Recent advances in the Study of Alcoholism. (Excerpta Medunca International Congress Series 407). Excerpta Medica, Amsterdam, pp 16–22Google Scholar
  66. Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393(6680):76–79PubMedGoogle Scholar
  67. Ericson M, Blomqvist O, Engel J, Söderpalm B (1998) Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine. Eur J Pharmacol 358:189–196PubMedGoogle Scholar
  68. Ericson M, Chau P, Clarke RB, Adermark L, Söderpalm B (2011) Rising taurine and ethanol concentrations in nucleus accumbens interact to produce dopamine release after ethanol administration. Addict Biol 16(3):377–385PubMedGoogle Scholar
  69. Ericson M, Clarke R, Chau P, Adermark L, Söderpalm B (2010) β-alanine elevates dopamine levels in the rat nucleus accumbens; antagonism by strychnine. Amino Acids 38(4):1051–1055PubMedGoogle Scholar
  70. Ericson M, Löf E, Stomberg R, Chau P, Söderpalm B (2008) Nicotinic acetylcholine receptors in the anterior, but not posterior, ventral tegmental area mediate ethanol-induced elevation of accumbal dopamine levels. J Pharmacol Exp Ther 326(1):76–82PubMedGoogle Scholar
  71. Ericson M, Löf E, Stomberg R, Söderpalm B (2009) The smoking cessation medication varenicline attenuates alcohol and nicotine interactions on the rat mesolimbic dopamine system. J Pharmacol Exp Ther 329(1):225–230PubMedGoogle Scholar
  72. Ericson M, Molander A, Löf E, Engel JA, Söderpalm B (2003) Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors. Eur J Pharmacol 467(1–3):85–93PubMedGoogle Scholar
  73. Ericson M, Molander A, Stomberg R, Söderpalm B (2006) Taurine elevates dopamine levels in the rat nucleus accumbens; antagonism by strychnine. Eur J Neurosci 23(12):3225–3229PubMedGoogle Scholar
  74. Fahlke C, Hansen S, Engel JA, Hård E (1994) Effects of ventral striatal 6-OHDA lesions or amphetamine sensitization on ethanol consumption in the rat. Pharmacol Biochem Behav 47:345–349PubMedGoogle Scholar
  75. Ferraro L, Tanganelli S, O’Connor WT, Antonelli T, Rambert F, Fuxe K (1996) The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. Eur J Pharmacol 306(1–3):33–39PubMedGoogle Scholar
  76. Floresco SB, Yang CR, Phillips AG, Blaha CD (1998) Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat. Eur J Neurosci 10(4):1241–1251PubMedGoogle Scholar
  77. Foddai M, Dosia G, Spiga S, Diana M (2004) Acetaldehyde increases dopaminergic neuronal activity in the VTA. Neuropsychopharmacology 29:530–536PubMedGoogle Scholar
  78. Forman SA, Righi DL, Miller KW (1989) Ethanol increases agonist affinity for nicotinic receptors from Torpedo. Biochim Biophys Acta 987(1):95–103PubMedGoogle Scholar
  79. Frohlich R, Patzelt C, Illes P (1994) Inhibition by ethanol of excitatory amino acid receptors and nicotinic acetylcholine receptors at rat locus coeruleus neurons. Naunyn-Schmied Arch Pharmacol 350:626–631Google Scholar
  80. Fucito LM, Toll BA, Wu R, Romano DM, Tek E, O’Malley SS (2011) A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology (Berl) 215(4):655–663Google Scholar
  81. García-Cabezas MA, Martínez-Sánchez P, Sánchez-González MA, Garzón M, Cavada C (2009) Dopamine innervation in the thalamus: monkey versus rat. Cereb Cortex 19:424–234PubMedGoogle Scholar
  82. George SR, Fan T, Ng GY, Jung SY, O’Dowd BF, Naranjo CA (1995) Low endogenous dopamine function in brain predisposes to high alcohol preference and consumption: reversal by increasing synaptic dopamine. J Pharmacol Exp Ther 273:373–379PubMedGoogle Scholar
  83. Gianoulakis C (1996) Implications of endogenous opioids and dopamine in alcoholism: human and basic science studies. Alcohol Alcohol 31(Suppl 1):33–42PubMedGoogle Scholar
  84. Gianoulakis C, Krishnan B, Thavundayil J (1996) Enhanced sensitivity of pituitary beta-endorphin to ethanol in subjects at high risk of alcoholism. Arch Gen Psychiatry 53(3):250–257PubMedGoogle Scholar
  85. Gonzales RA, Weiss F (1998) Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens. J Neurosci 18(24):10663–10671PubMedGoogle Scholar
  86. Grant KA (1994) Emerging neurochemical concepts in the actions of ethanol at ligand-gated ion channels. Behav Pharmacol 5(4–5):383–404PubMedGoogle Scholar
  87. Grudzinska J, Schemm R, Haeger S, Nicke A, Schmalzing G, Betz H, Laube B (2005) The beta subunit determines the ligand binding properties of synaptic glycine receptors. Neuron 45(5):727–739PubMedGoogle Scholar
  88. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48(1):23–29PubMedGoogle Scholar
  89. Hansen S, Fahlke C, Hård E, Thomasson R (1995) Effects of ibotenic acid lesions of the ventral striatum and the medial prefrontal cortex on ethanol consumption in the rat. Alcohol 12:397–402PubMedGoogle Scholar
  90. Harris BR, Prendergast MA, Gibson DA, Rogers DT, Blanchard JA, Holley RC, Fu MC, Hart SR, Pedigo NW, Littleton JM (2002) Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol Clin Exp Res 26(12):1779–1793PubMedGoogle Scholar
  91. Hedlund L, Wahlström G (1998a) The effect of diazepam on voluntary ethanol intake in a rat model of alcoholism. Alcohol Alcohol 33(3):207–219PubMedGoogle Scholar
  92. Hedlund L, Wahlström G (1998b) Citalopram as an inhibitor of voluntary ethanol intake in the male rat. Alcohol 16(4):295–303PubMedGoogle Scholar
  93. Heinz A, Siessmeier T, Wrase J, Buchholz HG, Grunder G, Kumakura Y, Cumming P, Schreckenberger M, Smolka MN, Rösch F, Mann K, Bartenstein P (2005) Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients. Am J Psychiatry 162:1515–1520PubMedGoogle Scholar
  94. Hevers W, Lüddens H (1998) The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol 18:35–86PubMedGoogle Scholar
  95. Hodge CW, Samson HH, Chappelle AM (1997) Alcohol self-administration: further examination of the role of dopamine receptors in the nucleus accumbens. Alcohol Clin Exp Res 21:1083–1091PubMedGoogle Scholar
  96. Hoffman PL, Rabe CS, Moses F, Tabakoff B (1989) N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. J Neurochem 52:1937–1940PubMedGoogle Scholar
  97. Howland JG, Taepavarapruk P, Phillips AG (2002) Glutamate receptor-dependent modulation of dopamine efflux in the nucleus accumbens by basolateral, but not central, nucleus of the amygdala in rats. J Neurosci 22(3):1137–1145PubMedGoogle Scholar
  98. Hyytiä P (1993) Involvement of mu-opioid receptors in alcohol drinking by alcohol-preferring AA rats. Pharmacol Biochem Behav 45(3):697–701PubMedGoogle Scholar
  99. Ikemoto S, McBride WJ, Murphy JM, Lumeng L, Li TK (1997) 6-OHDA-lesions of the nucleus accumbens disrupt the acquisition but not the maintenance of ethanol consumption in the alcohol-preferring P line of rats. Alcohol Clin Exp Res 21:1042–1046PubMedGoogle Scholar
  100. 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(2–3):337–338PubMedGoogle Scholar
  101. Inoue F, Frank GB (1967) Effects of ethyl alcohol on excitability and on neuromuscular transmission in frog skeletal muscle. Br J Pharmacol 30:186–193Google Scholar
  102. Iorio KR, Reinlib L, Tabakoff B, Hoffman PL (1992) Chronic exposure of cerebellar granule cells to ethanol results in increased N-methyl-D-aspartate receptor function. Mol Pharmacol 41:1142–1148PubMedGoogle Scholar
  103. Jensen AA, Frolund B, Liljefors T, Krogsgaard-Larsen P (2005) Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications and therapeutic inspirations. J Med Chem 48(15):4705–4745PubMedGoogle Scholar
  104. Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (2006a) Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol 11(1):45–54PubMedGoogle Scholar
  105. Jerlhag E, Grøtli M, Luthman K, Svensson L, Engel JA (2006b) Role of the subunit composition of central nicotinic acetylcholine receptors for the stimulatory and dopamine-enhancing effects of ethanol. Alcohol Alcohol 41(5):486–493PubMedGoogle Scholar
  106. Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA (2007) Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addict Biol 12(1):6–16PubMedGoogle Scholar
  107. Jerlhag E, Egecioglu E, Dickson SL, Svensson L, Engel JA (2008) Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens. Eur Neuropsychopharmacol 18(7):508–518PubMedGoogle Scholar
  108. Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA (2009) Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci U S A 106(27):11318–11323PubMedCentralPubMedGoogle Scholar
  109. Jiang LH, Ashby CR Jr, Kasser RJ, Wang RY (1990) The effect of intraventricular administration of the 5-HT3 receptor agonist 2-methylserotonin on the release of dopamine in the nucleus accumbens: an in vivo chronocoulometric study. Brain Res 513:156–160PubMedGoogle Scholar
  110. Jonsson S, Kerekes N, Hyytiä P, Ericson M, Söderpalm B (2009) Glycine receptor expression in the forebrain of male AA/ANA rats. Brain Res 1305(Supplement 1):S27–S36PubMedGoogle Scholar
  111. Kaczmarek HJ, Kiefer SW (2000) Microinjections of dopaminergic agents in the nucleus accumbens affect ethanol consumption but not palatability. Pharmacol Biochem Behav 66:307–312PubMedGoogle Scholar
  112. Kandel ER, Schwartz JH, Jessell TM (2000) Principles of neural science, 4th edn. McGraw-Hill, New York. ISBN 0-8385-7701-6Google Scholar
  113. Karreman M, Moghaddam B (1996) The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem 66(2):589–598PubMedGoogle Scholar
  114. Karreman M, Westerink BH, Moghaddam B (1996) Excitatory amino acid receptors in the ventral tegmental area regulate dopamine release in the ventral striatum. J Neurochem 67(2):601–607PubMedGoogle Scholar
  115. Karamanakos PN, Pappas P, Stephanou P, Marselos M (2001) Differentiation of disulfiram effects on central catecholamines and hepatic ethanol metabolism. Pharmacol Toxicol 88:106–110PubMedGoogle Scholar
  116. Katner SN, Kerr TM, Weiss F (1996) Ethanol anticipation enhances dopamine efflux in the nucleus accumbens of alcohol-preferring (P) but not Wistar rats. Behav Pharmacol 7(7):669–674PubMedGoogle Scholar
  117. Katner SN, Weiss F (1999) Ethanol-associated olfactory stimuli reinstate ethanol-seeking behavior after extinction and modify extracellular dopamine levels in the nucleus accumbens. Alcohol Clin Exp Res 23(11):1751–1760PubMedGoogle Scholar
  118. Kaur S, Ryabinin AE (2010) Ghrelin receptor antagonism decreases alcohol consumption and activation of perioculomotor urocortin-containing neurons. Alcohol Clin Exp Res 34(9):1525–1534PubMedCentralPubMedGoogle Scholar
  119. Kiianmaa K, Andersson K, Fuxe K (1979) On the role of ascending dopamine systems in the control of voluntary ethanol intake and ethanol intoxication. Pharmacol Biochem Behav 10(4):603–608PubMedGoogle Scholar
  120. Kim AK, Souza-Formigoni ML (2010) Disulfiram impairs the development of behavioural sensitization to the stimulant effect of ethanol. Behav Brain Res 207(2):441–446. Epub 2009 Nov 3Google Scholar
  121. Kim DJ, Yoon SJ, Choi B, Kim TS, Woo YS, Kim W, Myrick H, Peterson BS, Choi YB, Kim YK, Jeong J (2005) Increased fasting plasma ghrelin levels during alcohol abstinence. Alcohol Alcohol 40(1):76–79PubMedGoogle Scholar
  122. Kirsch J (2006) Glycinergic transmission. Cell Tissue Res 326(2):535–540PubMedGoogle Scholar
  123. Koistinen M, Tuomainen P, Hyytiä P, Kiianmaa K (2001) Naltrexone suppresses ethanol intake in 6-hydroxydopamine-treated rats. Alcohol Clin Exp Res 25:1605–1612PubMedGoogle Scholar
  124. Koob GF (1992) Neural mechanisms of drug reinforcement. The neurobiology of drug and alcohol addiction, vol 654, PW Kalivas and HH Samson. New York. pp 171–191Google Scholar
  125. Koob GF, LeMoal M (2001) Drug Addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129PubMedGoogle Scholar
  126. Korpi ER (1994) Role of GABAA receptors in the actions of alcohol and in alcoholism: recent advances. Alcohol Alcohol 29:115–129PubMedGoogle Scholar
  127. Kraus T, Schanze A, Gröschl M, Bayerlein K, Hillemacher T, Reulbach U, Kornhuber J, Bleich S (2005) Ghrelin levels are increased in alcoholism. Alcohol Clin Exp Res 29(12):2154–2157PubMedGoogle Scholar
  128. Kuhse J, Betz H, Kirsch J (1995) The inhibitory glycine receptor: architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex. Curr Opin Neurobiol 5(3):318–323PubMedGoogle Scholar
  129. Landgren S, Simms JA, Hyytiä P, Engel JA, Bartlett SE, Jerlhag E (2011) Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addict Biol. doi:  10.1111/j.1369-1600.2010.00280.x
  130. Larsson A, Edström L, Svensson L, Söderpalm B, Engel JA (2005) Voluntary ethanol intake increases extracellular acetylcholine levels in the ventral tegmental area in the rat. Alcohol Alcohol 40(5):349–358PubMedGoogle Scholar
  131. Larsson A, Jerlhag E, Svensson L, Söderpalm B, Engel JA (2004) Is an alpha-conotoxin MII-sensitive mechanism involved in the neurochemical, stimulatory, and rewarding effects of ethanol? Alcohol 34(2–3):239–250PubMedGoogle Scholar
  132. Le AD, Corrigall WA, Harding JW, Juzytsch W, Li TK (2000) Involvement of nicotinic receptors in alcohol self-administration. Alcohol Clin Exp Res 24(2):155–163PubMedGoogle Scholar
  133. Levy AD, Murphy JM, McBride WJ, Lumeng L, Li TK (1991) Microinjection of sulpiride into the nucleus accumbens increases ethanol drinking in alcohol-preferring (P) rats. Alcohol Alcohol Suppl 1:417–420PubMedGoogle Scholar
  134. Li Y, Xu TL (2002) State-dependent cross-inhibition between anionic GABA(A) and glycine ionotropic receptors in rat hippocampal CA1 neurons. Neuroreport 13:223–226PubMedGoogle Scholar
  135. Li Z, Zharikova A, Bastian J, Esperon L, Hebert N, Mathes C, Rowland NE, Peris J (2008) High temporal resolution of amino acid levels in rat nucleus accumbens during operant ethanol self-administration: involvement of elevated glycine in anticipation. J Neurochem 106(1):170–181PubMedGoogle Scholar
  136. Lidö HH, Stomberg R, Fagerberg A, Ericson M, Söderpalm B (2009) Glycine reuptake inhibition: a novel principle for prevention of ethanol-induced dopamine release. Alcohol Clin Exp Res 33(7):1–7Google Scholar
  137. Lisman JE, Pi HJ, Zhang Y, Otmakhova NA (2010) A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia. Biol Psychiatry 68(1):17–24PubMedCentralPubMedGoogle Scholar
  138. Liu W, Thielen RJ, Rodd ZA, McBride WJ (2006) Activation of serotonin-3 receptors increases dopamine release within the ventral tegmental area of Wistar and alcohol-preferring (P) rats. Alcohol 40:167–176PubMedCentralPubMedGoogle Scholar
  139. Löf E, Ericson M, Stomberg R, Söderpalm B (2007a) Characterization of ethanol-induced dopamine elevation in the rat nucleus accumbens. Eur J Pharmacol 555(2–3):148–155PubMedGoogle Scholar
  140. Löf E, Olausson P, deBejczy A, Stomberg R, McIntosh JM, Taylor JR, Söderpalm B (2007b) Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology (Berl) 195(3):333–343Google Scholar
  141. Lopreato GF, Banerjee P, Mihic SJ (2003) Amino acids in transmembrane domain two influence anesthetic enhancement of serotonin-3A receptor function. Brain Res Mol Brain Res 118:45–51PubMedGoogle Scholar
  142. Lovinger DM (1991) Ethanol potentiates ion current mediated by 5-HT3 receptors on neuroblastoma cells and isolated neurons. Alcohol Alcohol Suppl 1:181–185PubMedGoogle Scholar
  143. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724PubMedGoogle Scholar
  144. Lovinger DM, White G (1991) Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells, isolated adult mammalian neurons. Mol Pharmacol 40:263–270PubMedGoogle Scholar
  145. Lovinger DM, Zhou Q (1998) Alcohol effects on the 5-HT3 ligand-gated ion channel. Toxicol Lett 100–101:239–246PubMedGoogle Scholar
  146. Lüddens H, Korpi ER (1995) Biological function of GABAA/benzodiazepine receptor heterogeneity. J Psychiatr Res 29:77–94PubMedGoogle Scholar
  147. Lukas RJ, Changeux JP, Le Novère N, Albuquerque EX, Balfour DJ, Berg DK, Bertrand D, Chiappinelli VA, Clarke PB, Collins AC, Dani JA, Grady SR, Kellar KJ, Lindstrom JM, Marks MJ, Quik M, Taylor PW, Wonnacott S (1999) International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol Rev 51(2):397–401PubMedGoogle Scholar
  148. Lynch JW (2004) Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 84(4):1051–1095PubMedGoogle Scholar
  149. Lyness WH, Smith FL (1992) Influence of dopaminergic and serotonergic neurons on intravenous ethanol self-administration in the rat. Pharmacol Biochem Behav 42:187–192PubMedGoogle Scholar
  150. Malosio ML, Marqueze-Pouey B, Kuhse J, Betz H (1991) Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain. Embo J 10:2401–2409PubMedGoogle Scholar
  151. Mansour A, Fox CA, Akil H, Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18(1):22–29PubMedGoogle Scholar
  152. Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A, Kegeles L, Talbot P, Evans S, Krystal J, Laruelle M, Abi-Dargham A (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58:779–786PubMedGoogle Scholar
  153. Marzalec W, Aistrup GL, Narahashi T (1999) Ethanol-nicotine interactions at alpha-bungarotoxin-insensitive nicotinic acetylcholine receptors in rat cortical neurons. Alcohol Clin Exp Res 23:439–445Google Scholar
  154. Mascia MP, Maiya R, Borghese CM, Lobo IA, Hara K, Yamakura T, Gong DH, Beckstead MJ (2001) Does acetaldehyde mediate ethanol action in the central nervous system? Alcohol Clin Exp Res 25:1570–1575PubMedGoogle Scholar
  155. Mascia MP, Mihic SJ, Valenzuela CF, Schofield PR, Harris RA (1996) A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors. Mol Pharmacol 50(2):402–406PubMedGoogle Scholar
  156. McKee SA, Harrison EL, O’Malley SS, Krishnan-Sarin S, Shi J, Tetrault JM, Picciotto MR, Petrakis IL, Estevez N, Balchunas E (2009) Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 66:185–190PubMedCentralPubMedGoogle Scholar
  157. Mehta AK, Ticku MK (1988) Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels. J Pharmacol Exp Ther 246:558–564PubMedGoogle Scholar
  158. Mehta AK, Ticku MK (1999) An update on GABAA receptors. Brain Res Brain Res Rev 29:196–217PubMedGoogle Scholar
  159. Melendez RI, Rodd-Henricks ZA, Engleman EA, Li TK, McBride WJ, Murphy JM (2002) Microdialysis of dopamine in the nucleus accumbens of alcohol-preferring (P) rats during anticipation and operant self-administration of ethanol. Alcohol Clin Exp Res 26(3):318–325PubMedGoogle Scholar
  160. Melis M, Enrico P, Peana AT, Diana M (2007) Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system. Eur J Neurosci 26:2824–2833PubMedGoogle Scholar
  161. Mhatre MC, Ticku MK (1993) Alcohol: effects on GABAA receptor function and gene expression. Alcohol Alcohol Suppl 2:331–335PubMedGoogle Scholar
  162. Michel ME, Bolger G, Weissman BA (1985) Binding of a new opiate antagonist, nalmefene, to rat brain membranes. Methods Find Exp Clin Pharmacol 7(4):175–177PubMedGoogle Scholar
  163. Moghaddam B, Gruen RJ, Roth RH, Bunney BS, Adams RN (1990) Effect of L-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies. Brain Res 518(1-2):55–60PubMedGoogle Scholar
  164. Moghaddam B, Bolinao ML (1994) Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens. Neurosci Lett 178(1):99–102PubMedGoogle Scholar
  165. Molander A, Söderpalm B (2005a) Glycine receptors regulate dopamine release in the rat nucleus accumbens. Alcohol Clin Exp Res 29:17–26PubMedGoogle Scholar
  166. Molander A, Söderpalm B (2005b) Accumbal strychnine-sensitive glycine receptors: an access point for ethanol to the brain reward system. Alcohol Clin Exp Res 29:27–37PubMedGoogle Scholar
  167. Molander A, Lidö HH, Löf E, Ericson M, Söderpalm B (2007) The glycine reuptake inhibitor Org 25935 decreases ethanol intake and preference in male wistar rats. Alcohol Alcohol 42(1):11–18PubMedGoogle Scholar
  168. Molander A, Löf E, Stomberg R, Ericson M, Söderpalm B (2005) Involvement of accumbal glycine receptors in the regulation of voluntary ethanol intake in the rat. Alcohol Clin Exp Res 29:38–45PubMedGoogle Scholar
  169. Myers WD, Ng KT, Singer G (1982) Intravenous self-administration of acetaldehyde in the rat as a function of schedule, food deprivation and photoperiod. Pharmacol Biochem Behav 17:807–811PubMedGoogle Scholar
  170. Nealey KA, Smith AW, Davis SM, Smith DG, Walker BM (2011) κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats. Neuropharmacology 61(1–2):35–42PubMedGoogle Scholar
  171. Nordberg A, Wahlstrom G, Eriksson B (1985) Relations between muscimol, quinuclidinyl benzilate and nicotine binding sites in brain after very long treatment with ethanol in rats. Eur J Pharmacol 115(2–3):301–304PubMedGoogle Scholar
  172. Okada K (1967) Effects of alcohols and acetone on the neuromuscular junction of frog. Jpn J Physiol 17:412–413Google Scholar
  173. Olausson P, Jentsch JD, Taylor JR (2004a) Nicotine enhances responding with conditioned reinforcement. Psychopharmacology (Berl) 171:173–178Google Scholar
  174. Olausson P, Jentsch JD, Taylor JR (2004b) Repeated nicotine exposure enhances responding with conditioned reinforcement. Psychopharmacology (Berl) 173:98–104Google Scholar
  175. Olive MF, Nannini MA, Ou CJ, Koenig HN, Hodge CW (2002) Effects of acute acamprosate and homotaurine on ethanol intake and ethanol-stimulated mesolimbic dopamine release. Eur J Pharmacol 437(1–2):55–61PubMedGoogle Scholar
  176. Olsen RW, Hanchar HJ, Meera P, Wallner M (2007) GABAA receptor subtypes: the “one glass of wine” receptors. Alcohol 41:201–209PubMedCentralPubMedGoogle Scholar
  177. Ortiz A, Griffiths PJ, Littleton JM (1974) A comparison of the effects of chronic administration of ethanol and acetaldehyde to mice: evidence for a role of acetaldehyde in ethanol dependence. J Pharm Pharmacol 26:249–260PubMedGoogle Scholar
  178. Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O’Brien CP (2003) A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546–1552PubMedGoogle Scholar
  179. Parsons LH, Justice JB Jr (1993) Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Brain Res 606:195–199PubMedGoogle Scholar
  180. Penland S, Hoplight B, Obernier J, Crews FT (2001) Effects of nicotine on ethanol dependence and brain damage. Alcohol 24(1):45–54PubMedGoogle Scholar
  181. Peoples RW, White G, Lovinger DM, Weight FF (1997) Ethanol inhibition of N-methyl-D-aspartate-activated current in mouse hippocampal neurones: whole-cell patch-clamp analysis. Br J Pharmacol 122:1035–1042PubMedGoogle Scholar
  182. Pettit HO, Ettenberg A, Bloom FE, Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology (Berl) 84(2):167–173Google Scholar
  183. Petrakis I, Ralevski E, OBrien E, Jane S, Keegan K, Rounsaville B, Krystal J (2008) Mecamylamine treatment for alcohol dependence in smokers and non-smokers. Alcohol Clin Exp Ther Suppl 32(6):256AGoogle Scholar
  184. Phillips TJ, Brown KJ, Burkhart-Kasch S, Wenger CD, Kelly MA, Rubinstein M, Grandy DK, Low MJ (1998) Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors. Nat Neurosci 1:610–615PubMedGoogle Scholar
  185. Popp RL, Lickteig R, Browning MD, Lovinger DM (1998) Ethanol sensitivity and subunit composition of NMDA receptors in cultured striatal neurons. Neuropharmacology 37:45–56PubMedGoogle Scholar
  186. Quarfordt SD, Kalmus GW, Myers RD (1991) Ethanol drinking following 6-OHDA lesions of nucleus accumbens and tuberculum olfactorium of the rat. Alcohol 8:211–217PubMedGoogle Scholar
  187. Quertemont E, Tambour S, Tirelli E (2005) The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies. Prog Neurobiol 75(4):247–274PubMedGoogle Scholar
  188. Rabe CS, Tabakoff B (1990) Glycine site-directed agonists reverse the actions of ethanol at the N-methyl-D-aspartate receptor. Mol Pharmacol 38:753–757PubMedGoogle Scholar
  189. Racca C, Gardiol A, Triller A (1998) Cell-specific dendritic localization of glycine receptor alpha subunit messenger RNAs. Neuroscience 84(4):997–1012PubMedGoogle Scholar
  190. Rajendra S, Lynch JW, Schofield PR (1997) The glycine receptor. Pharmacol Ther 73(2):121–146PubMedGoogle Scholar
  191. Ramchandani VA, Umhau J, Pavon FJ, Ruiz-Velasco V, Margas W, Sun H, Damadzic R, Eskay R, Schoor M, Thorsell A, Schwandt ML, Sommer WH, George DT, Parsons LH, Herscovitch P, Hommer D, Heilig M (2011) A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry 16:809–817PubMedCentralPubMedGoogle Scholar
  192. Rassnick S, Pulvirenti L, Koob GF (1992) Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology (Berl) 109:92–98Google Scholar
  193. Rassnick S, Stinus L, Koob GF (1993) The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat. Brain Res 623:16–24PubMedGoogle Scholar
  194. Ray LA, Hutchison KE (2007) Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response: a double-blind placebo-controlled study. Arch Gen Psychiatry 64(9):1069–1077PubMedGoogle Scholar
  195. Reid MS, Mickalian JD, Delucchi KL, Berger SP (1999) A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects. Neuropsychopharmacology 20:297–307PubMedGoogle Scholar
  196. Reid MS, Mickalian JD, Delucchi KL, Hall SM, Berger SP (1998) An acute dose of nicotine enhances cue-induced cocaine craving. Drug Alcohol Depend 49:95–104PubMedGoogle Scholar
  197. Rezvani AH, Levin ED (2002) Nicotine-alcohol interactions and cognitive function in rats. Pharmacol Biochem Behav 72(4):865–872PubMedGoogle Scholar
  198. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18(3):247–291PubMedGoogle Scholar
  199. Rodd ZA, Bell RL, Oster SM, Toalston JE, Pommer TJ, McBride WJ, Murphy JM (2010) Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats. Alcohol 44:245–255PubMedGoogle Scholar
  200. Rodd ZA, Bell RL, Zhang Y, Murphy JM, Goldstein A, Zaffaroni A, Li TK, McBride WJ (2005) Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: involvement of dopamine and serotonin. Neuropsychopharmacology 30:330–338PubMedGoogle Scholar
  201. Rodd ZA, Gryszowka VE, Toalston JE, Oster SM, Ji D, Bell RL, McBride WJ (2007) The reinforcing actions of a serotonin-3 receptor agonist within the ventral tegmental area: evidence for subregional and genetic differences and involvement of dopamine neurons. J Pharmacol Exp Ther 321:1003–1012PubMedCentralPubMedGoogle Scholar
  202. Rodd-Hendricks 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 72:55–64Google Scholar
  203. Rüsch D, Musset B, Wulf H, Schuster A, Raines DE (2007) Subunit-dependent modulation of the 5-hydroxytryptamine type 3 receptor open-close equilibrium by n-alcohols. J Pharmacol Exp Ther 321:1069–1074PubMedGoogle Scholar
  204. Sánchez-González MA, García-Cabezas MA, Rico B, Cavada C (2005) The primate thalamus is a key target for brain dopamine. J Neurosci 25:6076–6083PubMedGoogle Scholar
  205. Santhakumar V, Wallner M, Otis TS (2007) Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition. Alcohol 41:211–221PubMedCentralPubMedGoogle Scholar
  206. Sato K, Zhang JH, Saika T, Sato M, Tada K, Tohyama M (1991) Localization of glycine receptor alpha 1 subunit mRNA-containing neurons in the rat brain: an analysis using in situ hybridization histochemistry. Neuroscience 43(2–3):381–395PubMedGoogle Scholar
  207. Sato K, Kiyama H, Tohyama M (1992) Regional distribution of cells expressing glycine receptor alpha 2 subunit mRNA in the rat brain. Brain Res 590(1–2):95–108PubMedGoogle Scholar
  208. 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(4):375–383PubMedGoogle Scholar
  209. Schilström B, Rawal N, Mameli-Engvall M, Nomikos GG, Svensson TH (2003) Dual effects of nicotine on dopamine neurons mediated by different nicotinic receptor subtypes. Int J Neuropsychopharmacol 6(1):1–11PubMedGoogle Scholar
  210. Schneider ER, Rada P, Darby RD, Leibowitz SF, Hoebel BG (2007) Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin. Alcohol Clin Exp Res 31(11):1858–1865PubMedGoogle Scholar
  211. Schulteis G, Markou A, Cole M, Koob GF (1995) Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci USA 92(13):5880–5884PubMedGoogle Scholar
  212. Schulz R, Wüster M, Duka T, Herz A (1980) Acute and chronic ethanol treatment changes endorphin levels in brain and pituitary. Psychopharmacology (Berl) 68(3):221–227Google Scholar
  213. Seizinger BR, Bovermann K, Maysinger D, Höllt V, Herz A (1983) Differential effects of acute and chronic ethanol treatment on particular opioid peptide systems in discrete regions of rat brain and pituitary. Pharmacol Biochem Behav 18 Suppl 1:361–369Google Scholar
  214. Shoemaker WJ, Vavrousek-Jakuba E, Arons CD, Kwok FC (2002) The acquisition and maintenance of voluntary ethanol drinking in the rat: effects of dopaminergic lesions and naloxone. Behav Brain Res 137:139–148PubMedGoogle Scholar
  215. Smith BR, Amit Z, Splawinsky J (1984) Conditioned place preference induced by intraventricular infusions of acetaldehyde. Alcohol 1:193–195PubMedGoogle Scholar
  216. Snell LD, Nunley KR, Lickteig RL, Browning MD, Tabakoff B, Hoffman PL (1996) Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion. Brain Res Mol Brain Res 40:71–78PubMedGoogle Scholar
  217. Snell LD, Tabakoff B, Hoffman PL (1993) Radioligand binding to the N-methyl-D-aspartate receptor/ionophore complex: alterations by ethanol in vitro and by chronic in vivo ethanol ingestion. Brain Res 602:91–98PubMedGoogle Scholar
  218. Söderpalm B, Ericson M, Olausson P, Blomqvist O, Engel JA (2000) Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res 113:85–96PubMedGoogle Scholar
  219. Söderpalm B, Löf E, Ericson M (2009) Mechanistic studies of ethanol’s interaction with the mesolimbic dopamine reward system. Pharmacopsychiatry 42(Suppl 1):S87–S94PubMedGoogle Scholar
  220. Song W, Chattipakorn SC, McMahon LL (2006) Glycine-gated chloride channels depress synaptic transmission in rat hippocampus. J Neurophysiol 95(4):2366–2379PubMedGoogle Scholar
  221. Spanagel R, Weiss F (1999) The dopamine hypothesis of reward: past and current status. Trends Neurosci 22(11):521–527PubMedGoogle Scholar
  222. Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE (2007) Varenicline, an {alpha}4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. PNAS 104(30):12518–12523PubMedGoogle Scholar
  223. Suzdak PD, Schwartz RD, Skolnick P, Paul SM (1986) Ethanol stimulates gamma-aminobutyric acid receptor-mediated chloride transport in rat brain synaptoneurosomes. Proc Natl Acad Sci U S A 83:4071–4075PubMedCentralPubMedGoogle Scholar
  224. Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, Fritschy JM, Rudolph U, Lüscher C (2010) Neural bases for addictive properties of benzodiazepines. Nature 463:769–774PubMedCentralPubMedGoogle Scholar
  225. Tanganelli S, O’Connor WT, Ferraro L, Bianchi C, Beani L, Ungerstedt U, Fuxe K (1994) Facilitation of GABA release by neurotensin is associated with a reduction of dopamine release in rat nucleus accumbens. Neuroscience 60(3):649–657PubMedGoogle Scholar
  226. Ticku MK (1990) Alcohol and GABA-benzodiazepine receptor function. Ann Med 22:241–246PubMedGoogle Scholar
  227. Ticku MK, Lowrimore P, Lehoullier P (1986) Ethanol enhances GABA-induced 36Cl-influx in primary spinal cord cultured neurons. Brain Res Bull 17:123–126PubMedGoogle Scholar
  228. Tizabi Y, Bai L, Copeland RL Jr, Taylor RE (2007) Combined effects of systemic alcohol and nicotine on dopamine release in the nucleus accumbens shell. Alcohol Alcohol 42(5):413–416PubMedGoogle Scholar
  229. Tizabi Y, Copeland RL Jr, Louis VA, Taylor RE (2002) Effects of combined systemic alcohol and central nicotine administration into ventral tegmental area on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res 26(3):394–399PubMedGoogle Scholar
  230. Trigo JM, Martin-García E, Berrendero F, Robledo P, Maldonado R (2010) The endogenous opioid system: a common substrate in drug addiction. Drug Alcohol Depend 108(3):183–194PubMedGoogle Scholar
  231. Urban NB, Kegeles LS, Slifstein M, Xu X, Martinez D, Sakr E, Castillo F, Moadel T, O’Malley SS, Krystal JH, Abi-Dargham A (2010) Sex differences in striatal dopamine release in young adults after oral alcohol challenge: a positron emission tomography imaging study with [¹¹C]raclopride. Biol Psychiatry 68:689–696PubMedCentralPubMedGoogle Scholar
  232. Vengeliene V, Leonardi-Essmann F, Sommer WH, Marston HM, Spanagel R (2010) Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats. Biol Psychiatry 68(8):704–711PubMedGoogle Scholar
  233. Volkow ND, Wang GJ, Fowler JS, Logan J, Hitzemann R, Ding YS, Pappas N, Shea C, Piscani K (1996) Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res 20:1594–1598PubMedGoogle Scholar
  234. Volkow ND, Wang GJ, Maynard L, Fowler JS, Jayne B, Telang F, Logan J, Ding YS, Gatley SJ, Hitzemann R, Wong C, Pappas N (2002) Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study. Psychiatry Res 116:163–172PubMedGoogle Scholar
  235. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M, Ma Y, Pradhan K, Wong C (2007) Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci 27:12700–12706PubMedGoogle Scholar
  236. Volpicelli JR, Davis MA, Olgin JE (1986) Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci 38(9):841–847PubMedGoogle Scholar
  237. Wallner M, Olsen RW (2008) Physiology and pharmacology of alcohol: the imidazobenzodiazepine alcohol antagonist site on subtypes of GABAA receptors as an opportunity for drug development? Br J Pharmacol 154:288–298PubMedGoogle Scholar
  238. Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology 33(3):643–652PubMedCentralPubMedGoogle Scholar
  239. Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258PubMedGoogle Scholar
  240. Weiss F, Parsons LH, Schulteis G, Hyytiä P, Lorang MT, Bloom FE, Koob GF (1996) Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. J Neurosci 16(10):3474–3485PubMedGoogle Scholar
  241. Wise RA (1987) The role of reward pathways in the development of drug dependence. Pharmacol Ther 35(1–2):227–263PubMedGoogle Scholar
  242. Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225PubMedGoogle Scholar
  243. Wozniak KM, Pert A, Linnoila M (1990) Antagonism of 5-HT3 receptors attenuates the effects of ethanol on extracellular dopamine. Eur J Pharmacol 187:287–289PubMedGoogle Scholar
  244. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (2000) The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141(11):4325–4328PubMedGoogle Scholar
  245. Wu G, Miller KW (1994) Ethanol enhances agonist-induced fast desensitization in nicotinic acetylcholine receptors. Biochemistry 33(31):9085–9091PubMedGoogle Scholar
  246. 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(2):307–318PubMedCentralPubMedGoogle Scholar
  247. Xiao C, Zhang J, Krnjevic K, Ye JH (2007) Effects of ethanol on midbrain neurons: role of opioid receptors. Alcohol Clin Exp Res 31(7):1106–1113PubMedGoogle Scholar
  248. Xiao C, Ye JH (2008) Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of mu-opioid receptors. Neuroscience 153(1):240–248PubMedCentralPubMedGoogle Scholar
  249. Yang X, Criswell HE, Breese GR (1999a) Action of ethanol on responses to nicotine from cerebellar interneurons and medial septal neurons: relationship to methyllycaconitine inhibition of nicotine responses. Alcohol Clin Exp Res 23:983–990PubMedGoogle Scholar
  250. Yang X, Criswell HE, Breese GR (1999b) Action of ethanol on responses to nicotine from cerebellar Purkinje neurons: relationship to methyllycaconitine (MLA) inhibition of nicotine responses. Neurochem Int 35:185–194PubMedGoogle Scholar
  251. Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryrock 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 16:1024–1028PubMedCentralPubMedGoogle Scholar
  252. Ye J (2000) Physiology and pharmacology of native glycine receptors in developing rat ventral tegmental area neurons. Brain Res 862(1–2):74–82PubMedGoogle Scholar
  253. Yoder KK, Constantinescu CC, Kareken DA, Normandin MD, Cheng TE, O’Connor SJ, Morris ED (2007) Heterogeneous effects of alcohol on dopamine release in the striatum: a PET study. Alcohol Clin Exp Res 31:965–973PubMedGoogle Scholar
  254. Yoshida K, Engel J, Liljequist S (1982) The effect of chronic ethanol administration of high affinity 3H-nicotinic binding in rat brain. Naunyn Schmiedebergs Arch Pharmacol 321(1):74–76 PubMedGoogle Scholar
  255. Yoshimoto K, McBride WJ, Lumeng L, Li TK (1992) Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens. Alcohol 9:17–22PubMedGoogle Scholar
  256. Yoshimoto K, Yayama K, Sorimachi Y, Tani J, Ogata M, Nishimura A, Yoshida T, Ueda S, Komura S (1996) Possibility of 5-HT3 receptor involvement in alcohol dependence: a microdialysis study of nucleus accumbens dopamine and serotonin release in rats with chronic alcohol consumption. Alcohol Clin Exp Res 20(9 Suppl):311A–319APubMedGoogle Scholar
  257. Young EM, Mahler S, Chi H, de Wit H (2005) Mecamylamine and ethanol preference in healthy volunteers. Alcohol Clin Exp Res 29:58–65PubMedGoogle Scholar
  258. Youngren KD, Daly DA, Moghaddam B (1993) Distinct actions of endogenous excitatory amino acids on the outflow of dopamine in the nucleus accumbens. J Pharmacol Exp Ther 264(1):289–293 PubMedGoogle Scholar
  259. Yu D, Zhang L, Eiselé JL, Bertrand D, Changeux JP, Weight FF (1996) Ethanol inhibition of nicotinic acetylcholine type alpha 7 receptors involves the amino-terminal domain of the receptor. Mol Pharmacol 50(4):1010–1016PubMedGoogle Scholar
  260. Zachariou V, Caldarone BJ, Weathers-Lowin A, George TP, Elsworth JD, Roth RH, Changeux JP, Picciotto MR (2001) Nicotine receptor inactivation decreases sensitivity to cocaine. Neuropsychopharmacology 24:576–589PubMedGoogle Scholar
  261. Zeise ML, Kasparov S, Capogna M, Zieglgänsberger W (1993) Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 231(1):47–52PubMedGoogle Scholar
  262. Zetterström T, Fillenz M (1990) Local administration of flurazepam has different effects on dopamine release in striatum and nucleus accumbens: a microdialysis study. Neuropharmacology 29(2):129–134PubMedGoogle Scholar
  263. Zhang HX, Thio LL (2007) Zinc enhances the inhibitory effects of strychnine-sensitive glycine receptors in mouse hippocampal neurons. J Neurophysiol 98(6):3666–3676PubMedGoogle Scholar
  264. Zhang L, Hosoi M, Fukuzawa M, Sun H, Rawlings RR, Weight FF (2002) Distinct molecular basis for differential sensitivity of the serotonin type 3A receptor to ethanol in the absence and presence of agonist. J Biol Chem 277:46256–46264PubMedGoogle Scholar
  265. Zhang LH, Gong N, Fei D, Xu L, Xu TL (2008) Glycine uptake regulates hippocampal network activity via glycine receptor-mediated tonic inhibition. Neuropsychopharmacology 33:701–711PubMedGoogle Scholar
  266. Zhang LH, Xu L, Xu TL (2006) Glycine receptor activation regulates short-term plasticity in CA1 area of hippocampal slices of rats. Biochem Biophys Res Commun 344:721–726PubMedGoogle Scholar
  267. Zheng F, Johnson SW (2001) Glycine receptor-mediated inhibition of dopamine and non-dopamine neurons of the rat ventral tegmental area in vitro. Brain Res 919(2):313–317PubMedGoogle Scholar
  268. Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ, Deitrich RA (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500–1505PubMedGoogle Scholar
  269. Zuo Y, Aistrup GL, Marszalec W, Gillespie A, Chavez-Noriega LE, Yeh JZ, Narahashi T (2001) Dual action of n-alcohols on neuronal nicotinic acetylcholine receptors. Mol Pharmacol 60(4):700–711PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Addiction Biology Unit, Section of Psychiatry and NeurochemistryInstitute of Neuroscience and Physiology Sahlgrenska Academy, University of GothenburgGothenburgSweden
  2. 2.BeroendeklinikenSahlgrenska University HospitalGothenburgSweden

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