KEGG   PATHWAY: hsa05034Help
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
BRITE hierarchy
Pathway map
Alcoholism
hsa05034

All organismsOrtholog table
Drug
D02780  
Acamprosate calcium (JAN/USAN)
D07058  
Acamprosate (INN)
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
7054  
TH; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
1644  
DDC; dopa decarboxylase (aromatic L-amino acid decarboxylase) [KO:K01593] [EC:4.1.1.28]
6570  
SLC18A1; solute carrier family 18 (vesicular monoamine), member 1 [KO:K08155]
6571  
SLC18A2; solute carrier family 18 (vesicular monoamine), member 2 [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 (neurotransmitter transporter, dopamine), member 3 [KO:K05036]
2902  
GRIN1; glutamate receptor, ionotropic, N-methyl D-aspartate 1 [KO:K05208]
2903  
GRIN2A; glutamate receptor, ionotropic, N-methyl D-aspartate 2A [KO:K05209]
2904  
GRIN2B; glutamate receptor, ionotropic, N-methyl D-aspartate 2B [KO:K05210]
2905  
GRIN2C; glutamate receptor, ionotropic, N-methyl D-aspartate 2C [KO:K05211]
2906  
GRIN2D; glutamate receptor, ionotropic, N-methyl D-aspartate 2D [KO:K05212]
116443  
GRIN3A; glutamate receptor, ionotropic, N-methyl-D-aspartate 3A [KO:K05213]
116444  
GRIN3B; glutamate receptor, ionotropic, N-methyl-D-aspartate 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]
83933  
HDAC10; histone deacetylase 10 [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]
79885  
HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
3014  
H2AFX; H2A histone family, member X [KO:K11251]
8338  
HIST2H2AC; histone cluster 2, H2ac [KO:K11251]
85235  
HIST1H2AH; histone cluster 1, H2ah [KO:K11251]
221613  
HIST1H2AA; histone cluster 1, H2aa [KO:K11251]
92815  
HIST3H2A; histone cluster 3, H2a [KO:K11251]
83740  
H2AFB3; H2A histone family, member B3 [KO:K11251]
3012  
HIST1H2AE; histone cluster 1, H2ae [KO:K11251]
8335  
HIST1H2AB; histone cluster 1, H2ab [KO:K11251]
55506  
H2AFY2; H2A histone family, member Y2 [KO:K11251]
9555  
H2AFY; H2A histone family, member Y [KO:K11251]
723790  
HIST2H2AA4; histone cluster 2, H2aa4 [KO:K11251]
55766  
H2AFJ; H2A histone family, member J [KO:K11251]
474382  
H2AFB1; H2A histone family, member B1 [KO:K11251]
8336  
HIST1H2AM; histone cluster 1, H2am [KO:K11251]
8337  
HIST2H2AA3; histone cluster 2, H2aa3 [KO:K11251]
8969  
HIST1H2AG; histone cluster 1, H2ag [KO:K11251]
317772  
HIST2H2AB; histone cluster 2, H2ab [KO:K11251]
94239  
H2AFV; H2A histone family, member V [KO:K11251]
3013  
HIST1H2AD; histone cluster 1, H2ad [KO:K11251]
3015  
H2AFZ; H2A histone family, member Z [KO:K11251]
8330  
HIST1H2AK; histone cluster 1, H2ak [KO:K11251]
8334  
HIST1H2AC; histone cluster 1, H2ac [KO:K11251]
8329  
HIST1H2AI; histone cluster 1, H2ai [KO:K11251]
8331  
HIST1H2AJ; histone cluster 1, H2aj [KO:K11251]
8332  
HIST1H2AL; histone cluster 1, H2al [KO:K11251]
474381  
H2AFB2; H2A histone family, member B2 [KO:K11251]
8341  
HIST1H2BN; histone cluster 1, H2bn [KO:K11252]
8345  
HIST1H2BH; histone cluster 1, H2bh [KO:K11252]
8342  
HIST1H2BM; histone cluster 1, H2bm [KO:K11252]
158983  
H2BFWT; H2B histone family, member W, testis-specific [KO:K11252]
255626  
HIST1H2BA; histone cluster 1, H2ba [KO:K11252]
440689  
HIST2H2BF; histone cluster 2, H2bf [KO:K11252]
8348  
HIST1H2BO; histone cluster 1, H2bo [KO:K11252]
3018  
HIST1H2BB; histone cluster 1, H2bb [KO:K11252]
8339  
HIST1H2BG; histone cluster 1, H2bg [KO:K11252]
8340  
HIST1H2BL; histone cluster 1, H2bl [KO:K11252]
8347  
HIST1H2BC; histone cluster 1, H2bc [KO:K11252]
3017  
HIST1H2BD; histone cluster 1, H2bd [KO:K11252]
8344  
HIST1H2BE; histone cluster 1, H2be [KO:K11252]
8346  
HIST1H2BI; histone cluster 1, H2bi [KO:K11252]
8349  
HIST2H2BE; histone cluster 2, H2be [KO:K11252]
8970  
HIST1H2BJ; histone cluster 1, H2bj [KO:K11252]
85236  
HIST1H2BK; histone cluster 1, H2bk [KO:K11252]
128312  
HIST3H2BB; histone cluster 3, H2bb [KO:K11252]
8343  
HIST1H2BF; histone cluster 1, H2bf [KO:K11252]
286436  
H2BFM; H2B histone family, member M [KO:K11252]
440093  
H3F3C; H3 histone, family 3C [KO:K11253]
3021  
H3F3B; H3 histone, family 3B (H3.3B) [KO:K11253]
8351  
HIST1H3D; histone cluster 1, H3d [KO:K11253]
8352  
HIST1H3C; histone cluster 1, H3c [KO:K11253]
8350  
HIST1H3A; histone cluster 1, H3a [KO:K11253]
3020  
H3F3A; H3 histone, family 3A [KO:K11253]
8290  
HIST3H3; histone cluster 3, H3 [KO:K11253]
126961  
HIST2H3C; histone cluster 2, H3c [KO:K11253]
333932  
HIST2H3A; histone cluster 2, H3a [KO:K11253]
653604  
HIST2H3D; histone cluster 2, H3d [KO:K11253]
8353  
HIST1H3E; histone cluster 1, H3e [KO:K11253]
8354  
HIST1H3I; histone cluster 1, H3i [KO:K11253]
8355  
HIST1H3G; histone cluster 1, H3g [KO:K11253]
8356  
HIST1H3J; histone cluster 1, H3j [KO:K11253]
8357  
HIST1H3H; histone cluster 1, H3h [KO:K11253]
8358  
HIST1H3B; histone cluster 1, H3b [KO:K11253]
8968  
HIST1H3F; histone cluster 1, H3f [KO:K11253]
121504  
HIST4H4; histone cluster 4, H4 [KO:K11254]
554313  
HIST2H4B; histone cluster 2, H4b [KO:K11254]
8294  
HIST1H4I; histone cluster 1, H4i [KO:K11254]
8360  
HIST1H4D; histone cluster 1, H4d [KO:K11254]
8361  
HIST1H4F; histone cluster 1, H4f [KO:K11254]
8362  
HIST1H4K; histone cluster 1, H4k [KO:K11254]
8363  
HIST1H4J; histone cluster 1, H4j [KO:K11254]
8364  
HIST1H4C; histone cluster 1, H4c [KO:K11254]
8365  
HIST1H4H; histone cluster 1, H4h [KO:K11254]
8366  
HIST1H4B; histone cluster 1, H4b [KO:K11254]
8367  
HIST1H4E; histone cluster 1, H4e [KO:K11254]
8368  
HIST1H4L; histone cluster 1, H4l [KO:K11254]
8370  
HIST2H4A; histone cluster 2, H4a [KO:K11254]
8359  
HIST1H4A; histone cluster 1, H4a [KO:K11254]
8369  
HIST1H4G; histone cluster 1, H4g [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; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 [KO:K04630]
2773  
GNAI3; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 [KO:K04630]
2771  
GNAI2; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2 [KO:K04630]
2775  
GNAO1; guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O [KO:K04534]
2782  
GNB1; guanine nucleotide binding protein (G protein), beta polypeptide 1 [KO:K04536]
2783  
GNB2; guanine nucleotide binding protein (G protein), beta polypeptide 2 [KO:K04537]
2784  
GNB3; guanine nucleotide binding protein (G protein), beta polypeptide 3 [KO:K07825]
59345  
GNB4; guanine nucleotide binding protein (G protein), beta polypeptide 4 [KO:K04538]
10681  
GNB5; guanine nucleotide binding protein (G protein), beta 5 [KO:K04539]
54331  
GNG2; guanine nucleotide binding protein (G protein), gamma 2 [KO:K07826]
2785  
GNG3; guanine nucleotide binding protein (G protein), gamma 3 [KO:K04540]
2786  
GNG4; guanine nucleotide binding protein (G protein), gamma 4 [KO:K04541]
2787  
GNG5; guanine nucleotide binding protein (G protein), gamma 5 [KO:K04542]
2788  
GNG7; guanine nucleotide binding protein (G protein), gamma 7 [KO:K04543]
94235  
GNG8; guanine nucleotide binding protein (G protein), gamma 8 [KO:K04544]
2790  
GNG10; guanine nucleotide binding protein (G protein), gamma 10 [KO:K04545]
2791  
GNG11; guanine nucleotide binding protein (G protein), gamma 11 [KO:K04546]
55970  
GNG12; guanine nucleotide binding protein (G protein), gamma 12 [KO:K04347]
648044  
guanine nucleotide binding protein (G protein); K04347 guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
51764  
GNG13; guanine nucleotide binding protein (G protein), gamma 13 [KO:K04547]
2792  
GNGT1; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 [KO:K04548]
2793  
GNGT2; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 2 [KO:K04549]
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]
1385  
CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  
ATF2; activating transcription factor 2 [KO:K04450]
468  
ATF4; activating transcription factor 4 (tax-responsive enhancer element B67) [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 tyrosine kinase, receptor, type 2 [KO:K04360] [EC:2.7.10.1]
25759  
SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K06279]
399694  
SHC4; SHC (Src homology 2 domain containing) family, member 4 [KO:K06279]
53358  
SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K06279]
6464  
SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
2885  
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
6654  
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655  
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
3265  
HRAS; v-Ha-ras Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
369  
ARAF; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
673  
BRAF; v-raf murine sarcoma viral oncogene homolog B1 [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; v-raf-1 murine leukemia viral oncogene homolog 1 [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 (phosphorylase kinase, delta) [KO:K02183]
808  
CALM3; calmodulin 3 (phosphorylase kinase, delta) [KO:K02183]
801  
CALM1; calmodulin 1 (phosphorylase kinase, delta) [KO:K02183]
163688  
CALML6; calmodulin-like 6 [KO:K02183]
51806  
CALML5; calmodulin-like 5 [KO:K02183]
84254  
CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1, alpha [KO:K07359] [EC:2.7.11.17]
10645  
CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:2.7.11.17]
814  
CAMK4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
2354  
FOSB; FBJ murine osteosarcoma viral oncogene homolog B [KO:K09029]
84152  
PPP1R1B; protein phosphatase 1, regulatory (inhibitor) subunit 1B [KO:K15494]
5499  
PPP1CA; protein phosphatase 1, catalytic subunit, alpha isozyme [KO:K06269] [EC:3.1.3.16]
5500  
PPP1CB; protein phosphatase 1, catalytic subunit, beta isozyme [KO:K06269] [EC:3.1.3.16]
5501  
PPP1CC; protein phosphatase 1, catalytic subunit, gamma isozyme [KO:K06269] [EC:3.1.3.16]
5569  
PKIA; protein kinase (cAMP-dependent, catalytic) inhibitor alpha [KO:K15985]
2030  
SLC29A1; solute carrier family 29 (nucleoside transporters), member 1 [KO:K15014]
5566  
PRKACA; protein kinase, cAMP-dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
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)
Reference
  Authors
Newton PM, Messing RO
  Title
Intracellular signaling pathways that regulate behavioral responses to ethanol.
  Journal
Pharmacol Ther 109:227-37 (2006)
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)
Reference
  Authors
Ron D, Jurd R
  Title
The "ups and downs" of signaling cascades in addiction.
  Journal
Sci STKE 2005:re14 (2005)
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)
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)
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)
Reference
  Authors
Zhang TA, Maldve RE, Morrisett RA
  Title
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
  Journal
Biochem Pharmacol 72:919-27 (2006)
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)
Reference
  Authors
Lovinger DM
  Title
NMDA receptors lose their inhibitions.
  Journal
Nat Neurosci 5:614-6 (2002)
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)
Reference
  Authors
Berke JD, Hyman SE
  Title
Addiction, dopamine, and the molecular mechanisms of memory.
  Journal
Neuron 25:515-32 (2000)
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)
Reference
  Authors
Lee AM, Messing RO
  Title
Protein kinases and addiction.
  Journal
Ann N Y Acad Sci 1141:22-57 (2008)
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)
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)
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)
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)
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)
KO pathway
 
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