KEGG   PATHWAY: ptr05034Help
ptr05034                    Pathway                                

Alcoholism - Pan troglodytes (chimpanzee)
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.
Human Diseases; Substance dependence
BRITE hierarchy
Pathway map
ptr05034  Alcoholism

Ortholog table
Other DBs
BSID: 585583
GO: 0045471
Pan troglodytes (chimpanzee) [GN:ptr]
450955  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:]
463409  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:]
464032  SLC18A1; chromaffin granule amine transporter [KO:K08155]
466213  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
465588  MAOB; amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:]
743285  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:]
750842  SLC6A3; sodium-dependent dopamine transporter isoform X1 [KO:K05036]
465176  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
454396  GRIN2A; glutamate receptor ionotropic, NMDA 2A precursor [KO:K05209]
473373  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
454868  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
456180  GRIN2D; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2D [KO:K05212]
736408  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
101058361  GRIN3B; glutamate receptor ionotropic, NMDA 3B isoform X1 [KO:K05214]
748850  histone deacetylase 1 isoform X1 [KO:K06067] [EC:]
462950  HDAC2; histone deacetylase 2 isoform X2 [KO:K06067] [EC:]
738624  HDAC3; histone deacetylase 3 isoform X2 [KO:K11404] [EC:]
454721  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:]
460060  HDAC4; histone deacetylase 4 isoform X5 [KO:K11406] [EC:]
100610515  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:]
466968  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:]
465712  HDAC8; histone deacetylase 8 isoform X13 [KO:K11405] [EC:]
463280  HDAC9; histone deacetylase 9 isoform X10 [KO:K11409] [EC:]
458935  HDAC10; histone deacetylase 10 isoform X2 [KO:K18671] [EC:]
460190  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:]
746557  HIST2H2AB; histone H2A type 2-B [KO:K11251]
736529  histone H2A type 1-like [KO:K11251]
457261  HIST2H2AC; histone H2A type 2-C [KO:K11251]
462486  HIST1H2AA; histone H2A type 1-A [KO:K11251]
469700  HIST3H2A; histone H2A type 3 [KO:K11251]
471887  histone H2A type 1-H-like [KO:K11251]
465306  H2AFJ; histone H2A.J [KO:K11251]
471884  HIST1H2AE; histone H2A type 1-B/E [KO:K11251]
450509  H2AFY2; core histone macro-H2A.2 [KO:K11251]
462076  H2AFY; core histone macro-H2A.1 [KO:K11251]
461400  H2AFZ; histone H2A.Z [KO:K11251]
462490  histone H2A type 1-C [KO:K11251]
453664  H2AFV; histone H2A.V isoform X1 [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-B/E [KO:K11251]
471894  histone H2A type 1 [KO:K11251]
737087  histone H2A type 1-J [KO:K11251]
746468  histone H2A type 2-A [KO:K11251]
462506  histone H2A type 1 [KO:K11251]
462493  histone H2A type 1-D [KO:K11251]
104001345  H2AFX; histone H2AX [KO:K11251]
107970947  protein H2A.5-like [KO:K11251]
107971249  histone H2A-Bbd type 2/3 [KO:K11251]
107971253  histone H2A-Bbd type 2/3 [KO:K11251]
107971372  histone H2A type 2-A [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 H2B type 1-A [KO:K11252]
457260  histone H2B type 2-F [KO:K11252]
748505  HIST1H2BB; histone H2B type 1-B [KO:K11252]
471880  histone H2B type 1 [KO:K11252]
471902  histone H2B type 1-F/J/L [KO:K11252]
462491  histone H1.4 [KO:K11252]
462500  histone H2B type 1-J [KO:K11252]
746513  histone H2B type 2-E [KO:K11252]
462501  histone H2B type 1-K [KO:K11252]
469702  histone H2B type 3-A [KO:K11252]
471883  histone H2B type 1 [KO:K11252]
471888  histone H2B type 1 [KO:K11252]
473712  histone H2B type W-T [KO:K11252]
104007471  histone H2B-like [KO:K11252]
473843  histone H2B type W-T-like [KO:K11252]
100609614  histone H2B type 1 [KO:K11252]
100610052  histone H2B type 1 [KO:K11252]
737596  LOW QUALITY PROTEIN: histone H2B type F-M [KO:K11252]
471904  histone H2B type 1-M [KO:K11252]
107973825  histone H2B type 3-B [KO:K11252]
112204063  histone H2B type 1-M-like [KO:K11252]
473608  histone H3.3-like [KO:K11253]
738262  H3F3B; histone H3.3 [KO:K11253]
737454  HIST1H3A; histone cluster 1, H3a [KO:K11253]
471875  histone H3.1-like [KO:K11253]
471876  histone H3.1 [KO:K11253]
746430  uncharacterized protein LOC746430 [KO:K11253]
104001101  histone H3.1 [KO:K11253]
104001083  histone H3.1 [KO:K11253]
107966142  histone H3.3 [KO:K11253]
107966300  histone H3 [KO:K11253]
107970566  histone H3.1t [KO:K11253]
465305  histone H4 [KO:K11254]
472228  uncharacterized protein LOC472228 [KO:K11254]
735611  histone H4 [KO:K11254]
736707  histone H4 [KO:K11254]
748513  histone H4 [KO:K11254]
457262  histone H4 [KO:K11254]
104006752  histone H4 [KO:K11254]
471907  histone H3.1 [KO:K11254]
107975094  histone H4 [KO:K11254]
459737  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:]
744598  DRD1; D(1A) dopamine receptor [KO:K04144]
469986  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X5 [KO:K04632]
451553  DRD2; D(2) dopamine receptor [KO:K04145]
457093  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
472425  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
744773  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
450173  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X2 [KO:K04534]
469458  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
739897  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100612078  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
460862  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
745402  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
467457  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
740869  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
743331  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
456977  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
744391  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
107969769  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
100611518  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
747185  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100609242  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 isoform X2 [KO:K04347]
107968762  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
747170  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
749133  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
458714  ADORA2A; adenosine receptor A2a [KO:K04266]
455009  ADORA2B; adenosine receptor A2b [KO:K04267]
470905  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:]
459901  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101059354  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
744513  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
451704  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
468672  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X3 [KO:K09048]
738928  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
457341  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
465081  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
463318  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X4 [KO:K09047]
107975108  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
464215  CRH; corticoliberin [KO:K05256]
744617  NPY; pro-neuropeptide Y [KO:K05232]
503511  BDNF; brain-derived neurotrophic factor precursor [KO:K04355]
735394  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:]
457351  SHC1; SHC-transforming protein 1 isoform X7 [KO:K06279]
749831  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
450176  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
453414  SHC4; SHC-transforming protein 4 [KO:K17449]
737245  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
459171  SOS1; son of sevenless homolog 1 isoform X2 [KO:K03099]
452897  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
466302  HRAS; GTPase HRas isoform X1 [KO:K02833]
473387  KRAS; GTPase KRas isoform X1 [KO:K07827]
742713  NRAS; GTPase NRas [KO:K07828]
100614256  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:]
463781  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:]
460182  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:]
450188  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
454037  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:]
458680  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
469860  PDYN; proenkephalin-B [KO:K15840]
737566  CALML5; calmodulin-like protein 5 [KO:K02183]
466008  CALML3; calmodulin-like protein 3 [KO:K02183]
459213  CALM2; calmodulin [KO:K02183]
738819  CALM1; calmodulin [KO:K02183]
456153  CALM3; calmodulin-3 [KO:K02183]
743250  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
453534  CALML4; calmodulin-like protein 4 isoform X2 [KO:K02183]
454438  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:]
452320  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:]
461992  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X2 [KO:K05869] [EC:]
107969757  FOSB; protein fosB [KO:K09029]
744755  PPP1R1B; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
462795  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:]
745709  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:]
743656  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:]
459118  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:]
748633  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X2 [KO:K15985]
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
Spanagel R
Alcoholism: a systems approach from molecular physiology to addictive behavior.
Physiol Rev 89:649-705 (2009)
Newton PM, Messing RO
Intracellular signaling pathways that regulate behavioral responses to ethanol.
Pharmacol Ther 109:227-37 (2006)
Mailliard WS, Diamond I
Recent advances in the neurobiology of alcoholism: the role of adenosine.
Pharmacol Ther 101:39-46 (2004)
Ron D, Jurd R
The "ups and downs" of signaling cascades in addiction.
Sci STKE 2005:re14 (2005)
Diana M, Brodie M, Muntoni A, Puddu MC, Pillolla G, Steffensen S, Spiga S, Little HJ
Enduring effects of chronic ethanol in the CNS: basis for alcoholism.
Alcohol Clin Exp Res 27:354-61 (2003)
Moonat S, Starkman BG, Sakharkar A, Pandey SC
Neuroscience of alcoholism: molecular and cellular mechanisms.
Cell Mol Life Sci 67:73-88 (2010)
Pandey SC
The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction.
Pharmacol Ther 104:47-58 (2004)
Zhang TA, Maldve RE, Morrisett RA
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
Biochem Pharmacol 72:919-27 (2006)
Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA
DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens.
Nat Neurosci 5:641-8 (2002)
Lovinger DM
NMDA receptors lose their inhibitions.
Nat Neurosci 5:614-6 (2002)
Hyman SE, Malenka RC, Nestler EJ
Neural mechanisms of addiction: the role of reward-related learning and memory.
Annu Rev Neurosci 29:565-98 (2006)
Berke JD, Hyman SE
Addiction, dopamine, and the molecular mechanisms of memory.
Neuron 25:515-32 (2000)
Clapp P, Bhave SV, Hoffman PL
How Adaptation of the Brain to Alcohol Leads to Dependence: A Pharmacological Perspective.
Alcohol Res Health 31:310-339 (2008)
Jeanes ZM, Buske TR, Morrisett RA
In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell.
J Pharmacol Exp Ther 336:155-64 (2011)
Lee AM, Messing RO
Protein kinases and addiction.
Ann N Y Acad Sci 1141:22-57 (2008)
Repunte-Canonigo V, Lutjens R, van der Stap LD, Sanna PP
Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.
Brain Res 1138:48-56 (2007)
Logrip ML, Janak PH, Ron D
Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.
FASEB J 22:2393-404 (2008)
Shukla SD, Velazquez J, French SW, Lu SC, Ticku MK, Zakhari S
Emerging role of epigenetics in the actions of alcohol.
Alcohol Clin Exp Res 32:1525-34 (2008)
Pascual M, Boix J, Felipo V, Guerri C
Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.
J Neurochem 108:920-31 (2009)
Li J, Cheng Y, Bian W, Liu X, Zhang C, Ye JH
Region-specific induction of FosB/DeltaFosB by voluntary alcohol intake: effects of naltrexone.
Alcohol Clin Exp Res 34:1742-50 (2010)
KO pathway

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