Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure

  • Cody A. Siciliano
  • Anushree N. Karkhanis
  • Katherine M. Holleran
  • James R. Melchior
  • Sara R. JonesEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 248)


Alcohol use disorders are a leading public health concern, engendering enormous costs in terms of both economic loss and human suffering. These disorders are characterized by compulsive and excessive alcohol use, as well as negative affect and alcohol craving during abstinence. Extensive research has implicated the dopamine system in both the acute pharmacological effects of alcohol and the symptomology of alcohol use disorders that develop after extended alcohol use. Preclinical research has shed light on many mechanisms by which chronic alcohol exposure dysregulates the dopamine system. However, many of the findings are inconsistent across experimental parameters such as alcohol exposure length, route of administration, and model organism. We propose that the dopaminergic alterations driving the core symptomology of alcohol use disorders are likely to be relatively stable across experimental settings. Recent work has been aimed at using multiple model organisms (mouse, rat, monkey) across various alcohol exposure procedures to search for commonalities. Here, we review recent advances in our understanding of the effects of chronic alcohol use on the dopamine system by highlighting findings that are consistent across experimental setting and species.


Alcohol Autoreceptors Cross-species Dopamine Kappa Opioid receptors Monkey Mouse Nonhuman primate Rat Uptake 



This work was funded by NIH grants U01 AA014091, R01 AA021099, P01 AA023299 (SRJ), T32 AA007565 (CAS, ANK, KMH, JRM), F31 DA037710, F32 MH111216, Brain and Behavior Research Foundation (CAS), K01 AA023874 (ANK), and F31 AA023144 (JRM).

Financial Disclosure: The authors declare no competing financial interests.


  1. Abrahao KP, Salinas AG, Lovinger DM (2017) Alcohol and the brain: neuronal molecular targets, synapses, and circuits. Neuron 96:1223–1238PubMedGoogle Scholar
  2. Alcantara AA, Chen V, Herring BE, Mendenhall JM, Berlanga ML (2003) Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat. Brain Res 986:22–29PubMedGoogle Scholar
  3. Allain F, Minogianis EA, Roberts DC, Samaha AN (2015) How fast and how often: the pharmacokinetics of drug use are decisive in addiction. Neurosci Biobehav Rev 56:166–179PubMedGoogle Scholar
  4. Anderson RI, Becker HC (2017) Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol. Alcohol Clin Exp Res 41:1402–1418PubMedPubMedCentralGoogle Scholar
  5. Anderson RI, Lopez MF, Becker HC (2016a) Forced swim stress increases ethanol consumption in C57BL/6J mice with a history of chronic intermittent ethanol exposure. Psychopharmacology 233:2035–2043PubMedPubMedCentralGoogle Scholar
  6. Anderson RI, Lopez MF, Becker HC (2016b) Stress-induced enhancement of ethanol intake in C57BL/6J mice with a history of chronic ethanol exposure: involvement of kappa opioid receptors. Front Cell Neurosci 10:45PubMedPubMedCentralGoogle Scholar
  7. Appel SB, Liu Z, McElvain MA, Brodie MS (2003) Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine. J Pharmacol Exp Ther 306:437–446PubMedGoogle Scholar
  8. Ariansen JL, Heien ML, Hermans A, Phillips PE, Hernadi I, Bermudez MA, Schultz W, Wightman RM (2012) Monitoring extracellular pH, oxygen, and dopamine during reward delivery in the striatum of primates. Front Behav Neurosci 6:36PubMedPubMedCentralGoogle Scholar
  9. Aryal P, Dvir H, Choe S, Slesinger PA (2009) A discrete alcohol pocket involved in GIRK channel activation. Nat Neurosci 12:988–995PubMedPubMedCentralGoogle Scholar
  10. Baker EJ, Farro J, Gonzales S, Helms C, Grant KA (2014) Chronic alcohol self-administration in monkeys shows long-term quantity/frequency categorical stability. Alcohol Clin Exp Res 38:2835–2843PubMedPubMedCentralGoogle Scholar
  11. Baker EJ, Walter NA, Salo A, Rivas Perea P, Moore S, Gonzales S, Grant KA (2017) Identifying future drinkers: behavioral analysis of monkeys initiating drinking to intoxication is predictive of future drinking classification. Alcohol Clin Exp Res 41:626–636PubMedPubMedCentralGoogle Scholar
  12. Bazov I, Kononenko O, Watanabe H, Kuntic V, Sarkisyan D, Taqi MM, Hussain MZ, Nyberg F, Yakovleva T, Bakalkin G (2013) The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction. Addict Biol 18:161–169PubMedGoogle Scholar
  13. Belin D, Everitt BJ (2008) Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57:432–441PubMedGoogle Scholar
  14. Bello EP, Mateo Y, Gelman DM, Noain D, Shin JH, Low MJ, Alvarez VA, Lovinger DM, Rubinstein M (2011) Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 14:1033–1038PubMedPubMedCentralGoogle Scholar
  15. Blaine SK, Sinha R (2017) Alcohol, stress, and glucocorticoids: from risk to dependence and relapse in alcohol use disorders. Neuropharmacology 122:136–147PubMedPubMedCentralGoogle Scholar
  16. Bonthius DJ, West JR (1990) Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure. Alcohol Clin Exp Res 14:107–118PubMedGoogle Scholar
  17. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K (2005) Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 8:1263–1268PubMedGoogle Scholar
  18. Bradberry CW (2002) Dose-dependent effect of ethanol on extracellular dopamine in mesolimbic striatum of awake rhesus monkeys: comparison with cocaine across individuals. Psychopharmacology 165:67–76PubMedGoogle Scholar
  19. Brodie MS (2002) Increased ethanol excitation of dopaminergic neurons of the ventral tegmental area after chronic ethanol treatment. Alcohol Clin Exp Res 26:1024–1030PubMedGoogle Scholar
  20. Brodie MS, Shefner SA, Dunwiddie TV (1990) Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Res 508:65–69PubMedGoogle Scholar
  21. Brodie MS, Pesold C, Appel SB (1999) Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res 23:1848–1852PubMedGoogle Scholar
  22. Bruchas MR, Chavkin C (2010) Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology 210:137–147PubMedPubMedCentralGoogle Scholar
  23. Budygin EA, John CE, Mateo Y, Daunais JB, Friedman DP, Grant KA, Jones SR (2003) Chronic ethanol exposure alters presynaptic dopamine function in the striatum of monkeys: a preliminary study. Synapse 50:266–268PubMedGoogle Scholar
  24. Budygin EA, Oleson EB, Mathews TA, Lack AK, Diaz MR, McCool BA, Jones SR (2007) Effects of chronic alcohol exposure on dopamine uptake in rat nucleus accumbens and caudate putamen. Psychopharmacology 193:495–501PubMedGoogle Scholar
  25. Calipari ES, Ferris MJ, Zimmer BA, Roberts DC, Jones SR (2013) Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter. Neuropsychopharmacology 38:2385–2392PubMedPubMedCentralGoogle Scholar
  26. Carlezon WA Jr, Chartoff EH (2007) Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2:2987–2995PubMedGoogle Scholar
  27. Cervera-Juanes R, Wilhem LJ, Park B, Lee R, Locke J, Helms C, Gonzales S, Wand G, Jones SR, Grant KA et al (2016) MAOA expression predicts vulnerability for alcohol use. Mol Psychiatry 21:472–479PubMedGoogle Scholar
  28. Chu B, Dopico AM, Lemos JR, Treistman SN (1998) Ethanol potentiation of calcium-activated potassium channels reconstituted into planar lipid bilayers. Mol Pharmacol 54:397–406PubMedGoogle Scholar
  29. Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, Bult CJ, Agarwala R, Cherry JL, DiCuccio M et al (2009) Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol 7:e1000112PubMedPubMedCentralGoogle Scholar
  30. Clarke R, Adermark L (2015) Dopaminergic regulation of striatal interneurons in reward and addiction: focus on alcohol. Neural Plast 2015:814567PubMedPubMedCentralGoogle Scholar
  31. Cools R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D’Esposito M (2009) Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration. J Neurosci 29:1538–1543PubMedPubMedCentralGoogle Scholar
  32. Cragg SJ, Rice ME (2004) DAncing past the DAT at a DA synapse. Trends Neurosci 27:270–277PubMedGoogle Scholar
  33. Cuzon Carlson VC, Seabold GK, Helms CM, Garg N, Odagiri M, Rau AR, Daunais J, Alvarez VA, Lovinger DM, Grant KA (2011) Synaptic and morphological neuroadaptations in the putamen associated with long-term, relapsing alcohol drinking in primates. Neuropsychopharmacology 36:2513–2528PubMedPubMedCentralGoogle Scholar
  34. Danjo T, Yoshimi K, Funabiki K, Yawata S, Nakanishi S (2014) Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens. Proc Natl Acad Sci U S A 111:6455–6460PubMedPubMedCentralGoogle Scholar
  35. Dawson DA, Goldstein RB, Grant BF (2007) Rates and correlates of relapse among individuals in remission from DSM-IV alcohol dependence: a 3-year follow-up. Alcohol Clin Exp Res 31:2036–2045PubMedGoogle Scholar
  36. Dawson DA, Goldstein RB, Chou SP, Ruan WJ, Grant BF (2008) Age at first drink and the first incidence of adult-onset DSM-IV alcohol use disorders. Alcohol Clin Exp Res 32:2149–2160PubMedPubMedCentralGoogle Scholar
  37. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278PubMedPubMedCentralGoogle Scholar
  38. 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 90:7966–7969PubMedPubMedCentralGoogle Scholar
  39. Diaz MR, Christian DT, Anderson NJ, McCool BA (2011) Chronic ethanol and withdrawal differentially modulate lateral/basolateral amygdala paracapsular and local GABAergic synapses. J Pharmacol Exp Ther 337:162–170PubMedPubMedCentralGoogle Scholar
  40. Dobrossy MD, Furlanetti LL, Coenen VA (2015) Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders. Neurosci Biobehav Rev 49:32–42PubMedGoogle Scholar
  41. Dziegielewski SF (2010) DSM-IV-TR in action, 2nd edn. Wiley, HobokenGoogle Scholar
  42. Ebner SR, Roitman MF, Potter DN, Rachlin AB, Chartoff EH (2010) Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens. Psychopharmacology 210:241–252PubMedPubMedCentralGoogle Scholar
  43. Eldridge MA, Lerchner W, Saunders RC, Kaneko H, Krausz KW, Gonzalez FJ, Ji B, Higuchi M, Minamimoto T, Richmond BJ (2016) Chemogenetic disconnection of monkey orbitofrontal and rhinal cortex reversibly disrupts reward value. Nat Neurosci 19:37–39PubMedGoogle Scholar
  44. Engel JA, Jerlhag E (2014) Alcohol: mechanisms along the mesolimbic dopamine system. Prog Brain Res 211:201–233PubMedGoogle Scholar
  45. Everitt BJ, Robbins TW (2013) From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. Neurosci Biobehav Rev 37:1946–1954PubMedGoogle Scholar
  46. Exley R, Cragg SJ (2008) Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission. Br J Pharmacol 153(Suppl 1):S283–S297PubMedGoogle Scholar
  47. Falk JL (1966) Schedule-induced polydipsia as a function of fixed interval length. J Exp Anal Behav 9:37–39PubMedPubMedCentralGoogle Scholar
  48. Ferris MJ, Calipari ES, Yorgason JT, Jones SR (2013) Examining the complex regulation and drug-induced plasticity of dopamine release and uptake using voltammetry in brain slices. ACS Chem Neurosci 4:693–703PubMedPubMedCentralGoogle Scholar
  49. Ferris MJ, Espana RA, Locke JL, Konstantopoulos JK, Rose JH, Chen R, Jones SR (2014) Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci U S A 111:E2751–E2759PubMedPubMedCentralGoogle Scholar
  50. Flusberg BA, Nimmerjahn A, Cocker ED, Mukamel EA, Barretto RP, Ko TH, Burns LD, Jung JC, Schnitzer MJ (2008) High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat Methods 5:935–938PubMedPubMedCentralGoogle Scholar
  51. Ford CP (2014) The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 282:13–22PubMedPubMedCentralGoogle Scholar
  52. Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466PubMedPubMedCentralGoogle Scholar
  53. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432PubMedGoogle Scholar
  54. Gilpin NW, Richardson HN, Cole M, Koob GF (2008) Vapor inhalation of alcohol in rats. Curr Protoc Neurosci Chapter 9:Unit 9.29PubMedGoogle Scholar
  55. Grace AA, Bunney BS (1983) Intracellular and extracellular electrophysiology of nigral dopaminergic neurons--1. Identification and characterization. Neuroscience 10:301–315PubMedGoogle Scholar
  56. Grace AA, Bunney BS (1984) The control of firing pattern in nigral dopamine neurons: single spike firing. J Neurosci 4:2866–2876PubMedGoogle Scholar
  57. Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30:220–227PubMedGoogle Scholar
  58. Grant KA, Bennett AJ (2003) Advances in nonhuman primate alcohol abuse and alcoholism research. Pharmacol Ther 100:235–255PubMedGoogle Scholar
  59. Grant KA, Leng X, Green HL, Szeliga KT, Rogers LS, Gonzales SW (2008) Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration. Alcohol Clin Exp Res 32:1824–1838PubMedPubMedCentralGoogle Scholar
  60. Grant BF, Goldstein RB, Saha TD, Chou SP, Jung J, Zhang H, Pickering RP, Ruan WJ, Smith SM, Huang B et al (2015) Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III. JAMA Psychiat 72:757–766Google Scholar
  61. Graybiel AM (1995) The basal ganglia. Trends Neurosci 18:60–62PubMedGoogle Scholar
  62. Graybiel AM (2008) Habits, rituals, and the evaluative brain. Annu Rev Neurosci 31:359–387PubMedGoogle Scholar
  63. Green AS, Grahame NJ (2008) Ethanol drinking in rodents: is free-choice drinking related to the reinforcing effects of ethanol? Alcohol 42:1–11PubMedPubMedCentralGoogle Scholar
  64. Griffin WC 3rd, Lopez MF, Yanke AB, Middaugh LD, Becker HC (2009) Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens. Psychopharmacology 201:569–580PubMedGoogle Scholar
  65. Hagman BT, Cohn AM (2011) Toward DSM-V: mapping the alcohol use disorder continuum in college students. Drug Alcohol Depend 118:202–208PubMedPubMedCentralGoogle Scholar
  66. Hasin DS, Stinson FS, Ogburn E, Grant BF (2007) Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 64(7):830–842PubMedGoogle Scholar
  67. Healey JC, Winder DG, Kash TL (2008) Chronic ethanol exposure leads to divergent control of dopaminergic synapses in distinct target regions. Alcohol 42:179–190PubMedPubMedCentralGoogle Scholar
  68. Hendricson AW, Thomas MP, Lippmann MJ, Morrisett RA (2003) Suppression of L-type voltage-gated calcium channel-dependent synaptic plasticity by ethanol: analysis of miniature synaptic currents and dendritic calcium transients. J Pharmacol Exp Ther 307:550–558PubMedGoogle Scholar
  69. Hernandez G, Trujillo-Pisanty I, Cossette MP, Conover K, Shizgal P (2012) Role of dopamine tone in the pursuit of brain stimulation reward. J Neurosci 32:11032–11041PubMedGoogle Scholar
  70. Humphries MD, Prescott TJ (2010) The ventral basal ganglia, a selection mechanism at the crossroads of space, strategy, and reward. Prog Neurobiol 90:385–417PubMedGoogle Scholar
  71. Hwa LS, Chu A, Levinson SA, Kayyali TM, DeBold JF, Miczek KA (2011) Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol. Alcohol Clin Exp Res 35:1938–1947PubMedPubMedCentralGoogle Scholar
  72. Imperato A, Di Chiara G (1986) Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. J Pharmacol Exp Ther 239:219–228PubMedGoogle Scholar
  73. Karkhanis AN, Rose JH, Huggins KN, Konstantopoulos JK, Jones SR (2015) Chronic intermittent ethanol exposure reduces presynaptic dopamine neurotransmission in the mouse nucleus accumbens. Drug Alcohol Depend 150:24–30PubMedPubMedCentralGoogle Scholar
  74. Karkhanis AN, Huggins KN, Rose JH, Jones SR (2016) Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: role of kappa opioid receptors. Neuropharmacology 110:190–197PubMedPubMedCentralGoogle Scholar
  75. Kashem MA, Ahmed S, Sarker R, Ahmed EU, Hargreaves GA, McGregor IS (2012) Long-term daily access to alcohol alters dopamine-related synthesis and signaling proteins in the rat striatum. Neurochem Int 61:1280–1288PubMedGoogle Scholar
  76. Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, Walker BM (2014) The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry 75:744–782Google Scholar
  77. Köhnke MD, Batra A, Kolb W, Köhnke AM, Lutz U, Schick S, Gaertner I (2005) Association of the dopamine transporter gene with alcoholism. Alcohol Alcohol 40(5):339–342PubMedGoogle Scholar
  78. Kokkinidis L, McCarter BD (1990) Postcocaine depression and sensitization of brain-stimulation reward: analysis of reinforcement and performance effects. Pharmacol Biochem Behav 36:463–471PubMedGoogle Scholar
  79. Koller BH, Smithies O (1992) Altering genes in animals by gene targeting. Annu Rev Immunol 10:705–730PubMedGoogle Scholar
  80. Koob GF (2014) Neurocircuitry of alcohol addiction: synthesis from animal models. Handb Clin Neurol 125:33–54PubMedGoogle Scholar
  81. Koyama S, Brodie MS, Appel SB (2007) Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. J Neurophysiol 97:1977–1985PubMedGoogle Scholar
  82. Kuzmin A, Chefer V, Bazov I, Meis J, Ogren SO, Shippenberg T, Bakalkin G (2013) Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment. Transl Psychiatry 3:e310PubMedPubMedCentralGoogle Scholar
  83. Laine TP, Ahonen A, Torniainen P, Heikkila J, Pyhtinen J, Rasanen P, Niemela O, Hillbom M (1999) Dopamine transporters increase in human brain after alcohol withdrawal. Mol Psychiatry 4:189–191. 104–185PubMedGoogle Scholar
  84. Lam MP, Marinelli PW, Bai L, Gianoulakis C (2008) Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study. Psychopharmacology 201:261–271PubMedGoogle Scholar
  85. Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, Hnasko TS, Palmiter RD, Chavkin C (2009) Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci U S A 106:19168–19173PubMedPubMedCentralGoogle Scholar
  86. Le AD, Quan B, Juzytch W, Fletcher PJ, Joharchi N, Shaham Y (1998) Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats. Psychopharmacology 135:169–174PubMedGoogle Scholar
  87. Levey AI, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA, Price DL, Maggio R, Brann MR, Ciliax BJ (1993) Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci U S A 90:8861–8865PubMedPubMedCentralGoogle Scholar
  88. Li TK, Lumeng L, McBride WJ, Waller MB (1979) Progress toward a voluntary oral consumption model of alcoholism. Drug Alcohol Depend 4:45–60PubMedGoogle Scholar
  89. Lovinger DM (2017) Presynaptic ethanol actions: potential roles in ethanol seeking. In: Grant KA (ed) Neuropharmacology of alcohol, Handbook of experimental pharmacology. Springer, HeidelbergGoogle Scholar
  90. Macey DJ, Schulteis G, Heinrichs SC, Koob GF (1996) Time-dependent quantifiable withdrawal from ethanol in the rat: effect of method of dependence induction. Alcohol 13:163–170PubMedGoogle Scholar
  91. Majchrowicz E, Mendelson JH (1970) Blood concentrations of acetaldehyde and ethanol in chronic alcoholics. Science 168:1100–1102PubMedGoogle Scholar
  92. Marinelli PW, Lam M, Bai L, Quirion R, Gianoulakis C (2006) A microdialysis profile of dynorphin A(1-8) release in the rat nucleus accumbens following alcohol administration. Alcohol Clin Exp Res 30:982–990PubMedGoogle Scholar
  93. Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A, Kegeles L, Talbot P, Evans S, Krystal J et al (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58:779–786PubMedGoogle Scholar
  94. Meador-Woodruff JH, Damask SP, Watson SJ Jr (1994) Differential expression of autoreceptors in the ascending dopamine systems of the human brain. Proc Natl Acad Sci U S A 91:8297–8301PubMedPubMedCentralGoogle Scholar
  95. Melchior JR, Jones SR (2017) Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo. Mol Cell Neurosci 85:93–104PubMedPubMedCentralGoogle Scholar
  96. Melis M, Spiga S, Diana M (2005) The dopamine hypothesis of drug addiction: hypodopaminergic state. Int Rev Neurobiol 63:101–154PubMedGoogle Scholar
  97. Meller E, Bohmaker K, Goldstein M, Basham DA (1993) Evidence that striatal synthesis-inhibiting autoreceptors are dopamine D3 receptors. Eur J Pharmacol 249:R5–R6PubMedGoogle Scholar
  98. Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of death in the United States, 2000. JAMA 291:1238–1245PubMedGoogle Scholar
  99. Morikawa H, Morrisett RA (2010) Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs. Int Rev Neurobiol 91:235–288PubMedPubMedCentralGoogle Scholar
  100. Morisot N, Ron D (2017) Alcohol-dependent molecular adaptations of the NMDA receptor system. Genes Brain Behav 16:139–148PubMedPubMedCentralGoogle Scholar
  101. Nabeshima T, Katoh A, Wada M, Kameyama T (1992) Stress-induced changes in brain met-enkephalin, Leu-enkephalin and dynorphin concentrations. Life Sci 51:211–217PubMedGoogle Scholar
  102. Nealey KA, Smith AW, Davis SM, Smith DG, Walker BM (2011) Kappa-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats. Neuropharmacology 61:35–42PubMedPubMedCentralGoogle Scholar
  103. Negus SS, Miller LL (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66:869–917PubMedPubMedCentralGoogle Scholar
  104. Nicola SM (2010) The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behavior. J Neurosci 30:16585–16600PubMedPubMedCentralGoogle Scholar
  105. Nimitvilai S, You C, Arora DS, McElvain MA, Vandegrift BJ, Brodie MS, Woodward JJ (2016) Differential effects of toluene and ethanol on dopaminergic neurons of the ventral tegmental area. Front Neurosci 10:434PubMedPubMedCentralGoogle Scholar
  106. Nimitvilai S, Uys JD, Woodward JJ, Randall PK, Ball LE, Williams RW, Jones BC, Lu L, Grant KA, Mulholland PJ (2017) Orbitofrontal neuroadaptations and cross-species synaptic biomarkers in heavy-drinking macaques. J Neurosci 37:3646–3660PubMedPubMedCentralGoogle Scholar
  107. O’Brien C (2011) Addiction and dependence in DSM-V. Addiction 106:866–867PubMedGoogle Scholar
  108. Okamoto T, Harnett MT, Morikawa H (2006) Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice. J Neurophysiol 95:619–626PubMedGoogle Scholar
  109. Penn PE, McBride WJ, Lumeng L, Gaff TM, Li TK (1978) Neurochemical and operant behavioral studies of a strain of alcohol-preferring rats. Pharmacol Biochem Behav 8:475–481PubMedGoogle Scholar
  110. Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422:614–618PubMedGoogle Scholar
  111. Pickens RW, Hatsukami DK, Spicer JW, Svikis DS (1985) Relapse by alcohol abusers. Alcohol Clin Exp Res 9:244–247PubMedGoogle Scholar
  112. Pierce RC, Crawford CA, Nonneman AJ, Mattingly BA, Bardo MT (1990) Effect of forebrain dopamine depletion on novelty-induced place preference behavior in rats. Pharmacol Biochem Behav 36:321–325PubMedGoogle Scholar
  113. Pleil KE, Lowery-Gionta EG, Crowley NA, Li C, Marcinkiewcz CA, Rose JH, McCall NM, Maldonado-Devincci AM, Morrow AL, Jones SR et al (2015a) Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala. Neuropharmacology 99:735–749PubMedPubMedCentralGoogle Scholar
  114. Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, Olson DP, Lowell BB, Grant KA, Thiele TE et al (2015b) NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci 18:545–552PubMedPubMedCentralGoogle Scholar
  115. Porrino LJ, Lyons D, Smith HR, Daunais JB, Nader MA (2004) Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. J Neurosci 24:3554–3562PubMedGoogle Scholar
  116. Rebec GV, Grabner CP, Johnson M, Pierce RC, Bardo MT (1997) Transient increases in catecholaminergic activity in medial prefrontal cortex and nucleus accumbens shell during novelty. Neuroscience 76:707–714PubMedGoogle Scholar
  117. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J (2009) Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373:2223–2233PubMedGoogle Scholar
  118. Renteria R, Buske TR, Morrisett RA (2017) Long-term subregion-specific encoding of enhanced ethanol intake by D1DR medium spiny neurons of the nucleus accumbens. Addict Biol.
  119. Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC (2005) Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice. Physiol Behav 84:53–63PubMedGoogle Scholar
  120. Rhodes JS, Ford MM, Yu CH, Brown LL, Finn DA, Garland T Jr, Crabbe JC (2007) Mouse inbred strain differences in ethanol drinking to intoxication. Genes Brain Behav 6:1–18PubMedGoogle Scholar
  121. Rimondini R, Sommer W, Heilig M (2003) A temporal threshold for induction of persistent alcohol preference: behavioral evidence in a rat model of intermittent intoxication. J Stud Alcohol 64:445–449PubMedGoogle Scholar
  122. Ron D, Barak S (2016) Molecular mechanisms underlying alcohol-drinking behaviours. Nat Rev Neurosci 17:576–591PubMedPubMedCentralGoogle Scholar
  123. Rose JH, Karkhanis AN, Chen R, Gioia D, Lopez MF, Becker HC, McCool BA, Jones SR (2016) Supersensitive kappa opioid receptors promotes ethanol withdrawal-related behaviors and reduce dopamine signaling in the nucleus accumbens. Int J Neuropsychopharmacol 19.
  124. Rossetti ZL, Melis F, Carboni S, Diana M, Gessa GL (1992) Alcohol withdrawal in rats is associated with a marked fall in extraneuronal dopamine. Alcohol Clin Exp Res 16:529–532PubMedGoogle Scholar
  125. Rossetti ZL, Isola D, De Vry J, Fadda F (1999) Effects of nimodipine on extracellular dopamine levels in the rat nucleus accumbens in ethanol withdrawal. Neuropharmacology 38:1361–1369PubMedGoogle Scholar
  126. Rothblat DS, Rubin E, Schneider JS (2001) Effects of chronic alcohol ingestion on the mesostriatal dopamine system in the rat. Neurosci Lett 300:63–66PubMedGoogle Scholar
  127. Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA et al (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90:991–1001PubMedGoogle Scholar
  128. Schulteis G, Markou A, Cole M, Koob GF (1995) Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci U S A 92:5880–5884PubMedPubMedCentralGoogle Scholar
  129. Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1–27PubMedGoogle Scholar
  130. Schultz W (2013) Updating dopamine reward signals. Curr Opin Neurobiol 23:229–238PubMedPubMedCentralGoogle Scholar
  131. Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599PubMedGoogle Scholar
  132. Seress L (2007) Comparative anatomy of the hippocampal dentate gyrus in adult and developing rodents, non-human primates and humans. Prog Brain Res 163:23–41PubMedGoogle Scholar
  133. Shnitko TA, Robinson DL (2015) Regional variation in phasic dopamine release during alcohol and sucrose self-administration in rats. ACS Chem Neurosci 6:147–154PubMedGoogle Scholar
  134. Siciliano CA, Calipari ES, Cuzon Carlson VC, Helms CM, Lovinger DM, Grant KA, Jones SR (2015a) Voluntary ethanol intake predicts kappa-opioid receptor supersensitivity and regionally distinct dopaminergic adaptations in macaques. J Neurosci 35:5959–5968PubMedPubMedCentralGoogle Scholar
  135. Siciliano CA, Calipari ES, Ferris MJ, Jones SR (2015b) Adaptations of presynaptic dopamine terminals induced by psychostimulant self-administration. ACS Chem Neurosci 6:27–36PubMedGoogle Scholar
  136. Siciliano CA, Calipari ES, Yorgason JT, Lovinger DM, Mateo Y, Jimenez VA, Helms CM, Grant KA, Jones SR (2016a) Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques. Psychopharmacology 233:1435–1443PubMedPubMedCentralGoogle Scholar
  137. Siciliano CA, Calipari ES, Yorgason JT, Mateo Y, Helms CM, Lovinger DM, Grant KA, Jones SR (2016b) Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core. Drug Alcohol Depend 158:159–163PubMedGoogle Scholar
  138. Siciliano CA, Locke JL, Mathews TA, Lopez MF, Becker HC, Jones SR (2017) Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains. Alcohol 58:25–32PubMedGoogle Scholar
  139. Silberberg M, Silberberg R (1954) Factors modifying the lifespan of mice. Am J Phys 177:23–26Google Scholar
  140. Soderpalm B, Lof E, Ericson M (2009) Mechanistic studies of ethanol's interaction with the mesolimbic dopamine reward system. Pharmacopsychiatry 42(Suppl 1):S87–S94PubMedGoogle Scholar
  141. Stauffer WR, Lak A, Yang A, Borel M, Paulsen O, Boyden ES, Schultz W (2016) Dopamine neuron-specific Optogenetic stimulation in rhesus macaques. Cell 166:1564–1571. e1566PubMedPubMedCentralGoogle Scholar
  142. Steiner H, Gerfen CR (1993) Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum. J Neurosci 13:5066–5081PubMedGoogle Scholar
  143. Steiner H, Gerfen CR (1996) Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction. J Comp Neurol 376:530–541PubMedGoogle Scholar
  144. Svingos AL, Chavkin C, Colago EE, Pickel VM (2001) Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse 42:185–192PubMedGoogle Scholar
  145. Tigges G, Gordon T, McClure H, Hall E, Peters A (1988) Survival rate and life span of rhesus monkeys at the Yerkes regional primate research center. Am J Primatol 15:263–273Google Scholar
  146. Tiihonen J, Kuikka J, Bergstrom K, Hakola P, Karhu J, Ryynanen OP, Fohr J (1995) Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics. Nat Med 1:654–657PubMedGoogle Scholar
  147. Tupala E, Tiihonen J (2004) Dopamine and alcoholism: neurobiological basis of ethanol abuse. Prog Neuro-Psychopharmacol Biol Psychiatry 28:1221–1247Google Scholar
  148. Tupala E, Halonen P, Tiihonen J (2006) Visualization of the cortical dopamine transporter in type 1 and 2 alcoholics with human whole hemisphere autoradiography. Eur Neuropsychopharmacol 16:552–560PubMedGoogle Scholar
  149. Twining RC, Wheeler DS, Ebben AL, Jacobsen AJ, Robble MA, Mantsch JR, Wheeler RA (2015) Aversive stimuli drive drug seeking in a state of low dopamine tone. Biol Psychiatry 77:895–902PubMedGoogle Scholar
  150. Venniro M, Caprioli D, Shaham Y (2016) Animal models of drug relapse and craving: from drug priming-induced reinstatement to incubation of craving after voluntary abstinence. Prog Brain Res 224:25–52PubMedGoogle Scholar
  151. Vivian JA, Green HL, Young JE, Majerksy LS, Thomas BW, Shively CA, Tobin JR, Nader MA, Grant KA (2001) Induction and maintenance of ethanol self-administration in cynomolgus monkeys (Macaca fascicularis): long-term characterization of sex and individual differences. Alcohol Clin Exp Res 25:1087–1097PubMedGoogle Scholar
  152. 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
  153. Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N et al (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827–830PubMedGoogle Scholar
  154. 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
  155. Walker BM, Zorrilla EP, Koob GF (2011) Systemic kappa-opioid receptor antagonism by nor-binaltorphimine reduces dependence-induced excessive alcohol self-administration in rats. Addict Biol 16:116–119PubMedPubMedCentralGoogle Scholar
  156. Wanat MJ, Willuhn I, Clark JJ, Phillips PE (2009) Phasic dopamine release in appetitive behaviors and drug addiction. Curr Drug Abuse Rev 2:195–213PubMedPubMedCentralGoogle Scholar
  157. 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
  158. Werling LL, Frattali A, Portoghese PS, Takemori AE, Cox BM (1988) Kappa receptor regulation of dopamine release from striatum and cortex of rats and guinea pigs. J Pharmacol Exp Ther 246:282–286PubMedGoogle Scholar
  159. Wightman RM (1988) Voltammetry with microscopic electrodes in new domains. Science 240:415–420PubMedGoogle Scholar
  160. Wightman RM, Strope E, Plotsky PM, Adams RN (1976) Monitoring of transmitter metabolites by voltammetry in cerebrospinal fluid following neural pathway stimulation. Nature 262:145–146PubMedGoogle Scholar
  161. Yen CH, Yeh YW, Liang CS, Ho PS, Kuo SC, Huang CC, Chen CY, Shih MC, Ma KH, Peng GS et al (2015) Reduced dopamine transporter availability and neurocognitive deficits in male patients with alcohol dependence. PLoS One 10:e0131017PubMedPubMedCentralGoogle Scholar
  162. Yen CH, Shih MC, Cheng CY, Ma KH, Lu RB, Huang SY (2016) Incongruent reduction of dopamine transporter availability in different subgroups of alcohol dependence. Medicine (Baltimore) 95:e4048Google Scholar
  163. Yim HJ, Schallert T, Randall PK, Gonzales RA (1998) Comparison of local and systemic ethanol effects on extracellular dopamine concentration in rat nucleus accumbens by microdialysis. Alcohol Clin Exp Res 22:367–374PubMedGoogle Scholar
  164. Yorgason JT, Ferris MJ, Steffensen SC, Jones SR (2014) Frequency-dependent effects of ethanol on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res 38:438–447PubMedGoogle Scholar
  165. Yorgason JT, Rose JH, McIntosh JM, Ferris MJ, Jones SR (2015) Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: role of nicotinic acetylcholine receptors. Neuroscience 284:854–864PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Cody A. Siciliano
    • 1
  • Anushree N. Karkhanis
    • 2
  • Katherine M. Holleran
    • 2
  • James R. Melchior
    • 2
  • Sara R. Jones
    • 2
    Email author
  1. 1.The Picower Institute for Learning and Memory, Department of Brain and Cognitive SciencesMassachusetts Institute of Technology (MIT)CambridgeUSA
  2. 2.Department of Physiology and PharmacologyWake Forest School of MedicineWinston-SalemUSA

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