KEGG   PATHWAY: ecb05034
Entry
ecb05034                    Pathway                                
Name
Alcoholism - Equus caballus (horse)
Description
Alcoholism, also called dependence on alcohol (ethanol), is a chronic relapsing disorder that is progressive and has serious detrimental health outcomes. As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression, whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may play an important role in neuroadaptation in response to chronic alcohol exposure.
Class
Human Diseases; Substance dependence
Pathway map
ecb05034  Alcoholism
ecb05034

Other DBs
GO: 0045471
Organism
Equus caballus (horse) [GN:ecb]
Gene
100146648  TH; tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
100052557  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
100055485  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
100058805  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
100033867  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
100033868  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
100054747  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
100059861  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
100051329  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
100063746  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
100052410  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
102148904  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
100062954  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
111774159  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
100072578  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
100070281  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
100061405  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
100051252  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
100067014  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
100062208  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
100050617  HDAC7; histone deacetylase 7 isoform X4 [KO:K11408] [EC:3.5.1.98]
100052401  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
106780857  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
100146361  HDAC10; histone deacetylase 10 isoform X4 [KO:K18671] [EC:3.5.1.98]
100055240  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
100053105  histone H2A type 1 [KO:K11251]
100063355  core histone macro-H2A.2 isoform X1 [KO:K11251]
100061017  histone H2A type 3 [KO:K11251]
100053897  histone H2A type 1-B/E [KO:K11251]
100052624  histone H2A type 1 [KO:K11251]
100054058  histone H2A type 2-A [KO:K11251]
100053545  histone H2A type 1-C [KO:K11251]
100062747  core histone macro-H2A.1 isoform X1 [KO:K11251]
100052942  histone H2A type 1-D [KO:K11251]
100053206  histone H2A type 1-E [KO:K11251]
100629965  histone H2A.V [KO:K11251]
100147394  histone H2A type 1 [KO:K11251]
100052837  histone H2A type 1 [KO:K11251]
100054424  histone H2A type 1-D [KO:K11251]
102149092  histone H2A-Bbd type 2/3 [KO:K11251]
100053325  histone H2A type 1-H [KO:K11251]
100054146  histone H2A type 1-E [KO:K11251]
100055360  histone H2A-Bbd type 1 [KO:K11251]
100063021  histone H2A type 1-H [KO:K11251]
100146489  histone H2A.Z [KO:K11251]
102150778  histone H2A.J [KO:K11251]
100058587  histone H2A type 2-C [KO:K11251]
100053378  histone H2A type 1 [KO:K11251]
100053994  histone H2A type 1-D [KO:K11251]
100054113  LOW QUALITY PROTEIN: histone H2A type 2-A-like [KO:K11251]
106783189  histone H2A type 2-B [KO:K11251]
111774230  histone H2AX [KO:K11251]
111771533  histone H2A-Bbd type 2/3-like [KO:K11251]
111771537  histone H2A-Bbd type 1-like [KO:K11251]
111771646  histone H2A-Bbd type 2/3-like [KO:K11251]
100060980  histone H2B type 3-A [KO:K11252]
100053645  histone H2B type 1-M [KO:K11252]
100147687  histone H2B-like [KO:K11252]
100052568  histone H2B type 2-E [KO:K11252]
100073295  histone H2B subacrosomal variant [KO:K11252]
100052889  histone H2B type 1-N [KO:K11252]
100059737  histone H2B type 2-F [KO:K11252]
100054473  histone H2B type 1 [KO:K11252]
100068222  histone H2B type 1 [KO:K11252]
100053968  histone H2B type 2-E [KO:K11252]
100054211  histone H2B type 2-E [KO:K11252]
100053847  histone H2B type 1 [KO:K11252]
100054015  histone H2B type 2-E [KO:K11252]
100053695  histone H2B type 1 [KO:K11252]
100068321  histone H2B type 1-L [KO:K11252]
100053156  histone H2B type 1-B [KO:K11252]
100052703  histone H2B type 1-A [KO:K11252]
100053472  histone H2B type 1-J [KO:K11252]
100053279  histone H2B type 1-K [KO:K11252]
100053499  histone H2B type 1 [KO:K11252]
100062934  histone H2B type 2-E [KO:K11252]
100053978  late histone H2B.L4-like [KO:K11252]
100054123  late histone H2B.L4-like [KO:K11252]
102150908  late histone H2B.L4-like [KO:K11252]
102150902  histone H2B type 3-B [KO:K11252]
100054193  histone H2B type 2-E-like [KO:K11252]
111772364  late histone H2B.L4-like [KO:K11252]
111772365  late histone H2B.L4-like [KO:K11252]
100053181  LOW QUALITY PROTEIN: putative histone H2B type 2-D [KO:K11252]
111771477  late histone H2B.L4-like [KO:K11252]
100052783  histone H3.1 [KO:K11253]
100059700  histone H3 [KO:K11253]
100061535  histone H3.1 [KO:K11253]
100068151  histone H3.1 [KO:K11253]
100054378  uncharacterized protein LOC100054378 [KO:K11253]
100053065  histone H3.1 [KO:K11253]
100054462  histone H3.3 [KO:K11253]
106782280  histone H3.1 [KO:K11253]
100053259  histone H3.1 [KO:K11253]
111773533  LOW QUALITY PROTEIN: histone H3 [KO:K11253]
102149722  histone H3.1-like [KO:K11253]
106782249  LOW QUALITY PROTEIN: histone H3.1 [KO:K11253]
111774036  histone H3.3 [KO:K11253]
100054236  uncharacterized protein LOC100054236 [KO:K11253]
100054332  histone H4 [KO:K11254]
100053018  histone H4 [KO:K11254]
100054521  histone H4 [KO:K11254]
100053403  histone H4 [KO:K11254]
100063835  histone H4 [KO:K11254]
100054164  histone H4 [KO:K11254]
100630823  histone H4 [KO:K11254]
100054253  LOW QUALITY PROTEIN: histone H4 [KO:K11254]
106782239  histone H4 [KO:K11254]
106782250  histone H4 [KO:K11254]
100052511  histone H4 [KO:K11254]
102148494  histone H4-like [KO:K11254]
100063802  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
100058846  DRD1; D(1A) dopamine receptor [KO:K04144]
100056464  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100050675  neuroendocrine secretory protein 55 [KO:K04632]
100062195  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
100055673  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100062085  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100058238  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100051282  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100061395  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100067486  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100052560  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
100058274  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100146498  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100630067  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100063795  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
100058605  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100064813  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
100059736  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
106782014  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
100630493  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100051499  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100063518  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
100630574  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
100065327  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100051430  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
100069660  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X2 [KO:K04549]
100072768  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
100055498  SLC29A1; equilibrative nucleoside transporter 1 [KO:K15014]
100052412  SLC29A2; equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
100034039  ADORA2A; adenosine receptor A2a [KO:K04266]
100063319  ADORA2B; adenosine receptor A2b isoform X1 [KO:K04267]
100070498  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100052828  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100064302  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X3 [KO:K04345] [EC:2.7.11.11]
100066388  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
100053304  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100070334  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100062307  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100064828  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100057002  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100067794  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100063153  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100054803  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100059348  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100063840  CRH; corticoliberin [KO:K05256]
100053806  NPY; pro-neuropeptide Y [KO:K05232]
100009689  BDNF; brain-derived neurotrophic factor precursor [KO:K04355]
100061700  NTRK2; BDNF/NT-3 growth factors receptor isoform X3 [KO:K04360] [EC:2.7.10.1]
100063053  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100146209  SHC2; SHC-transforming protein 2 [KO:K17447]
100061926  SHC3; SHC-transforming protein 3 [KO:K17448]
100055699  SHC4; SHC-transforming protein 4 [KO:K17449]
100051866  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100053889  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100066282  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100055481  HRAS; GTPase HRas isoform X1 [KO:K02833]
100064473  KRAS; GTPase KRas isoform X1 [KO:K07827]
100051785  LOW QUALITY PROTEIN: GTPase KRas-like [KO:K07827]
100059469  NRAS; GTPase NRas [KO:K07828]
100061212  ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:2.7.11.1]
100065760  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
100051110  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100065996  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
100057701  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
100066173  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100053108  PDYN; proenkephalin-B [KO:K15840]
100057133  CALML5; calmodulin-like protein 5 [KO:K02183]
100062752  CALM1; calmodulin-1 [KO:K02183]
100070422  calmodulin-like protein 3 [KO:K02183]
100071150  CALM3; calmodulin-3 [KO:K02183]
100629145  CALM2; calmodulin-2 [KO:K02183]
100064482  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
100052798  CALML4; calmodulin-like protein 4 isoform X2 [KO:K02183]
100060657  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
100058510  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
100073192  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
100065680  FOSB; protein fosB isoform X1 [KO:K09029]
100068204  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X2 [KO:K15494]
100071067  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100058160  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100059233  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100629596  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X2 [KO:K15985]
Compound
C00025  L-Glutamate
C00027  Hydrogen peroxide
C00076  Calcium cation
C00082  L-Tyrosine
C00212  Adenosine
C00355  3,4-Dihydroxy-L-phenylalanine
C00469  Ethanol
C00575  3',5'-Cyclic AMP
C01161  3,4-Dihydroxyphenylacetate
C03758  Dopamine
Reference
PMID:19342616
  Authors
Spanagel R
  Title
Alcoholism: a systems approach from molecular physiology to addictive behavior.
  Journal
Physiol Rev 89:649-705 (2009)
DOI:10.1152/physrev.00013.2008
Reference
PMID:16102840
  Authors
Newton PM, Messing RO
  Title
Intracellular signaling pathways that regulate behavioral responses to ethanol.
  Journal
Pharmacol Ther 109:227-37 (2006)
DOI:10.1016/j.pharmthera.2005.07.004
Reference
PMID:14729391
  Authors
Mailliard WS, Diamond I
  Title
Recent advances in the neurobiology of alcoholism: the role of adenosine.
  Journal
Pharmacol Ther 101:39-46 (2004)
DOI:10.1016/j.pharmthera.2003.10.002
Reference
PMID:16278489
  Authors
Ron D, Jurd R
  Title
The "ups and downs" of signaling cascades in addiction.
  Journal
Sci STKE 2005:re14 (2005)
DOI:10.1126/stke.3092005re14
Reference
PMID:12605085
  Authors
Diana M, Brodie M, Muntoni A, Puddu MC, Pillolla G, Steffensen S, Spiga S, Little HJ
  Title
Enduring effects of chronic ethanol in the CNS: basis for alcoholism.
  Journal
Alcohol Clin Exp Res 27:354-61 (2003)
DOI:10.1097/01.ALC.0000057121.36127.19
Reference
PMID:19756388
  Authors
Moonat S, Starkman BG, Sakharkar A, Pandey SC
  Title
Neuroscience of alcoholism: molecular and cellular mechanisms.
  Journal
Cell Mol Life Sci 67:73-88 (2010)
DOI:10.1007/s00018-009-0135-y
Reference
PMID:15500908
  Authors
Pandey SC
  Title
The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction.
  Journal
Pharmacol Ther 104:47-58 (2004)
DOI:10.1016/j.pharmthera.2004.08.002
Reference
PMID:16764827
  Authors
Zhang TA, Maldve RE, Morrisett RA
  Title
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
  Journal
Biochem Pharmacol 72:919-27 (2006)
DOI:10.1016/j.bcp.2006.04.022
Reference
PMID:12068305
  Authors
Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA
  Title
DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens.
  Journal
Nat Neurosci 5:641-8 (2002)
DOI:10.1038/nn877
Reference
PMID:12085089
  Authors
Lovinger DM
  Title
NMDA receptors lose their inhibitions.
  Journal
Nat Neurosci 5:614-6 (2002)
DOI:10.1038/nn0702-614
Reference
PMID:16776597
  Authors
Hyman SE, Malenka RC, Nestler EJ
  Title
Neural mechanisms of addiction: the role of reward-related learning and memory.
  Journal
Annu Rev Neurosci 29:565-98 (2006)
DOI:10.1146/annurev.neuro.29.051605.113009
Reference
PMID:10774721
  Authors
Berke JD, Hyman SE
  Title
Addiction, dopamine, and the molecular mechanisms of memory.
  Journal
Neuron 25:515-32 (2000)
DOI:10.1016/S0896-6273(00)81056-9
Reference
PMID:20729980
  Authors
Clapp P, Bhave SV, Hoffman PL
  Title
How Adaptation of the Brain to Alcohol Leads to Dependence: A Pharmacological Perspective.
  Journal
Alcohol Res Health 31:310-339 (2008)
Reference
PMID:20947635
  Authors
Jeanes ZM, Buske TR, Morrisett RA
  Title
In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell.
  Journal
J Pharmacol Exp Ther 336:155-64 (2011)
DOI:10.1124/jpet.110.171009
Reference
PMID:18991950
  Authors
Lee AM, Messing RO
  Title
Protein kinases and addiction.
  Journal
Ann N Y Acad Sci 1141:22-57 (2008)
DOI:10.1196/annals.1441.022
Reference
PMID:17270154
  Authors
Repunte-Canonigo V, Lutjens R, van der Stap LD, Sanna PP
  Title
Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.
  Journal
Brain Res 1138:48-56 (2007)
DOI:10.1016/j.brainres.2006.09.115
Reference
PMID:18310464
  Authors
Logrip ML, Janak PH, Ron D
  Title
Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.
  Journal
FASEB J 22:2393-404 (2008)
DOI:10.1096/fj.07-099135
Reference
PMID:18616668
  Authors
Shukla SD, Velazquez J, French SW, Lu SC, Ticku MK, Zakhari S
  Title
Emerging role of epigenetics in the actions of alcohol.
  Journal
Alcohol Clin Exp Res 32:1525-34 (2008)
DOI:10.1111/j.1530-0277.2008.00729.x
Reference
PMID:19077056
  Authors
Pascual M, Boix J, Felipo V, Guerri C
  Title
Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.
  Journal
J Neurochem 108:920-31 (2009)
DOI:10.1111/j.1471-4159.2008.05835.x
Reference
PMID:20626732
  Authors
Li J, Cheng Y, Bian W, Liu X, Zhang C, Ye JH
  Title
Region-specific induction of FosB/DeltaFosB by voluntary alcohol intake: effects of naltrexone.
  Journal
Alcohol Clin Exp Res 34:1742-50 (2010)
DOI:10.1111/j.1530-0277.2010.01261.x
Related
pathway
ecb04010  MAPK signaling pathway
ecb04728  Dopaminergic synapse
KO pathway
ko05034   

  All links  
Genome (1)   
   KEGG GENOME (1)   
Gene (194)   
   KEGG GENES (194)   
All databases (195)   

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