KEGG   PATHWAY: ptr05034Help
Entry
ptr05034                    Pathway                                

Name
Alcoholism - Pan troglodytes (chimpanzee)
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
ptr05034

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BSID: 
GO: 
Organism
Pan troglodytes (chimpanzee) [GN:ptr]
Gene
450955  
TH; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
463409  
DDC; dopa decarboxylase [KO:K01593] [EC:4.1.1.28]
464032  
SLC18A1; solute carrier family 18 member A1 [KO:K08155]
466213  
SLC18A2; solute carrier family 18 member A2 [KO:K08155]
465588  
MAOB; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
743285  
MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
750842  
SLC6A3; solute carrier family 6 member 3 [KO:K05036]
465176  
GRIN1; glutamate receptor ionotropic, NMDA 1 [KO:K05208]
454396  
GRIN2A; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
473373  
GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
454868  
GRIN2C; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
456180  
GRIN2D; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
736408  
GRIN3A; glutamate ionotropic receptor NMDA type subunit 3A [KO:K05213]
GRIN3B; glutamate ionotropic receptor NMDA type subunit 3B [KO:K05214]
748850  
HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
462950  
HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
738624  
HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
454721  
HDAC5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
460060  
HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
466968  
HDAC7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
465712  
HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
463280  
HDAC9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
458935  
HDAC10; histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
460190  
HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
746557  
HIST2H2AB; histone cluster 2 H2A family member b [KO:K11251]
736529  
histone H2A type 1-like [KO:K11251]
457261  
HIST2H2AC; histone cluster 2 H2A family member c [KO:K11251]
462486  
HIST1H2AA; histone cluster 1 H2A family member a [KO:K11251]
469700  
HIST3H2A; histone cluster 3, H2a [KO:K11251]
471887  
histone H2A type 1-H-like [KO:K11251]
465306  
H2AFJ; histone H2A.J [KO:K11251]
471884  
HIST1H2AE; histone cluster 1 H2A family member e [KO:K11251]
450509  
H2AFY2; H2A histone family member Y2 [KO:K11251]
462076  
H2AFY; H2A histone family member Y [KO:K11251]
461400  
H2AFZ; H2A histone family, member Z [KO:K11251]
462490  
HIST1H2AC; histone H2A type 1-C [KO:K11251]
453664  
H2AFV; H2A histone family member V [KO:K11251]
471895  
histone H2A type 1-H [KO:K11251]
471905  
histone H2A type 1 [KO:K11251]
471909  
histone H2A type 1 [KO:K11251]
748495  
histone H2A type 1 [KO:K11251]
471894  
histone H2A type 1 [KO:K11251]
737087  
histone H2A type 1-J [KO:K11251]
746468  
HIST2H2AA4; histone H2A type 2-A [KO:K11251]
histone H2A-Bbd type 2/3 [KO:K11251]
462506  
histone H2A type 1 [KO:K11251]
462493  
histone H2A type 1-D [KO:K11251]
H2AFX; H2A histone family member X [KO:K11251]
histone H2A-Bbd type 2/3 [KO:K11251]
histone H2A-Bbd type 2/3 [KO:K11251]
histone H2A type 2-A [KO:K11251]
histone H2A.V [KO:K11251]
462508  
histone H2B type 1-N [KO:K11252]
462509  
histone H2B type 1-O [KO:K11252]
463172  
histone H2B type 1-H [KO:K11252]
471869  
HIST1H2BA; histone cluster 1 H2B family member a [KO:K11252]
457260  
histone H2B type 2-F [KO:K11252]
748505  
HIST1H2BB; histone cluster 1 H2B family member b [KO:K11252]
471880  
histone H2B type 1 [KO:K11252]
471902  
histone H2B type 1-F/J/L [KO:K11252]
462491  
histone H2B type 1-M-like [KO:K11252]
462500  
HIST1H2BK; histone H2B type 1-J [KO:K11252]
746513  
HIST1H2BD; histone H2B type 2-E [KO:K11252]
462501  
HIST1H2BK; histone H2B type 1-K [KO:K11252]
469701  
histone H2B type 3-B [KO:K11252]
469702  
HIST1H2BB; histone cluster 1, H2bd [KO:K11252]
471883  
histone H2B type 1 [KO:K11252]
471888  
histone H2B type 1 [KO:K11252]
473712  
histone H2B type W-T [KO:K11252]
histone H2B-like [KO:K11252]
473843  
histone H2B type W-T-like [KO:K11252]
histone H2B type 1 [KO:K11252]
histone H2B type 1 [KO:K11252]
737596  
histone H2B type F-M [KO:K11252]
471904  
histone H2B type 1-M [KO:K11252]
473608  
histone H3.3-like [KO:K11253]
738262  
H3F3B; H3 histone, family 3B [KO:K11253]
737454  
HIST1H3A; histone cluster 1, H3a [KO:K11253]
469476  
histone H3 [KO:K11253]
471875  
histone H3.1-like [KO:K11253]
471876  
histone H3.1 [KO:K11253]
471907  
histone H4 [KO:K11253]
746430  
histone H3 [KO:K11253]
uncharacterized LOC100608783 [KO:K11253]
H3F3A; H3 histone, family 3A [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.3 [KO:K11253]
histone H3 [KO:K11253]
histone H3.1t [KO:K11253]
465305  
histone H4 [KO:K11254]
472228  
uncharacterized LOC472228 [KO:K11254]
735611  
histone H4 [KO:K11254]
736707  
histone H4 [KO:K11254]
748513  
histone H4 [KO:K11254]
457262  
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
459737  
HAT1; histone acetyltransferase 1 [KO:K11303] [EC:2.3.1.48]
744598  
DRD1; dopamine receptor D1 [KO:K04144]
469986  
GNAS; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
451553  
DRD2; dopamine receptor D2 [KO:K04145]
457093  
GNAI3; G protein subunit alpha i3 [KO:K04630]
472425  
GNAI1; G protein subunit alpha i1 [KO:K04630]
744773  
GNAI2; G protein subunit alpha i2 [KO:K04630]
450173  
GNAO1; G protein subunit alpha o1 [KO:K04534]
469458  
GNB1; G protein subunit beta 1 [KO:K04536]
739897  
GNB2; G protein subunit beta 2 [KO:K04537]
guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
GNB3; G protein subunit beta 3 [KO:K07825]
460862  
GNB4; G protein subunit beta 4 [KO:K04538]
745402  
GNB5; G protein subunit beta 5 [KO:K04539]
467457  
GNG2; G protein subunit gamma 2 [KO:K07826]
740869  
GNG3; G protein subunit gamma 3 [KO:K04540]
743331  
GNG4; G protein subunit gamma 4 [KO:K04541]
456977  
GNG5; G protein subunit gamma 5 [KO:K04542]
744391  
GNG7; G protein subunit gamma 7 [KO:K04543]
GNG8; G protein subunit gamma 8 [KO:K04544]
747185  
GNG11; G protein subunit gamma 11 [KO:K04546]
GNG12; G protein subunit gamma 12 [KO:K04347]
GNG13; G protein subunit gamma 13 [KO:K04547]
747170  
GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
749133  
GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
458714  
ADORA2A; adenosine A2a receptor [KO:K04266]
455009  
ADORA2B; adenosine A2b receptor [KO:K04267]
470905  
ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
459901  
CREB1; cAMP responsive element binding protein 1 [KO:K05870]
ATF2; activating transcription factor 2 [KO:K04450]
744513  
ATF4; activating transcription factor 4 [KO:K04374]
451704  
CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
468672  
CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
738928  
CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
457341  
CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
465081  
CREB3; cAMP responsive element binding protein 3 [KO:K09048]
463318  
CREB5; cAMP responsive element binding protein 5 [KO:K09047]
745411  
ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
ATF6B; activating transcription factor 6 beta [KO:K09049]
464215  
CRH; corticotropin releasing hormone [KO:K05256]
744617  
NPY; neuropeptide Y [KO:K05232]
503511  
BDNF; brain derived neurotrophic factor [KO:K04355]
735394  
NTRK2; neurotrophic receptor tyrosine kinase 2 [KO:K04360] [EC:2.7.10.1]
457351  
SHC1; SHC adaptor protein 1 [KO:K06279]
749831  
SHC2; SHC adaptor protein 2 [KO:K17447]
450176  
SHC3; SHC adaptor protein 3 [KO:K17448]
453414  
SHC4; SHC adaptor protein 4 [KO:K17449]
737245  
GRB2; growth factor receptor bound protein 2 [KO:K04364]
459171  
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
452897  
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
466302  
HRAS; HRas proto-oncogene, GTPase [KO:K02833]
473387  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
742713  
NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
463781  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
460182  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
450188  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
454037  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
458680  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
469860  
PDYN; prodynorphin [KO:K15840]
737566  
CALML5; calmodulin like 5 [KO:K02183]
466008  
CALML3; calmodulin like 3 [KO:K02183]
459213  
CALM2; calmodulin 2 [KO:K02183]
738819  
CALM1; calmodulin 1 [KO:K02183]
456153  
CALM3; calmodulin 3 [KO:K02183]
743250  
CALML6; calmodulin like 6 [KO:K02183]
453534  
CALML4; calmodulin like 4 [KO:K02183]
454438  
CAMKK1; calcium/calmodulin dependent protein kinase kinase 1 [KO:K07359] [EC:2.7.11.17]
452320  
CAMKK2; calcium/calmodulin dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
461992  
CAMK4; calcium/calmodulin dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
FOSB; FosB proto-oncogene, AP-1 transcription factor subunit [KO:K09029]
744755  
PPP1R1B; protein phosphatase 1 regulatory inhibitor subunit 1B [KO:K15494]
462795  
PPP1CC; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
745709  
PPP1CA; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
743656  
PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
459118  
PPP1CB; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
748633  
PKIA; protein kinase (cAMP-dependent, catalytic) 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)
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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