KEGG   PATHWAY: hsa05034
Entry
hsa05034                    Pathway                                

Name
Alcoholism - Homo sapiens (human)
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
hsa05034  Alcoholism
hsa05034

Disease
H01611  Alcohol dependence
Drug
D02780  Acamprosate calcium (JAN/USAN)
D05145  Neramexane mesylate (USAN)
D07058  Acamprosate (INN)
Other DBs
GO: 0045471
Organism
Homo sapiens (human) [GN:hsa]
Gene
7054  TH; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
1644  DDC; dopa decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
6570  SLC18A1; solute carrier family 18 member A1 [KO:K08155]
6571  SLC18A2; solute carrier family 18 member A2 [KO:K08155]
4129  MAOB; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
4128  MAOA; monoamine oxidase A [KO:K00274] [EC:1.4.3.4]
6531  SLC6A3; solute carrier family 6 member 3 [KO:K05036]
2902  GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
2903  GRIN2A; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
2904  GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
2905  GRIN2C; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
2906  GRIN2D; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
116443  GRIN3A; glutamate ionotropic receptor NMDA type subunit 3A [KO:K05213]
116444  GRIN3B; glutamate ionotropic receptor NMDA type subunit 3B [KO:K05214]
3065  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
3066  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
8841  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
9759  HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
10014  HDAC5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
10013  HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
51564  HDAC7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
55869  HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
9734  HDAC9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
83933  HDAC10; histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
79885  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
3014  H2AX; H2A.X variant histone [KO:K11251]
8338  H2AC20; H2A clustered histone 20 [KO:K11251]
85235  H2AC12; H2A clustered histone 12 [KO:K11251]
221613  H2AC1; H2A clustered histone 1 [KO:K11251]
92815  H2AW; H2A.W histone [KO:K11251]
83740  H2AB3; H2A.B variant histone 3 [KO:K11251]
3012  H2AC8; H2A clustered histone 8 [KO:K11251]
8335  H2AC4; H2A clustered histone 4 [KO:K11251]
55506  MACROH2A2; macroH2A.2 histone [KO:K11251]
9555  MACROH2A1; macroH2A.1 histone [KO:K11251]
723790  H2AC19; H2A clustered histone 19 [KO:K11251]
55766  H2AJ; H2A.J histone [KO:K11251]
474382  H2AB1; H2A.B variant histone 1 [KO:K11251]
8336  H2AC17; H2A clustered histone 17 [KO:K11251]
8337  H2AC18; H2A clustered histone 18 [KO:K11251]
8969  H2AC11; H2A clustered histone 11 [KO:K11251]
317772  H2AC21; H2A clustered histone 21 [KO:K11251]
94239  H2AZ2; H2A.Z variant histone 2 [KO:K11251]
3013  H2AC7; H2A clustered histone 7 [KO:K11251]
3015  H2AZ1; H2A.Z variant histone 1 [KO:K11251]
8330  H2AC15; H2A clustered histone 15 [KO:K11251]
8334  H2AC6; H2A clustered histone 6 [KO:K11251]
8329  H2AC13; H2A clustered histone 13 [KO:K11251]
8331  H2AC14; H2A clustered histone 14 [KO:K11251]
8332  H2AC16; H2A clustered histone 16 [KO:K11251]
474381  H2AB2; H2A.B variant histone 2 [KO:K11251]
8341  H2BC15; H2B clustered histone 15 [KO:K11252]
8345  H2BC9; H2B clustered histone 9 [KO:K11252]
8342  H2BC14; H2B clustered histone 14 [KO:K11252]
158983  H2BW1; H2B.W histone 1 [KO:K11252]
255626  H2BC1; H2B clustered histone 1 [KO:K11252]
440689  H2BC18; H2B clustered histone 18 [KO:K11252]
8348  H2BC17; H2B clustered histone 17 [KO:K11252]
3018  H2BC3; H2B clustered histone 3 [KO:K11252]
8339  H2BC8; H2B clustered histone 8 [KO:K11252]
8340  H2BC13; H2B clustered histone 13 [KO:K11252]
8347  H2BC4; H2B clustered histone 4 [KO:K11252]
3017  H2BC5; H2B clustered histone 5 [KO:K11252]
8344  H2BC6; H2B clustered histone 6 [KO:K11252]
8346  H2BC10; H2B clustered histone 10 [KO:K11252]
8349  H2BC21; H2B clustered histone 21 [KO:K11252]
8970  H2BC11; H2B clustered histone 11 [KO:K11252]
85236  H2BC12; H2B clustered histone 12 [KO:K11252]
128312  H2BU1; H2B.U histone 1 [KO:K11252]
8343  H2BC7; H2B clustered histone 7 [KO:K11252]
286436  H2BW2; H2B.W histone 2 [KO:K11252]
102724334  histone H2B type F-S-like [KO:K11252]
114483833  H2BE1; H2B.E variant histone 1 [KO:K11252]
54145  H2BS1; H2B.S histone 1 [KO:K11252]
440093  H3-5; H3.5 histone [KO:K11253]
3021  H3-3B; H3.3 histone B [KO:K11253]
8351  H3C4; H3 clustered histone 4 [KO:K11253]
8352  H3C3; H3 clustered histone 3 [KO:K11253]
8350  H3C1; H3 clustered histone 1 [KO:K11253]
3020  H3-3A; H3.3 histone A [KO:K11253]
8290  H3-4; H3.4 histone [KO:K11253]
126961  H3C14; H3 clustered histone 14 [KO:K11253]
333932  H3C15; H3 clustered histone 15 [KO:K11253]
653604  H3C13; H3 clustered histone 13 [KO:K11253]
8353  H3C6; H3 clustered histone 6 [KO:K11253]
8354  H3C11; H3 clustered histone 11 [KO:K11253]
8355  H3C8; H3 clustered histone 8 [KO:K11253]
8356  H3C12; H3 clustered histone 12 [KO:K11253]
8357  H3C10; H3 clustered histone 10 [KO:K11253]
8358  H3C2; H3 clustered histone 2 [KO:K11253]
8968  H3C7; H3 clustered histone 7 [KO:K11253]
121504  H4-16; H4 histone 16 [KO:K11254]
554313  H4C15; H4 clustered histone 15 [KO:K11254]
8294  H4C9; H4 clustered histone 9 [KO:K11254]
8360  H4C4; H4 clustered histone 4 [KO:K11254]
8361  H4C6; H4 clustered histone 6 [KO:K11254]
8362  H4C12; H4 clustered histone 12 [KO:K11254]
8363  H4C11; H4 clustered histone 11 [KO:K11254]
8364  H4C3; H4 clustered histone 3 [KO:K11254]
8365  H4C8; H4 clustered histone 8 [KO:K11254]
8366  H4C2; H4 clustered histone 2 [KO:K11254]
8367  H4C5; H4 clustered histone 5 [KO:K11254]
8368  H4C13; H4 clustered histone 13 [KO:K11254]
8370  H4C14; H4 clustered histone 14 [KO:K11254]
8359  H4C1; H4 clustered histone 1 [KO:K11254]
8369  H4C7; H4 clustered histone 7 [KO:K11254]
8520  HAT1; histone acetyltransferase 1 [KO:K11303] [EC:2.3.1.48]
1812  DRD1; dopamine receptor D1 [KO:K04144]
2778  GNAS; GNAS complex locus [KO:K04632]
1813  DRD2; dopamine receptor D2 [KO:K04145]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
2775  GNAO1; G protein subunit alpha o1 [KO:K04534]
2782  GNB1; G protein subunit beta 1 [KO:K04536]
2783  GNB2; G protein subunit beta 2 [KO:K04537]
2784  GNB3; G protein subunit beta 3 [KO:K07825]
59345  GNB4; G protein subunit beta 4 [KO:K04538]
10681  GNB5; G protein subunit beta 5 [KO:K04539]
54331  GNG2; G protein subunit gamma 2 [KO:K07826]
2785  GNG3; G protein subunit gamma 3 [KO:K04540]
2786  GNG4; G protein subunit gamma 4 [KO:K04541]
2787  GNG5; G protein subunit gamma 5 [KO:K04542]
2788  GNG7; G protein subunit gamma 7 [KO:K04543]
94235  GNG8; G protein subunit gamma 8 [KO:K04544]
2790  GNG10; G protein subunit gamma 10 [KO:K04545]
2791  GNG11; G protein subunit gamma 11 [KO:K04546]
55970  GNG12; G protein subunit gamma 12 [KO:K04347]
51764  GNG13; G protein subunit gamma 13 [KO:K04547]
2792  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
2793  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
55315  SLC29A3; solute carrier family 29 member 3 [KO:K15014]
2030  SLC29A1; solute carrier family 29 member 1 (Augustine blood group) [KO:K15014]
3177  SLC29A2; solute carrier family 29 member 2 [KO:K15014]
135  ADORA2A; adenosine A2a receptor [KO:K04266]
136  ADORA2B; adenosine A2b receptor [KO:K04267]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
468  ATF4; activating transcription factor 4 [KO:K04374]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
1392  CRH; corticotropin releasing hormone [KO:K05256]
4852  NPY; neuropeptide Y [KO:K05232]
627  BDNF; brain derived neurotrophic factor [KO:K04355]
4915  NTRK2; neurotrophic receptor tyrosine kinase 2 [KO:K04360] [EC:2.7.10.1]
6464  SHC1; SHC adaptor protein 1 [KO:K06279]
25759  SHC2; SHC adaptor protein 2 [KO:K17447]
53358  SHC3; SHC adaptor protein 3 [KO:K17448]
399694  SHC4; SHC adaptor protein 4 [KO:K17449]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
369  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5173  PDYN; prodynorphin [KO:K15840]
810  CALML3; calmodulin like 3 [KO:K02183]
805  CALM2; calmodulin 2 [KO:K02183]
808  CALM3; calmodulin 3 [KO:K02183]
801  CALM1; calmodulin 1 [KO:K02183]
163688  CALML6; calmodulin like 6 [KO:K02183]
51806  CALML5; calmodulin like 5 [KO:K02183]
91860  CALML4; calmodulin like 4 [KO:K02183]
84254  CAMKK1; calcium/calmodulin dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
10645  CAMKK2; calcium/calmodulin dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
814  CAMK4; calcium/calmodulin dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
2354  FOSB; FosB proto-oncogene, AP-1 transcription factor subunit [KO:K09029]
84152  PPP1R1B; protein phosphatase 1 regulatory inhibitor subunit 1B [KO:K15494]
5499  PPP1CA; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
5500  PPP1CB; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
5501  PPP1CC; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
5569  PKIA; cAMP-dependent protein kinase inhibitor alpha [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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  Authors
Lovinger DM
  Title
NMDA receptors lose their inhibitions.
  Journal
Nat Neurosci 5:614-6 (2002)
DOI:10.1038/nn0702-614
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
hsa04010  MAPK signaling pathway
hsa04728  Dopaminergic synapse
KO pathway
ko05034   

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