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Signaling Pathways Mediating Alcohol Effects

  • Dorit Ron
  • Robert O. MessingEmail author
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 13)

Abstract

Ethanol’s effects on intracellular signaling pathways contribute to acute effects of ethanol as well as to neuroadaptive responses to repeated ethanol exposure. In this chapter we review recent discoveries that demonstrate how ethanol alters signaling pathways involving several receptor tyrosine kinases and intracellular tyrosine and serine-threonine kinases, with consequences for regulation of cell surface receptor function, gene expression, protein translation, neuronal excitability and animal behavior. We also describe recent work that demonstrates a key role for ethanol in regulating the function of scaffolding proteins that organize signaling complexes into functional units. Finally, we review recent exciting studies demonstrating ethanol modulation of DNA and histone modification and the expression of microRNAs, indicating epigenetic mechanisms by which ethanol regulates neuronal gene expression and addictive behaviors.

Keywords

Phosphorylation Signal transduction Growth factor Epigenetic Kinase 

Notes

Acknowledgment

The authors like to thank Carol Webb for editorial support.

References

  1. Abel T, Nguyen PV (2008) Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog Brain Res 169:97–115PubMedCentralPubMedGoogle Scholar
  2. Adell A, Myers RD (1994) Increased alcohol intake in low alcohol drinking rats after chronic infusion of the [beta]-carboline harman into the hippocampus. Pharmacol Biochem Behav 49(4):949–953PubMedGoogle Scholar
  3. Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3(5):383–394PubMedGoogle Scholar
  4. Arimoto K, Fukuda H, Imajoh-Ohmi S, Saito H, Takekawa M (2008) Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol 10(11):1324–1332PubMedGoogle Scholar
  5. Arkin MR, Whitty A (2009) The road less traveled: modulating signal transduction enzymes by inhibiting their protein–protein interactions. Curr Opin Chem Biol 13(3):284–290PubMedGoogle Scholar
  6. Arolfo MP, Yao L, Gordon AS, Diamond I, Janak PH (2004) Ethanol operant self-administration in rats is regulated by adenosine A2 receptors. Alcohol Clin Exp Res 28(9):1308–1316PubMedGoogle Scholar
  7. Arolfo MP, Overstreet DH, Yao L, Fan P, Lawrence AJ, Tao G, Keung WM, Vallee BL, Olive MF, Gass JT, Rubin E, Anni H, Hodge CW, Besheer J, Zablocki J, Leung K, Blackburn BK, Lange LG, Diamond I (2009) Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcohol Clin Exp Res 33(11):1935–1944PubMedGoogle Scholar
  8. Ashique AM, Kharazia V, Yaka R, Phamluong K, Peterson AS, Ron D (2006) Localization of the scaffolding protein RACK1 in the developing and adult mouse brain. Brain Res 1069(1):31–38PubMedGoogle Scholar
  9. Asyyed A, Storm D, Diamond I (2006) Ethanol activates cAMP response element-mediated gene expression in select regions of the mouse brain. Brain Res 1106(1):63–71PubMedGoogle Scholar
  10. Bajo M, Cruz MT, Siggins GR, Messing R, Roberto M (2008) Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc Natl Acad Sci U S A 105(24):8410–8415PubMedCentralPubMedGoogle Scholar
  11. Barroso-Chinea P, Cruz-Muros I, Aymerich MS, Rodriguez-Diaz M, Afonso-Oramas D, Lanciego JL, Gonzalez-Hernandez T (2005) Striatal expression of GDNF and differential vulnerability of midbrain dopaminergic cells. Eur J Neurosci 21(7):1815–1827PubMedGoogle Scholar
  12. Beggs HE, Soriano P, Maness PF (1994) NCAM-dependent neurite outgrowth is inhibited in neurons from Fyn-minus mice. J Cell Biol 127(3):825–833PubMedGoogle Scholar
  13. Bjork K, Terasmaa A, Sun H, Thorsell A, Sommer WH, Heilig M (2010) Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors. Addict Biol 15(3):299–303PubMedCentralPubMedGoogle Scholar
  14. Blazer LL, Neubig RR (2009) Small molecule protein–protein interaction inhibitors as CNS therapeutic agents: current progress and future hurdles. Neuropsychopharmacology 34(1):126–141PubMedGoogle Scholar
  15. Bleich S, Hillemacher T (2009) Homocysteine, alcoholism and its molecular networks. Pharmacopsychiatry 42(Suppl 1):S102–S109PubMedGoogle Scholar
  16. Bodrikov V, Leshchyns’ka I, Sytnyk V, Overvoorde J, den Hertog J, Schachner M (2005) RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. J Cell Biol 168(1):127–139PubMedGoogle Scholar
  17. Borghese CM, Storustovu S, Ebert B, Herd MB, Belelli D, Lambert JJ, Marshall G, Wafford KA, Harris RA (2006) The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol. J Pharmacol Exp Ther 316(3):1360–1368PubMedGoogle Scholar
  18. Bowers BJ, Wehner JM (2001) Ethanol consumption and behavioral impulsivity are increased in protein kinase Cγ null mutant mice. J Neurosci 21(21):RC180PubMedGoogle Scholar
  19. Bowers BJ, Owen EH, Collins AC, Abeliovich A, Tonegawa S, Wehner JM (1999) Decreased ethanol sensitivity and tolerance development in gamma-protein kinase C null mutant mice is dependent on genetic background. Alcohol Clin Exp Res 23(3):387–397PubMedGoogle Scholar
  20. Bowers BJ, Collins AC, Tritto T, Wehner JM (2000) Mice lacking PKC gamma exhibit decreased anxiety. Behav Genet 30(2):111–121PubMedGoogle Scholar
  21. Brackenbury WJ, Davis TH, Chen C, Slat EA, Detrow MJ, Dickendesher TL, Ranscht B, Isom LL (2008) Voltage-gated Na + channel beta1 subunit-mediated neurite outgrowth requires Fyn kinase and contributes to postnatal CNS development in vivo. J Neurosci 28(12):3246–3256PubMedGoogle Scholar
  22. Brandon EP, Idzerda RL, McKnight GS (1997) PKA isoforms, neural pathways, and behaviour: making the connection. Curr Opin Neurobiol 7(3):397–403PubMedGoogle Scholar
  23. Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26(11):657–664PubMedGoogle Scholar
  24. 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(1):65–69PubMedGoogle Scholar
  25. Cadd G, McKnight GS (1989) Distinct patterns of cAMP-dependent protein kinase gene expression in mouse brain. Neuron 3(1):71–79PubMedGoogle Scholar
  26. Camp M, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson RM, Noronha B, Chen YC, Coba M, Grant S, Holmes A (2011) A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol 16(3):428–439PubMedCentralPubMedGoogle Scholar
  27. Carnicella S, Ron D (2009) GDNF—a potential target to treat addiction. Pharmacol Ther 122(1):9–18PubMedCentralPubMedGoogle Scholar
  28. Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D (2008) GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc Natl Acad Sci U S A 105(23):8114–8119PubMedCentralPubMedGoogle Scholar
  29. Carnicella S, Ahmadiantehrani S, He DY, Nielsen CK, Bartlett SE, Janak PH, Ron D (2009a) Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor. Biol Psychiatry 66(2):146–153PubMedCentralPubMedGoogle Scholar
  30. Carnicella S, Ahmadiantehrani S, Janak PH, Ron D (2009b) GDNF is an endogenous negative regulator of ethanol-mediated reward and of ethanol consumption after a period of abstinence. Alcohol Clin Exp Res 33(6):1012–1024PubMedCentralPubMedGoogle Scholar
  31. Carnicella S, He DY, Yowell QV, Glick SD, Ron D (2010) Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration. Addict Biol 15(4):424–433PubMedCentralPubMedGoogle Scholar
  32. Carpenter-Hyland EP, Chandler LJ (2006) Homeostatic plasticity during alcohol exposure promotes enlargement of dendritic spines. Eur J Neurosci 24(12):3496–3506PubMedGoogle Scholar
  33. Chandler LJ, Sutton G (2005) Acute ethanol inhibits extracellular signal-regulated kinase, protein kinase B, and adenosine 3′:5′-cyclic monophosphate response element binding protein activity in an age- and brain region-specific manner. Alcohol Clin Exp Res 29(4):672–682PubMedGoogle Scholar
  34. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24(18):4401–4411PubMedGoogle Scholar
  35. Chico LK, Van Eldik LJ, Watterson DM (2009) Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 8(11):892–909PubMedCentralPubMedGoogle Scholar
  36. Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L (2005) Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 25(42):9694–9703PubMedGoogle Scholar
  37. Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, Diamond I, Bonci A, Messing RO (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci 7(8):855–861PubMedGoogle Scholar
  38. Choi D-S, Wei W, Deitchman JK, Kharazia VN, Lesscher HMB, McMahon T, Wang D, Qi Z-H, Sieghart W, Zhang C, Shokat KM, Mody I, Messing RO (2008) Protein kinase C delta regulates ethanol intoxication and enhancement of GABA-stimulated tonic current. J Neurosci 28:11890–11899PubMedCentralPubMedGoogle Scholar
  39. Chou WH, Choi DS, Zhang H, Mu D, McMahon T, Kharazia VN, Lowell CA, Ferriero DM, Messing RO (2004) Neutrophil protein kinase Cdelta as a mediator of stroke-reperfusion injury. J Clin Invest 114(1):49–56PubMedCentralPubMedGoogle Scholar
  40. Chou WH, Wang D, McMahon T, Qi ZH, Song M, Zhang C, Shokat KM, Messing RO (2010) GABAA receptor trafficking is regulated by protein kinase C(epsilon) and the N-ethylmaleimide-sensitive factor. J Neurosci 30(42):13955–13965PubMedCentralPubMedGoogle Scholar
  41. Chu K, Koob GF, Cole M, Zorrilla EP, Roberts AJ (2007) Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout. Pharmacol Biochem Behav 86(4):813–821PubMedCentralPubMedGoogle Scholar
  42. Cooper DM (2003) Regulation and organization of adenylyl cyclases and cAMP. Biochem J 375(Pt 3):517–529PubMedGoogle Scholar
  43. Corl AB, Rodan AR, Heberlein U (2005) Insulin signaling in the nervous system regulates ethanol intoxication in Drosophila melanogaster. Nat Neurosci 8(1):18–19PubMedGoogle Scholar
  44. Corl AB, Berger KH, Ophir-Shohat G, Gesch J, Simms JA, Bartlett SE, Heberlein U (2009) Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors. Cell 137(5):949–960PubMedGoogle Scholar
  45. Correia SS, Duarte CB, Faro CJ, Pires EV, Carvalho AL (2003) Protein kinase C gamma associates directly with the GluR4 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit. Effect on receptor phosphorylation. J Biol Chem 278(8):6307–6313PubMedGoogle Scholar
  46. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N (2009) Translational control of long-lasting synaptic plasticity and memory. Neuron 61(1):10–26PubMedGoogle Scholar
  47. Coyle SM, Gilbert WV, Doudna JA (2009) Direct link between RACK1 function and localization at the ribosome in vivo. Mol Cell Biol 29(6):1626–1634PubMedCentralPubMedGoogle Scholar
  48. Cozzoli DK, Goulding SP, Zhang PW, Xiao B, Hu JH, Ary AW, Obara I, Rahn A, Abou-Ziab H, Tyrrel B, Marini C, Yoneyama N, Metten P, Snelling C, Dehoff MH, Crabbe JC, Finn DA, Klugmann M, Worley PF, Szumlinski KK (2009) Binge drinking upregulates accumbens mGluR5-Homer2-P13K signaling: functional implications for alcoholism. J Neurosci 29(27):8655–8668PubMedCentralPubMedGoogle Scholar
  49. Criswell HE, Breese GR (2005) A conceptualization of integrated actions of ethanol contributing to its GABAmimetic profile: a commentary. Neuropsychopharmacology 30(8):1407–1425PubMedGoogle Scholar
  50. Csukai M, Chen C-H, Mochly-Rosen D (1997) β′-COP: a COPI cotamer protein is also an epsilon protein kinase C specific RACK. FASEB J 11:A1187Google Scholar
  51. Das J, Pany S, Rahman GM, Slater SJ (2009) PKC epsilon has an alcohol-binding site in its second cysteine-rich regulatory domain. Biochem J 421(3):405–413PubMedGoogle Scholar
  52. 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(14):5274–5278PubMedCentralPubMedGoogle Scholar
  53. Dulac C (2010) Brain function and chromatin plasticity. Nature 465(7299):728–735PubMedCentralPubMedGoogle Scholar
  54. Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M et al (1996) GDNF signalling through the Ret receptor tyrosine kinase. Nature 381(6585):789–793PubMedGoogle Scholar
  55. Eddison M, Guarnieri DJ, Cheng L, Liu CH, Mofatt KG, Davis G, Heberlein U (2011) Arouser controls ethanol sensitivity through its regulation of synapse number. In revisionGoogle Scholar
  56. Engelman JA (2009) Targeting P13K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562PubMedGoogle Scholar
  57. Faccidomo S, Besheer J, Stanford PC, Hodge CW (2009) Increased operant responding for ethanol in male C57BL/6 J mice: specific regulation by the ERK1/2, but not JNK, MAP kinase pathway. Psychopharmacology (Berl) 204(1):135–147Google Scholar
  58. Fagni L, Worley PF, Ango F (2002) Homer as both a scaffold and transduction molecule. Sci STKE 2002(137):RE8PubMedGoogle Scholar
  59. Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci 6(3):215–229PubMedGoogle Scholar
  60. Finn DA, Snelling C, Fretwell AM, Tanchuck MA, Underwood L, Cole M, Crabbe JC, Roberts AJ (2007) Increased drinking during withdrawal from intermittent ethanol exposure is blocked by the CRF receptor antagonist D-Phe-CRF(12–41). Alcohol Clin Exp Res 31(6):939–949PubMedGoogle Scholar
  61. Fleming RL, Wilson WA, Swartzwelder HS (2007) Magnitude and ethanol sensitivity of tonic GABAA receptor-mediated inhibition in dentate gyrus changes from adolescence to adulthood. J Neurophysiology 97(5):3806–3811Google Scholar
  62. Forsyth CB, Tang Y, Shaikh M, Zhang L, Keshavarzian A (2010) Alcohol stimulates activation of Snail, epidermal growth factor receptor signaling, and biomarkers of epithelial-mesenchymal transition in colon and breast cancer cells. Alcohol Clin Exp Res 34(1):19–31PubMedCentralPubMedGoogle Scholar
  63. Fukami K, Inanobe S, Kanemaru K, Nakamura Y (2010) Phospholipase C is a key enzyme regulating intracellular calcium and modulating the phosphoinositide balance. Prog Lipid Res 49(4):429–437PubMedGoogle Scholar
  64. Funk CK, O’Dell LE, Crawford EF, Koob GF (2006) Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci 26(44):11324–11332PubMedGoogle Scholar
  65. Gentry RT, Rappaport MS, Dole VP (1983) Serial determination of plasma ethanol concentrations in mice. Physiol Behav 31(4):529–532PubMedGoogle Scholar
  66. Gessa GL, Muntoni F, Collu M, Vargiu L, Mereu G (1985) Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area. Brain Res 348(1):201–203PubMedGoogle Scholar
  67. Ghitza UE, Zhai H, Wu P, Airavaara M, Shaham Y, Lu L (2010) Role of BDNF and GDNF in drug reward and relapse: a review. Neurosci Biobehav Rev 35(2):157–171PubMedCentralPubMedGoogle Scholar
  68. Gibb SL, Jeanblanc J, Barak S, Yowell QV, Yaka R, Ron D (2011) Lyn kinase regulates mesolimbic dopamine release: Implication for alcohol reward. J Neurosci 31(6):2180–2187PubMedGoogle Scholar
  69. Gilpin NW, Stewart RB, Murphy JM, Li TK, Badia-Elder NE (2003) Neuropeptide Y reduces oral ethanol intake in alcohol-preferring (P) rats following a period of imposed ethanol abstinence. Alcohol Clin Exp Res 27(5):787–794PubMedGoogle Scholar
  70. Gilpin NW, Misra K, Koob GF (2008) Neuropeptide Y in the central nucleus of the amygdala suppresses dependence-induced increases in alcohol drinking. Pharmacol Biochem Behav 90(3):475–480PubMedCentralPubMedGoogle Scholar
  71. Girault JA, Valjent E, Caboche J, Herve D (2007) ERK2: a logical and gate critical for drug-induced plasticity? Curr Opin Pharmacol 7(1):77–85PubMedGoogle Scholar
  72. Glykys J, Mody I (2007) Activation of GABAA receptors: views from outside the synaptic cleft. Neuron 56(5):763–770PubMedGoogle Scholar
  73. Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I (2007) A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci 10(1):40–48PubMedGoogle Scholar
  74. Gonzales RA, Job MO, Doyon WM (2004) The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement. Pharmacol Ther 103(2):121–146PubMedGoogle Scholar
  75. Gordon AS, Yao L, Wu ZL, Coe IR, Diamond I (1997) Ethanol alters the subcellular localization of delta- and epsilon protein kinase C in NG108–15 cells. Mol Pharmacol 52(4):554–559PubMedGoogle Scholar
  76. Gordon AS, Yao L, Jiang Z, Fishburn CS, Fuchs S, Diamond I (2001) Ethanol acts synergistically with a D2 dopamine agonist to cause translocation of protein kinase C. Mol Pharmacol 59(1):153–160PubMedGoogle Scholar
  77. Hansson AC, Cippitelli A, Sommer WH, Ciccocioppo R, Heilig M (2007) Region-specific down-regulation of Crhr1 gene expression in alcohol-preferring msP rats following ad lib access to alcohol. Addict biol 12(1):30–34PubMedGoogle Scholar
  78. Hansson AC, Rimondini R, Neznanova O, Sommer WH, Heilig M (2008) Neuroplasticity in brain reward circuitry following a history of ethanol dependence. Eur J Neurosci 27(8):1912–1922PubMedCentralPubMedGoogle Scholar
  79. Harris RA, Proctor WR, McQuilkin SJ, Klein RL, Mascia MP, Whatley V, Whiting PJ, Dunwiddie TV (1995) Ethanol increases GABAA responses in cells stably transfected with receptor subunits. Alcoholism: clinical and experimental research 19:226–232Google Scholar
  80. Harris RA, Mihic SJ, Brozowski S, Hadingham K, Whiting PJ (1997) Ethanol, flunitrazepam, and pentobarbital modulation of GABAA receptors expressed in mammalian cells and Xenopus oocytes. Alcohol Clin Exp Res 21(3):444–451PubMedGoogle Scholar
  81. Hauge C, Frodin M (2006) RSK and MSK in MAP kinase signalling. J Cell Sci 119(15):3021–3023PubMedGoogle Scholar
  82. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945PubMedGoogle Scholar
  83. Hayashi T, Huganir RL (2004) Tyrosine phosphorylation and regulation of the AMPA receptor by SRC family tyrosine kinases. J Neurosci 24(27):6152–6160PubMedGoogle Scholar
  84. Hayashi MK, Ames HM, Hayashi Y (2006) Tetrameric hub structure of postsynaptic scaffolding protein homer. J Neurosci 26(33):8492–8501PubMedGoogle Scholar
  85. He DY, Vagts AJ, Yaka R, Ron D (2002) Ethanol induces gene expression via nuclear compartmentalization of receptor for activated C kinase 1. Mol Pharmacol 62(2):272–280PubMedGoogle Scholar
  86. He DY, Neasta J, Ron D (2010) Epigenetic regulation of BDNF expression via the scaffolding protein RACK1. J Biol Chem 285(25):19043–19050PubMedGoogle Scholar
  87. Heberlein A, Muschler M, Wilhelm J, Frieling H, Lenz B, Groschl M, Kornhuber J, Bleich S, Hillemacher T (2010) BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal. Prog Neuropsychopharmacol Biol Psychiatry 34(6):1060–1064PubMedGoogle Scholar
  88. Heilig M (2004) The NPY system in stress, anxiety and depression. Neuropeptides 38(4):213–224PubMedGoogle Scholar
  89. Hensler JG, Ladenheim EE, Lyons WE (2003) Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (±) mice. J Neurochem 85(5):1139–1147PubMedGoogle Scholar
  90. Hermanto U, Zong CS, Li W, Wang LH (2002) RACK1, an insulin-like growth factor I (IGF-I) receptor-interacting protein, modulates IGF-I-dependent integrin signaling and promotes cell spreading and contact with extracellular matrix. Mol Cell Biol 22(7):2345–2365PubMedCentralPubMedGoogle Scholar
  91. Hicks SD, Middleton FA, Miller MW (2010) Ethanol-induced methylation of cell cycle genes in neural stem cells. J Neurochem 114(6):1767–1780PubMedGoogle Scholar
  92. Hirai T, Chida K (2003) Protein kinase Czeta (PKCzeta): activation mechanisms and cellular functions. J Biochem 133(1):1–7PubMedGoogle Scholar
  93. Hodge CW, Mehmert KK, Kelley SP, McMahon T, Haywood A, Olive MF, Wang D, Sanchez-Perez AM, Messing RO (1999) Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon. Nat Neurosci 2(11):997–1002PubMedGoogle Scholar
  94. Hodge CW, Raber J, McMahon T, Walter H, Sanchez-Perez AM, Olive MF, Mehmert K, Morrow AL, Messing RO (2002) Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase C epsilon. J Clin Invest 110(7):1003–1010PubMedCentralPubMedGoogle Scholar
  95. Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33(2):67–75PubMedCentralPubMedGoogle Scholar
  96. Hopf FW, Cascini MG, Gordon AS, Diamond I, Bonci A (2003) Cooperative activation of dopamine D1 and D2 receptors increases spike firing of nucleus accumbens neurons via G-protein betagamma subunits. J Neurosci 23(12):5079–5087PubMedGoogle Scholar
  97. Huttunen P, Myers RD (1987) Anatomical localization in hippocampus of tetrahydro-beta-carboline-induced alcohol drinking in the rat. Alcohol 4(3):181–187PubMedGoogle Scholar
  98. Hyytiä P, Koob GF (1995) GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats. Eur J Pharmacol 283(1–3):151–159PubMedGoogle Scholar
  99. Hyytia P, Ingman K, Soini SL, Laitinen JT, Korpi ER (1999) Effects of continuous opioid receptor blockade on alcohol intake and up-regulation of opioid receptor subtype signalling in a genetic model of high alcohol drinking. Naunyn Schmiedebergs Arch Pharmacol 360(4):391–401PubMedGoogle Scholar
  100. Ibba F, Vinci S, Spiga S, Peana AT, Assaretti AR, Spina L, Longoni R, Acquas E (2009) Ethanol-induced extracellular signal regulated kinase: role of dopamine D1 receptors. Alcohol Clin Exp Res 33(5):858–867PubMedGoogle Scholar
  101. Jeanblanc J, He DY, McGough NN, Logrip ML, Phamluong K, Janak PH, Ron D (2006) The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J Neurosci 26(5):1457–1464PubMedGoogle Scholar
  102. Jeanblanc J, He DY, Carnicella S, Kharazia V, Janak PH, Ron D (2009) Endogenous BDNF in the dorsolateral striatum gates alcohol drinking. J Neurosci 29(43):13494–13502PubMedCentralPubMedGoogle Scholar
  103. Jiang ZL, Ye J (2003) Protein kinase C(epsilon) is involved in ethanol potentiation of glycine-gated Cl(-) current in rat neurons of ventral tegmental area. Neuropharmacology 44(4):493–502PubMedGoogle Scholar
  104. Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85(7):1113–1124PubMedGoogle Scholar
  105. Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29(2):95–102PubMedGoogle Scholar
  106. Kalia LV, Gingrich JR, Salter MW (2004) Src in synaptic transmission and plasticity. Oncogene 23(48):8007–8016PubMedGoogle Scholar
  107. Kaminen-Ahola N, Ahola A, Maga M, Mallitt KA, Fahey P, Cox TC, Whitelaw E, Chong S (2010) Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet 6(1):e1000811PubMedCentralPubMedGoogle Scholar
  108. Khasar SG, Lin YH, Martin A, Dadgar J, McMahon T, Wang D, Hundle B, Aley KO, Isenberg W, McCarter G, Green PG, Hodge CW, Levine JD, Messing RO (1999) A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. Neuron 24(1):253–260PubMedGoogle Scholar
  109. Kiely PA, Sant A, O’Connor R (2002) RACK1 is an IGF-1 Receptor interacting protein that can regulate IGF-1- mediated Akt activation and protection from cell death. J Biol Chem 8(6):6Google Scholar
  110. Kiely PA, Baillie GS, Barrett R, Buckley DA, Adams DR, Houslay MD, O’Connor R (2009) Phosphorylation of RACK1 on tyrosine 52 by c-Abl is required for insulin-like growth factor I-mediated regulation of focal adhesion kinase. J Biol Chem 284(30):20263–20274PubMedGoogle Scholar
  111. Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5(10):771–781PubMedGoogle Scholar
  112. Klugmann M, Szumlinski KK (2008) Targeting Homer genes using adeno-associated viral vector: lessons learned from behavioural and neurochemical studies. Behav Pharmacol 19(5–6):485–500PubMedGoogle Scholar
  113. Koob GF (2009) Brain stress systems in the amygdala and addiction. Brain Res 1293:61–75PubMedCentralPubMedGoogle Scholar
  114. Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21(3):467–476PubMedGoogle Scholar
  115. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705PubMedGoogle Scholar
  116. Kumar S, Kralic JE, O’Buckley TK, Grobin AC, Morrow AL (2003) Chronic ethanol consumption enhances internalization of alpha1 subunit-containing GABAA receptors in cerebral cortex. J Neurochem 86(3):700–708PubMedGoogle Scholar
  117. Kumar S, Lane BM, Morrow AL (2006) Differential effects of systemic ethanol administration on protein kinase cepsilon, gamma, and beta isoform expression, membrane translocation, and target phosphorylation: reversal by chronic ethanol exposure. J Pharmacol Exp Ther 319(3):1366–1375PubMedGoogle Scholar
  118. Kumar S, Suryanarayanan A, Boyd KN, Comerford CE, Lai MA, Ren Q, Morrow AL (2010) Ethanol reduces GABAA alpha1 subunit receptor surface expression by a protein kinase Cgamma-dependent mechanism in cultured cerebral cortical neurons. Mol Pharmacol 77(5):793–803PubMedGoogle Scholar
  119. Lai CC, Kuo TI, Lin HH (2007) The role of protein kinase A in acute ethanol-induced neurobehavioral actions in rats. Anesth Analg 105(1):89–96PubMedGoogle Scholar
  120. Laron Z (2009) Insulin and the brain. Arch Physiol Biochem 115(2):112–116PubMedGoogle Scholar
  121. Lee AM, Messing RO (2008) Protein kinases and addiction. Ann N Y Acad Sci 1141:22–57PubMedCentralPubMedGoogle Scholar
  122. Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H (2004) Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J Neurosci 24(9):2304–2312PubMedGoogle Scholar
  123. Lee CC, Huang CC, Wu MY, Hsu KS (2005) Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 280(18):18543–18550PubMedGoogle Scholar
  124. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445(7124):168–176PubMedGoogle Scholar
  125. Lesscher HM, McMahon T, Lasek AW, Chou WH, Connolly J, Kharazia V, Messing RO (2008) Amygdala protein kinase C epsilon regulates corticotropin-releasing factor and anxiety-like behavior. Genes Brain Behav 7(3):323–333PubMedGoogle Scholar
  126. Lesscher HM, Wallace MJ, Zeng L, Wang V, Deitchman JK, McMahon T, Messing RO, Newton PM (2009) Amygdala protein kinase C epsilon controls alcohol consumption. Genes Brain Behav Feb 11 [Epub ahead of print]Google Scholar
  127. Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317PubMedGoogle Scholar
  128. Li J, Li YH, Yuan XR (2003) Changes of phosphorylation of cAMP response element binding protein in rat nucleus accumbens after chronic ethanol intake: naloxone reversal. Acta Pharmacol Sin 24(9):930–936PubMedGoogle Scholar
  129. Liang J, Suryanarayanan A, Abriam A, Snyder B, Olsen RW, Spigelman I (2007) Mechanisms of reversible GABAA receptor plasticity after ethanol intoxication. J Neurosci 27(45):12367–12377PubMedGoogle Scholar
  130. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260(5111):1130–1132PubMedGoogle Scholar
  131. Logrip ML, Janak PH, Ron D (2008) Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake. Faseb J 22(7):2393–2404PubMedGoogle Scholar
  132. Logrip ML, Janak PH, Ron D (2009) Escalating ethanol intake is associated with altered corticostriatal BDNF expression. J Neurochem [in Press]Google Scholar
  133. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35(4):605–623PubMedGoogle Scholar
  134. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the P13K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11(1–2):32–50PubMedCentralPubMedGoogle Scholar
  135. Lu L, Koya E, Zhai H, Hope BT, Shaham Y (2006) Role of ERK in cocaine addiction. Trends Neurosci 29(12):695–703PubMedGoogle Scholar
  136. Maas JW Jr, Vogt SK, Chan GC, Pineda VV, Storm DR, Muglia LJ (2005) Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity. J Neurosci 25(16):4118–4126PubMedGoogle Scholar
  137. Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA (2002) DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens. Nat Neurosci 5(7):641–648PubMedGoogle Scholar
  138. Mao L, Yang L, Tang Q, Samdani S, Zhang G, Wang JQ (2005) The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons. J Neurosci 25(10):2741–2752PubMedGoogle Scholar
  139. Martin-García E, Darbra S, Pallarès M (2007) Intrahippocampal allopregnanolone decreases voluntary chronic alcohol consumption in non-selected rats. Prog Neuropsychopharmacol Biol Psychiatry 31(4):823–831PubMedGoogle Scholar
  140. Martinowich K, Manji H, Lu B (2007) New insights into BDNF function in depression and anxiety. Nat Neurosci 10(9):1089–1093PubMedGoogle Scholar
  141. Matsushita S, Arai H, Matsui T, Yuzuriha T, Urakami K, Masaki T, Higuchi S (2005) Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease. J Neural Transm 112(5):703–711PubMedGoogle Scholar
  142. McGough NN, He DY, Logrip ML, Jeanblanc J, Phamluong K, Luong K, Kharazia V, Janak PH, Ron D (2004) RACK1 and brain-derived neurotrophic factor: a homeostatic pathway that regulates alcohol addiction. J Neurosci 24(46):10542–10552PubMedGoogle Scholar
  143. McMahon T, Andersen R, Metten P, Crabbe JC, Messing RO (2000) Protein kinase C epsilon mediates up-regulation of N-type calcium channels by ethanol. Mol Pharmacol 57(1):53–58PubMedGoogle Scholar
  144. Merchenthaler I, Liposits Z, Reid JJ, Wetsel WC (1993) Light and electron microscopic immunocytochemical localization of PKCδ immunoreactivity in the rat central nervous system. J Comp Neurol 336:378–399PubMedGoogle Scholar
  145. Messing RO (2007) Alcohol and the nervous system. In: Aminoff MJ (ed) Neurology and General Medicine, 3rd edn. Churchill Livingstone, New York, pp 721–734Google Scholar
  146. Messing RO, Petersen PJ, Henrich CJ (1991) Chronic ethanol exposure increases levels of protein kinase C δ and ε and protein kinase C-mediated phosphorylation in cultured neural cells. J Biol Chem 266:23428–23432PubMedGoogle Scholar
  147. Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53(6):857–869PubMedGoogle Scholar
  148. Miranda RC, Pietrzykowski AZ, Tang Y, Sathyan P, Mayfield D, Keshavarzian A, Sampson W, Hereld D (2010) MicroRNAs: master regulators of ethanol abuse and toxicity? Alcohol Clin Exp Res 34(4):575–587PubMedCentralPubMedGoogle Scholar
  149. Misra K, Pandey SC (2006) The decreased cyclic-AMP dependent-protein kinase A function in the nucleus accumbens: a role in alcohol drinking but not in anxiety-like behaviors in rats. Neuropsychopharmacology 31(7):1406–1419PubMedGoogle Scholar
  150. Miyame M, Diamond I, Weiner MW, Camacho SA, Figueredo VM (1997) Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury. Proc Nat Acad Sci 94:3235–3239Google Scholar
  151. Moller C, Wiklund L, Sommer W, Thorsell A, Heilig M (1997) Decreased experimental anxiety and voluntary ethanol consumption in rats following central but not basolateral amygdala lesions. Brain Res 760(1–2):94–101PubMedGoogle Scholar
  152. Moonat S, Sakharkar AJ, Zhang H, Pandey SC (2011) The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism. Addict Biol 16(2):238–250PubMedCentralPubMedGoogle Scholar
  153. Mourton T, Hellberg CB, Burden-Gulley SM, Hinman J, Rhee A, Brady-Kalnay SM (2001) The PTPmu protein tyrosine phosphatase binds and recruits the scaffolding protein RACK1 to cell–cell contacts. J Biol Chem 13:13Google Scholar
  154. Nagy J (2008) Alcohol related changes in regulation of NMDA receptor functions. Curr Neuropharmacol 6(1):39–54PubMedGoogle Scholar
  155. Nagy LE, Diamond I, Casso DJ, Franklin C, Gordon AS (1990) Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter. J Biol Chem 265:1946–1951PubMedGoogle Scholar
  156. Naik MU, Benedikz E, Hernandez I, Libien J, Hrabe J, Valsamis M, Dow-Edwards D, Osman M, Sacktor TC (2000) Distribution of protein kinase Mzeta and the complete protein kinase C isoform family in rat brain. J Comp Neurol 426(2):243–258PubMedGoogle Scholar
  157. Neasta J, Ben Hamida S, Yowell Q, Carnicella S, Ron D (2010) Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders. Proc Natl Acad Sci U S A 107:424–433Google Scholar
  158. Neasta J, Ben Hamida S, Yowell QV, Carnicella S, Ron D (2011a) AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors. Biol Psychiatry [In Revision]Google Scholar
  159. Neasta J, Hamida SB, Yowell QV, Carnicella S, Ron D (2011b) AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors. Biol PsychiatryGoogle Scholar
  160. Newton AC (2010) Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab 298(3):E395–E402PubMedGoogle Scholar
  161. Newton PM, Ron D (2007) Protein kinase C and alcohol addiction. Pharmacol Res 55(6):570–577PubMedGoogle Scholar
  162. Neznanova O, Bjork K, Rimondini R, Hansson AC, Hyytia P, Heilig M, Sommer WH (2009) Acute ethanol challenge inhibits glycogen synthase kinase-3beta in the rat prefrontal cortex. Int J Neuropsychopharmacol 12(2):275–280PubMedCentralPubMedGoogle Scholar
  163. Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR (2004) Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303(5663):1512–1514PubMedGoogle Scholar
  164. Nishizuka Y (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9(7):484–496PubMedGoogle Scholar
  165. Olive MF, Mehmert KK, Messing RO, Hodge CW (2000) Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCε-deficient mice. Eur J Neurosci 12(11):4131–4140PubMedGoogle Scholar
  166. Pandey SC, Mittal N, Lumeng L, Li TK (1999a) Involvement of the cyclic AMP-responsive element binding protein gene transcription factor in genetic preference for alcohol drinking behavior. Alcohol Clin Exp Res 23(9):1425–1434PubMedGoogle Scholar
  167. Pandey SC, Zhang D, Mittal N, Nayyar D (1999b) Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal-related anxiety. J Pharmacol Exp Ther 288(2):866–878PubMedGoogle Scholar
  168. Pandey SC, Roy A, Mittal N (2001) Effects of chronic ethanol intake and its withdrawal on the expression and phosphorylation of the creb gene transcription factor in rat cortex. J Pharmacol Exp Ther 296(3):857–868PubMedGoogle Scholar
  169. Pandey SC, Roy A, Zhang H (2003) The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. Alcohol Clin Exp Res 27(3):396–409PubMedGoogle Scholar
  170. Pandey SC, Roy A, Zhang H, Xu T (2004) Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J Neurosci 24(21):5022–5030PubMedGoogle Scholar
  171. Pandey SC, Zhang H, Roy A, Xu T (2005) Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest 115(10):2762–2773PubMedCentralPubMedGoogle Scholar
  172. Pandey SC, Zhang H, Roy A, Misra K (2006) Central and medial amygdaloid brain-derived neurotrophic factor signaling plays a critical role in alcohol-drinking and anxiety-like behaviors. J Neurosci 26(32):8320–8331PubMedGoogle Scholar
  173. Pandey SC, Ugale R, Zhang H, Tang L, Prakash A (2008a) Brain chromatin remodeling: a novel mechanism of alcoholism. J Neurosci 28(14):3729–3737PubMedGoogle Scholar
  174. Pandey SC, Zhang H, Ugale R, Prakash A, Xu T, Misra K (2008b) Effector immediate-early gene arc in the amygdala plays a critical role in alcoholism. J Neurosci 28(10):2589–2600PubMedGoogle Scholar
  175. Pascoli V, Besnard A, Herve D, Pages C, Heck N, Girault JA, Caboche J, Vanhoutte P (2011) Cyclic Adenosine Monophosphate-Independent Tyrosine Phosphorylation of NR2B Mediates Cocaine-Induced Extracellular Signal-Regulated Kinase Activation. Biol Psychiatry 69(3):218–227PubMedGoogle Scholar
  176. Patterson RL, van Rossum DB, Barrow RK, Snyder SH (2004) RACK1 binds to inositol 1, 4, 5-trisphosphate receptors and mediates Ca2 + release. Proc Natl Acad Sci U S A 101(8):2328–2332PubMedCentralPubMedGoogle Scholar
  177. Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, Siegelmann HT, Treistman SN (2008) Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 59(2):274–287PubMedCentralPubMedGoogle Scholar
  178. Pochon NA, Menoud A, Tseng JL, Zurn AD, Aebischer P (1997) Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization. Eur J Neurosci 9(3):463–471PubMedGoogle Scholar
  179. Prakash A, Zhang H, Pandey SC (2008) Innate differences in the expression of brain-derived neurotrophic factor in the regions within the extended amygdala between alcohol preferring and nonpreferring rats. Alcohol Clin Exp Res 32(6):909–920PubMedGoogle Scholar
  180. Primeaux SD, Wilson SP, Bray GA, York DA, Wilson MA (2006) Overexpression of neuropeptide Y in the central nucleus of the amygdala decreases ethanol self-administration in “anxious” rats. Alcohol Clin Exp Res 30(5):791–801PubMedGoogle Scholar
  181. Qi ZH, Song M, Wallace MJ, Wang D, Newton PM, McMahon T, Chou WH, Zhang C, Shokat KM, Messing RO (2007) Protein kinase C epsilon regulates GABAA receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma 2 subunits. J Biol Chem 282:33052–33063PubMedGoogle Scholar
  182. Qiang M, Denny A, Chen J, Ticku MK, Yan B, Henderson G (2010) The site specific demethylation in the 5′-regulatory area of NMDA receptor 2B subunit gene associated with CIE-induced up-regulation of transcription. PLoS One 5(1):e8798PubMedCentralPubMedGoogle Scholar
  183. Repunte-Canonigo V, Lutjens R, van der Stap LD, Sanna PP (2007) Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure. Brain Res 1138:48–56PubMedGoogle Scholar
  184. Rex EB, Rankin ML, Ariano MA, Sibley DR (2008) Ethanol regulation of D(1) dopamine receptor signaling is mediated by protein kinase C in an isozyme-specific manner. Neuropsychopharmacology 33(12):2900–2911PubMedGoogle Scholar
  185. Risinger FO, Freeman PA, Greengard P, Fienberg AA (2001) Motivational effects of ethanol in DARPP-32 knock-out mice. J Neurosci 21(1):340–348PubMedGoogle Scholar
  186. Ron D (2004) Signaling cascades regulating NMDA receptor sensitivity to ethanol. Neuroscientist 10(4):325–336PubMedCentralPubMedGoogle Scholar
  187. Ron D, Jurd R (2005) The “ups and downs” of signaling cascades in addiction. Sci STKE 2005(309):re14PubMedGoogle Scholar
  188. Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D (1994) Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci U S A 91(3):839–843PubMedCentralPubMedGoogle Scholar
  189. Ron D, Jiang Z, Yao L, Vagts A, Diamond I, Gordon A (1999) Coordinated movement of RACK1 with activated betaIIPKC. J Biol Chem 274(38):27039–27046PubMedGoogle Scholar
  190. Ron D, Vagts AJ, Dohrman DP, Yaka R, Jiang Z, Yao L, Crabbe J, Grisel JE, Diamond I (2000) Uncoupling of {beta}IIPKC from its targeting protein RACK1 in response to ethanol in cultured cells and mouse brain. Faseb J 14(14):2303–2314PubMedGoogle Scholar
  191. Rong R, Ahn JY, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH, Ye K (2003) P13Kinase enhancer-Homer complex couples mGluRI to P13Kinase, preventing neuronal apoptosis. Nat Neurosci 6(11):1153–1161PubMedGoogle Scholar
  192. Rosse C, Linch M, Kermorgant S, Cameron AJ, Boeckeler K, Parker PJ (2010) PKC and the control of localized signal dynamics. Nat Rev Mol Cell Biol 11(2):103–112PubMedGoogle Scholar
  193. Roy A, Pandey SC (2002) The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure. Alcohol Clin Exp Res 26(6):796–803PubMedGoogle Scholar
  194. Ryabinin AE, Yoneyama N, Tanchuck MA, Mark GP, Finn DA (2008) Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption. Neuroscience 151(3):780–790PubMedCentralPubMedGoogle Scholar
  195. Sala C, Piech V, Wilson NR, Passafaro M, Liu G, Sheng M (2001) Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31(1):115–130PubMedGoogle Scholar
  196. Salter MW, Kalia LV (2004) Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 5(4):317–328PubMedGoogle Scholar
  197. Sanna PP, Simpson C, Lutjens R, Koob G (2002) ERK regulation in chronic ethanol exposure and withdrawal. Brain Res 948(1–2):186–191PubMedGoogle Scholar
  198. Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH (2009) BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One 4(6):e6007PubMedCentralPubMedGoogle Scholar
  199. Smith TF, Gaitatzes C, Saxena K, Neer EJ (1999) The WD repeat: a common architecture for diverse functions [In Process Citation]. Trends Biochem Sci 24(5):181–185PubMedGoogle Scholar
  200. Soloviev MM, Ciruela F, Chan WY, McIlhinney RA (2000) Mouse brain and muscle tissues constitutively express high levels of Homer proteins. Eur J Biochem 267(3):634–639PubMedGoogle Scholar
  201. Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, Heilig MA (2008) Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence. Biological psychiatry 63(2):139–145PubMedGoogle Scholar
  202. Souroujon MC, Yao L, Chen H, Endemann G, Khaner H, Geeraert V, Schechtman D, Gordon AS, Diamond I, Mochly-Rosen D (2004) State-specific monoclonal antibodies identify an intermediate state in epsilon protein kinase C activation. J Biol Chem 279(17):17617–17624PubMedGoogle Scholar
  203. Sperber BR, Boyle-Walsh EA, Engleka MJ, Gadue P, Peterson AC, Stein PL, Scherer SS, McMorris FA (2001) A unique role for Fyn in CNS myelination. J Neurosci 21(6):2039–2047PubMedGoogle Scholar
  204. Stubbs CD, Slater SJ (1999) Ethanol and protein kinase C. Alcohol Clin Exp Res 23(9):1552–1560PubMedGoogle Scholar
  205. Sundstrom-Poromaa I, Smith DH, Gong QH, Sabado TN, Li X, Light A, Wiedmann M, Williams K, Smith SS (2002) Hormonally regulated alpha(4)beta(2)delta GABA(A) receptors are a target for alcohol. Nat Neurosci 5(8):721–722PubMedCentralPubMedGoogle Scholar
  206. Suvarna N, Borgland SL, Wang J, Phamluong K, Auberson YP, Bonci A, Ron D (2005) Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras. J Biol Chem 280(36):31450–31459PubMedGoogle Scholar
  207. Svenningsson P, Nairn AC, Greengard P (2005) DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J 7(2):E353–E360PubMedGoogle Scholar
  208. Szumlinski KK, Lominac KD, Oleson EB, Walker JK, Mason A, Dehoff MH, Klugman M, Cagle S, Welt K, During M, Worley PF, Middaugh LD, Kalivas PW (2005) Homer2 is necessary for EtOH-induced neuroplasticity. J Neurosci 25(30):7054–7061PubMedGoogle Scholar
  209. Szyf M, Weaver IC, Champagne FA, Diorio J, Meaney MJ (2005) Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Front Neuroendocrinol 26(3–4):139–162PubMedGoogle Scholar
  210. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H (2004) Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 24(44):9760–9769PubMedGoogle Scholar
  211. Tanaka K, Hashimoto H, Shintani N, Yamamoto A, Baba A (2004) Reduced hypothermic and hypnotic responses to ethanol in PACAP-deficient mice. Regul Pept 123(1–3):95–98PubMedGoogle Scholar
  212. Thiele TE, Marsh DJ, Ste. Marie L, Bernstein IL, Palmiter RD (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396(6709):366–369PubMedGoogle Scholar
  213. Thiele TE, Willis B, Stadler J, Reynolds JG, Bernstein IL, McKnight GS (2000) High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J Neurosci 20(10):RC75PubMedGoogle Scholar
  214. Thomas U (2002) Modulation of synaptic signalling complexes by Homer proteins. J Neurochem 81(3):407–413PubMedGoogle Scholar
  215. Thornton C, Tang KC, Phamluong K, Luong K, Vagts A, Nikanjam D, Yaka R, Ron D (2004) Spatial and temporal regulation of RACK1 function and NMDA receptor activity through WD40 motif-mediated dimerization. J Biol ChemGoogle Scholar
  216. Thorsell A, Johnson J, Heilig M (2007) Effect of the adenosine A2a receptor antagonist 3, 7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar Rats. Alcohol Clin Exp Res 31(8):1302–1307PubMedGoogle Scholar
  217. Treistman SN, Martin GE (2009) BK Channels: mediators and models for alcohol tolerance. Trends Neurosci 32(12):629–637PubMedGoogle Scholar
  218. Trupp M, Belluardo N, Funakoshi H, Ibanez CF (1997) Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor- alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci 17(10):3554–3567PubMedGoogle Scholar
  219. Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8(5):355–367PubMedGoogle Scholar
  220. Umemori H, Ogura H, Tozawa N, Mikoshiba K, Nishizumi H, Yamamoto T (2003) Impairment of N-methyl-D-aspartate receptor-controlled motor activity in LYN-deficient mice. Neuroscience 118(3):709–713PubMedGoogle Scholar
  221. Urizar NL, Yang Z, Edenberg HJ, Davis RL (2007) Drosophila homer is required in a small set of neurons including the ellipsoid body for normal ethanol sensitivity and tolerance. J Neurosci 27(17):4541–4551PubMedGoogle Scholar
  222. 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):704–711 Oct 15PubMedGoogle Scholar
  223. Walaas SI, Zhao YH, Sudol M (1993) Neuronal localization of the tyrosine-specific protein kinase p62c-yes in rat basal ganglia. Neurochem Res 18(1):43–46PubMedGoogle Scholar
  224. Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463(1–3):199–216PubMedGoogle Scholar
  225. Wallace MJ, Newton PM, Oyasu M, McMahon T, Chou WH, Connolly J, Messing RO (2007) Acute functional tolerance to ethanol mediated by protein kinase C epsilon. Neuropsychopharmacology 32(1):127–136PubMedGoogle Scholar
  226. Wallner M, Hanchar HJ, Olsen RW (2003) Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Nat Acad Sci 100(25):15218–15223PubMedGoogle Scholar
  227. Wand G, Levine M, Zweifel L, Schwindinger W, Abel T (2001) The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol. J Neurosci 21(14):5297–5303PubMedGoogle Scholar
  228. Wang H, Storm DR (2003) Calmodulin-regulated adenylyl cyclases: cross-talk and plasticity in the central nervous system. Mol Pharmacol 63(3):463–468PubMedGoogle Scholar
  229. Wang XQ, Yu SP (2005) Novel regulation of Na, K-ATPase by Src tyrosine kinases in cortical neurons. J Neurochem 93(6):1515–1523PubMedGoogle Scholar
  230. Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F, Wang YT (2003) Control of synaptic strength, a novel function of Akt. Neuron 38(6):915–928PubMedGoogle Scholar
  231. Wang J, Carnicella S, Phamluong K, Jeanblanc J, Ronesi JA, Chaudhri N, Janak PH, Lovinger DM, Ron D (2007) Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior. J Neurosci 27(13):3593–3602PubMedGoogle Scholar
  232. Wang J, Carnicella S, Ahmadiantehrani S, He DY, Barak S, Kharazia V, Ben Hamida S, Zapata A, Shippenberg TS, Ron D (2010a) Nucleus accumbens-derived glial cell line-derived neurotrophic factor is a retrograde enhancer of dopaminergic tone in the mesocorticolimbic system. J Neurosci 30(43):14502–14512PubMedCentralPubMedGoogle Scholar
  233. Wang J, Lanfranco MF, Gibb SL, Yowell QV, Carnicella S, Ron D (2010b) Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J Neurosci 30(30):10187–10198PubMedCentralPubMedGoogle Scholar
  234. Wei W, Zhang N, Peng Z, Houser CR, Mody I (2003) Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci 23(33):10650–10661PubMedGoogle Scholar
  235. Wei W, Faria LC, Mody I (2004) Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci 24(38):8379–8382PubMedGoogle Scholar
  236. Weiner JL, Valenzuela CF (2006) Ethanol modulation of GABAergic transmission: the view from the slice. Pharmacol Ther 111(3):533–554PubMedGoogle Scholar
  237. 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
  238. Wilkie MB, Besheer J, Kelley SP, Kumar S, O’Buckley TK, Morrow AL, Hodge CW (2007) Acute ethanol administration rapidly increases phosphorylation of conventional protein kinase C in specific mammalian brain regions in vivo. Alcohol Clin Exp Res 31(7):1259–12567PubMedCentralPubMedGoogle Scholar
  239. Wojnar M, Brower KJ, Strobbe S, Ilgen M, Matsumoto H, Nowosad I, Sliwerska E, Burmeister M (2009) Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence. Alcohol Clin Exp Res 33(4):693–702PubMedCentralPubMedGoogle Scholar
  240. Wong RW, Guillaud L (2004) The role of epidermal growth factor and its receptors in mammalian CNS. Cytokine Growth Factor Rev 15(2–3):147–156PubMedGoogle Scholar
  241. Wu PH, Coultrap S, Browning MD, Proctor WR (2010) Correlated changes in NMDA receptor phosphorylation, functional activity, and sedation by chronic ethanol consumption. J Neurochem 115(5):1112–1122PubMedCentralPubMedGoogle Scholar
  242. Yaka R, Thornton C, Vagts AJ, Phamluong K, Bonci A, Ron D (2002) NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1. Proc Natl Acad Sci U S A 99(8):5710–5715PubMedCentralPubMedGoogle Scholar
  243. Yaka R, He DY, Phamluong K, Ron D (2003a) Pituitary adenylate cyclase-activating polypeptide (PACAP(1–38)) enhances N-Methyl-D-aspartate receptor function and brain-derived neurotrophic factor expression via RACK1. J Biol Chem 278(11):9630–9638PubMedGoogle Scholar
  244. Yaka R, Phamluong K, Ron D (2003b) Scaffolding of Fyn kinase to the nmda receptor determines brain region sensitivity to ethanol. J Neurosci 23(9):3623–3632PubMedCentralPubMedGoogle Scholar
  245. Yaka R, Tang KC, Camarini R, Janak PH, Ron D (2003c) Fyn kinase and NR2B-containing NMDA receptors regulate acute ethanol sensitivity but not ethanol intake or conditioned reward. Alcohol Clin Exp Res 27(11):1736–1742PubMedCentralPubMedGoogle Scholar
  246. Yamashita M, Marszalec W, Yeh JZ, Narahashi T (2006) Effects of ethanol on tonic GABA currents in cerebellar granule cells and mammalian cells recombinantly expressing GABA(A) receptors. J Pharmacol Exp Ther 319(1):431–438PubMedGoogle Scholar
  247. Yang X, Horn K, Baraban JM, Wand GS (1998a) Chronic ethanol administration decreases phosphorylation of cyclic AMP response element-binding protein in granule cells of rat cerebellum. J Neurochem 70(1):224–232PubMedGoogle Scholar
  248. Yang X, Horn K, Wand GS (1998b) Chronic ethanol exposure impairs phosphorylation of CREB and CRE-binding activity in rat striatum. Alcohol Clin Exp Res 22(2):382–390PubMedGoogle Scholar
  249. Yao L, Arolfo MP, Dohrman DP, Jiang Z, Fan P, Fuchs S, Janak PH, Gordon AS, Diamond I (2002) Betagamma dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell 109(6):733–743PubMedGoogle Scholar
  250. Yao L, Fan P, Jiang Z, Mailliard WS, Gordon AS, Diamond I (2003) Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers. Proc Natl Acad Sci U S A 100(24):14379–14384PubMedCentralPubMedGoogle Scholar
  251. Yao L, Fan P, Jiang Z, Gordon A, Mochly-Rosen D, Diamond I (2008) Dopamine and ethanol cause translocation of epsilonPKC associated with epsilonRACK: cross-talk between cAMP-dependent protein kinase A and protein kinase C signaling pathways. Mol Pharmacol 73(4):1105–1112PubMedCentralPubMedGoogle Scholar
  252. Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I (2010) Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis. Nat MedGoogle Scholar
  253. Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB (1999) The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. J Biol Chem 274(21):14909–14917PubMedGoogle Scholar
  254. Yin HH, Knowlton BJ (2006) The role of the basal ganglia in habit formation. Nat Rev Neurosci 7(6):464–476PubMedGoogle Scholar
  255. Yin HH, Ostlund SB, Knowlton BJ, Balleine BW (2005) The role of the dorsomedial striatum in instrumental conditioning. Eur J Neurosci 22(2):513–523PubMedGoogle Scholar
  256. Yoshii A, Constantine-Paton M (2010) Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70(5):304–322PubMedCentralPubMedGoogle Scholar
  257. Youngson NA, Whitelaw E (2008) Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 9:233–257PubMedGoogle Scholar
  258. Zhang H, Pandey SC (2003) Effects of PKA modulation on the expression of neuropeptide Y in rat amygdaloid structures during ethanol withdrawal. Peptides 24(9):1397–1402PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Ernest Gallo Clinic and Research CenterUniversity of California San FranciscoEmeryvilleUSA

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