KEGG   PATHWAY: pcw05034
Entry
pcw05034                    Pathway                                
Name
Alcoholism - Phascolarctos cinereus (koala)
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
pcw05034  Alcoholism
pcw05034

Other DBs
GO: 0045471
Organism
Phascolarctos cinereus (koala) [GN:pcw]
Gene
110197189  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
110205577  tyrosine 3-monooxygenase-like [KO:K00501] [EC:1.14.16.2]
110205002  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
110209553  SLC18A2; synaptic vesicular amine transporter isoform X1 [KO:K08155]
110196419  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
110214802  MAOA; LOW QUALITY PROTEIN: amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
110214856  amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:1.4.3.4]
110201221  SLC6A3; sodium-dependent dopamine transporter isoform X1 [KO:K05036]
110205260  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
110198344  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
110218783  GRIN2B; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2B [KO:K05210]
110219335  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
110219850  GRIN2D; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2D [KO:K05212]
110219078  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
110196127  GRIN3B; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 3B [KO:K05214]
110206263  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
110222906  histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
110220842  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
110198825  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
110215725  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
110201470  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
110221690  HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
110217595  HDAC9; LOW QUALITY PROTEIN: histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
110205922  HDAC10; histone deacetylase 10 isoform X1 [KO:K18671] [EC:3.5.1.98]
110204971  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
110220185  histone H2A type 2-B [KO:K11251]
110220195  histone H2A type 2-C [KO:K11251]
110209677  histone H2A.Z [KO:K11251]
110194435  histone H2A type 1-H-like [KO:K11251]
110194439  histone H2A type 1-J [KO:K11251]
110194440  histone H2A type 3 [KO:K11251]
110194441  histone H2A type 3 [KO:K11251]
110194442  histone H2A type 1 [KO:K11251]
110194454  histone H2A type 3-like [KO:K11251]
110200089  core histone macro-H2A.2 [KO:K11251]
110207214  histone H2AX [KO:K11251]
110211741  LOW QUALITY PROTEIN: core histone macro-H2A.1 [KO:K11251]
110206559  histone H2A.V isoform X1 [KO:K11251]
110220105  histone H2A type 2-A-like isoform X1 [KO:K11251]
110220120  histone H2A type 2-A-like isoform X1 [KO:K11251]
110197514  histone H2A-beta, sperm-like [KO:K11251]
110204949  histone H2A type 2-B-like [KO:K11251]
110204194  histone H2A type 3 [KO:K11251]
110204198  histone H2A type 3 [KO:K11251]
110220165  histone H2B type 1-F/J/L-like isoform X1 [KO:K11252]
110220201  LOW QUALITY PROTEIN: histone H2B type 2-E-like [KO:K11252]
110193495  histone H2B-like [KO:K11252]
110194444  histone H2B type 1-M-like [KO:K11252]
110194446  histone H2B type 2-E [KO:K11252]
110194447  histone H2B type 2-E [KO:K11252]
110194448  histone H2B type 1-B-like [KO:K11252]
110201982  late histone H2B.L4-like [KO:K11252]
110220095  histone H2B type 2-E-like isoform X1 [KO:K11252]
110204195  histone H2B type 2-E [KO:K11252]
110204199  histone H2B type 2-E [KO:K11252]
110208673  LOW QUALITY PROTEIN: histone H2B type 2-F [KO:K11252]
110215594  histone H3.3-like [KO:K11253]
110220150  histone H3 [KO:K11253]
110194436  histone H3-like [KO:K11253]
110194443  histone H3-like isoform X1 [KO:K11253]
110219374  histone H3.3 [KO:K11253]
110205518  histone H3.3 [KO:K11253]
110206580  histone H3.3-like [KO:K11253]
110220137  histone H3 isoform X1 [KO:K11253]
110194232  uncharacterized protein LOC110194232 [KO:K11253]
110194233  LOW QUALITY PROTEIN: histone H3-like centromeric protein CSE4 [KO:K11253]
110204197  histone H3 [KO:K11253]
110220158  histone H4 [KO:K11254]
110194452  histone H4-like [KO:K11254]
110216660  uncharacterized protein LOC110216660 [KO:K11254]
110202808  uncharacterized protein LOC110202808 [KO:K11254]
110204200  histone H4 [KO:K11254]
110216652  uncharacterized protein LOC110216652 [KO:K11254]
110211572  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
110196092  DRD1; D(1A) dopamine receptor [KO:K04144]
110205152  GNAS; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
110210666  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
110216929  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
110218213  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha isoform X1 [KO:K04630]
110206959  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
110193656  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
110200602  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
110202795  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
110213789  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
110204582  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
110204813  GNB5; LOW QUALITY PROTEIN: guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
110195466  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
110217882  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
110209930  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
110223453  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
110202405  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
110198231  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
110202413  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
110212886  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
110214163  GNG14; uncharacterized LOC105372280 homolog [KO:K04347]
110222026  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
110202430  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
110215704  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
110213511  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
110209395  equilibrative nucleoside transporter 1-like isoform X1 [KO:K15014]
110214015  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
110195496  SLC29A2; equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
110201764  ADORA2A; adenosine receptor A2a [KO:K04266]
110222171  ADORA2B; adenosine receptor A2b [KO:K04267]
110208122  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
110209926  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
110214178  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
110199822  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
110223284  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
110211588  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
110205802  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
110224036  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
110216252  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
110201451  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
110197489  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
110211994  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
110213063  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
110199423  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
110219041  CRH; corticoliberin [KO:K05256]
110212988  NPY; pro-neuropeptide Y [KO:K05232]
110202027  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
110194558  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
110198538  SHC-transforming protein 1-like [KO:K06279]
110211965  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
110223483  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
110223827  SHC3; SHC-transforming protein 3 [KO:K17448]
110201503  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
110219266  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
110211774  SOS2; son of sevenless homolog 2 [KO:K03099]
110201388  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
110202954  HRAS; GTPase HRas isoform X1 [KO:K02833]
110193352  KRAS; GTPase KRas isoform X1 [KO:K07827]
110219182  NRAS; GTPase NRas [KO:K07828]
110203410  GTPase NRas-like [KO:K07828]
110203411  GTPase HRas-like [KO:K07828]
110202309  GTPase HRas-like [KO:K07828]
110201017  ARAF; LOW QUALITY PROTEIN: serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
110216339  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
110204892  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
110205943  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
110221918  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
110215167  MAPK1; LOW QUALITY PROTEIN: mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
110193721  PDYN; proenkephalin-B [KO:K15840]
110217739  CALM1; calmodulin [KO:K02183]
110197786  CALML6; calmodulin-like protein 6 [KO:K02183]
110218482  CALM2; calmodulin [KO:K02183]
110199039  calmodulin-A-like [KO:K02183]
110202401  CALM3; calmodulin isoform X1 [KO:K02183]
110205749  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
110193091  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
110196822  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
110222132  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
110203638  FOSB; protein fosB isoform X1 [KO:K09029]
110215746  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
110206445  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
110196829  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
110195486  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
110199204  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X1 [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
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
pcw04010  MAPK signaling pathway
pcw04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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