KEGG   PATHWAY: ko05034
Entry
ko05034                     Pathway                                
Name
Alcoholism
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
ko05034  Alcoholism
ko05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Orthology
K00274  MAO, aofH; monoamine oxidase [EC:1.4.3.4]
K00501  TH; tyrosine 3-monooxygenase [EC:1.14.16.2]
K00908  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [EC:2.7.11.17]
K01593  DDC, TDC; aromatic-L-amino-acid/L-tryptophan decarboxylase [EC:4.1.1.28 4.1.1.105]
K02183  CALM; calmodulin
K02833  HRAS; GTPase HRas
K03099  SOS; son of sevenless
K04144  DRD1; dopamine receptor D1
K04145  DRD2; dopamine receptor D2
K04266  ADORA2A, ADOR; adenosine receptor A2a
K04267  ADORA2B; adenosine receptor A2b
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04347  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04355  BDNF; brain-derived neurotrophic factor
K04360  NTRK2, TRKB; neurotrophic tyrosine kinase receptor type 2 [EC:2.7.10.1]
K04364  GRB2; growth factor receptor-bound protein 2
K04365  BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04374  ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04450  ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04534  GNAO, G-ALPHA-O; guanine nucleotide-binding protein G(o) subunit alpha
K04536  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K04538  GNB4; guanine nucleotide-binding protein subunit beta-4
K04539  GNB5; guanine nucleotide-binding protein subunit beta-5
K04540  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04547  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K04630  GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K05036  SLC6A3, DAT; solute carrier family 6 (neurotransmitter transporter, dopamine) member 3
K05208  GRIN1; glutamate receptor ionotropic, NMDA 1
K05209  GRIN2A; glutamate receptor ionotropic, NMDA 2A
K05210  GRIN2B; glutamate receptor ionotropic, NMDA 2B
K05211  GRIN2C; glutamate receptor ionotropic, NMDA 2C
K05212  GRIN2D; glutamate receptor ionotropic, NMDA 2D
K05213  GRIN3A; glutamate receptor ionotropic, NMDA 3A
K05214  GRIN3B; glutamate receptor ionotropic, NMDA 3B
K05232  NPY; neuropeptide Y
K05256  CRH; corticotropin-releasing hormone
K05869  CAMK4; calcium/calmodulin-dependent protein kinase IV [EC:2.7.11.17]
K05870  CREB1; cyclic AMP-responsive element-binding protein 1
K06067  HDAC1_2; histone deacetylase 1/2 [EC:3.5.1.98]
K06269  PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K06279  SHC1; SHC-transforming protein 1
K07359  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [EC:2.7.11.17]
K07825  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K07826  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08155  SLC18A1_2, VMAT; MFS transporter, DHA1 family, solute carrier family 18 (vesicular amine transporter), member 1/2
K08845  ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K09029  FOSB; protein FosB
K09047  CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048  CREB3; cyclic AMP-responsive element-binding protein 3
K09049  ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K11251  H2A; histone H2A
K11252  H2B; histone H2B
K11253  H3; histone H3
K11254  H4; histone H4
K11303  HAT1, KAT1; histone acetyltransferase 1 [EC:2.3.1.48]
K11404  HDAC3; histone deacetylase 3 [EC:3.5.1.98]
K11405  HDAC8; histone deacetylase 8 [EC:3.5.1.98]
K11406  HDAC4_5; histone deacetylase 4/5 [EC:3.5.1.98]
K11407  HDAC6; histone deacetylase 6 [EC:3.5.1.98]
K11408  HDAC7; histone deacetylase 7 [EC:3.5.1.98]
K11409  HDAC9; histone deacetylase 9 [EC:3.5.1.98]
K11418  HDAC11; histone deacetylase 11 [EC:3.5.1.98]
K15014  SLC29A1_2_3, ENT1_2_3; solute carrier family 29 (equilibrative nucleoside transporter), member 1/2/3
K15494  PPP1R1B, DARPP32; protein phosphatase 1 regulatory subunit 1B
K15840  PDYN, PENKB; proenkephalin B (prodynorphin)
K15985  PKIA; cAMP-dependent protein kinase inhibitor alpha
K17447  SHC2; SHC-transforming protein 2
K17448  SHC3; SHC-transforming protein 3
K17449  SHC4; SHC-transforming protein 4
K18671  HDAC10; histone deacetylase 10 [EC:3.5.1.98]
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
ko04010  MAPK signaling pathway
ko04728  Dopaminergic synapse

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