KEGG   PATHWAY: pvp05034
Entry
pvp05034                    Pathway                                
Name
Alcoholism - Pteropus vampyrus (large flying fox)
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
pvp05034  Alcoholism
pvp05034

Other DBs
GO: 0045471
Organism
Pteropus vampyrus (large flying fox) [GN:pvp]
Gene
105299526  TH; tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
105303559  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
105296664  SLC18A1; chromaffin granule amine transporter [KO:K08155]
105291491  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
105305432  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
105305433  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
105301307  SLC6A3; LOW QUALITY PROTEIN: sodium-dependent dopamine transporter [KO:K05036]
105298564  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
105290959  GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
105302783  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
105293418  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
105304199  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
105296292  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
105302266  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
105290575  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
105295257  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
105297029  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
105305213  histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
105303496  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
105310009  HDAC6; histone deacetylase 6 isoform X2 [KO:K11407] [EC:3.5.1.98]
105297500  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
105307757  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
105295022  HDAC9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
105308284  HDAC10; histone deacetylase 10 isoform X2 [KO:K18671] [EC:3.5.1.98]
105294980  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
111728728  histone H2A type 1 [KO:K11251]
105296308  histone H2A type 2-C-like [KO:K11251]
105296321  histone H2A type 1-A-like [KO:K11251]
105296322  histone H2A type 1-A [KO:K11251]
105296328  histone H2A type 1 [KO:K11251]
111728749  histone H2A type 2-C [KO:K11251]
105311102  histone H2A type 1-like [KO:K11251]
105299771  histone H2A-Bbd type 1 [KO:K11251]
111743863  histone H2A type 1-like [KO:K11251]
105296302  histone H2A type 1-H [KO:K11251]
105299998  LOW QUALITY PROTEIN: histone H2A type 3 [KO:K11251]
105300115  core histone macro-H2A.2 [KO:K11251]
105293587  core histone macro-H2A.1 isoform X1 [KO:K11251]
105308756  histone H2A.V [KO:K11251]
105308856  histone H2AX [KO:K11251]
105309239  histone H2A-Bbd type 2/3-like [KO:K11251]
105309975  histone H2A type 2-A isoform X2 [KO:K11251]
105302515  histone H2A-Bbd type 2/3 [KO:K11251]
105302777  histone H2A.J [KO:K11251]
105296305  histone H2B 1/2-like [KO:K11252]
105296306  histone H2B type 1 isoform X1 [KO:K11252]
105296318  histone H2B type 1 [KO:K11252]
105296327  histone H2B type 1-A [KO:K11252]
105308687  histone H2B type 2-E [KO:K11252]
105311488  histone H2B, gonadal-like [KO:K11252]
111739453  histone H2B-like [KO:K11252]
105309974  histone H2B type 2-F [KO:K11252]
105309978  histone H2B type 2-E [KO:K11252]
105310606  late histone H2B.L4-like [KO:K11252]
105311111  histone H2B type 1-A [KO:K11252]
105311489  histone H2B, gonadal-like [KO:K11252]
105311490  late histone H2B.L4-like [KO:K11252]
105311491  histone H2B-like [KO:K11252]
105311492  histone H2B-like [KO:K11252]
105311720  histone H2B type 1-K [KO:K11252]
105311756  histone H2B, sperm-like [KO:K11252]
105311769  histone H2B type 1-K-like [KO:K11252]
105303775  uncharacterized protein LOC105303775 [KO:K11252]
105296310  histone H3.1 [KO:K11253]
105307067  histone H3.3-like [KO:K11253]
105291893  histone H3.3-like [KO:K11253]
105296402  histone H3.1 [KO:K11253]
105292582  histone H3.3 [KO:K11253]
105299948  histone H3.1 [KO:K11253]
105293361  histone H3.3 [KO:K11253]
105309976  histone H3 [KO:K11253]
105302803  LOW QUALITY PROTEIN: histone H4 [KO:K11254]
105296307  histone H4 [KO:K11254]
105296311  histone H4 [KO:K11254]
111743870  histone H4 [KO:K11254]
105290446  HAT1; histone acetyltransferase type B catalytic subunit isoform X2 [KO:K11303] [EC:2.3.1.48]
105307882  DRD1; D(1A) dopamine receptor [KO:K04144]
105296083  neuroendocrine secretory protein 55-like [KO:K04632]
105295663  DRD2; D(2) dopamine receptor [KO:K04145]
105297202  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105295155  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105295517  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105292074  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
105303584  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105299738  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
105295952  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
105307521  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
105288758  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105309385  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
105297807  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X2 [KO:K04540]
105302718  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 isoform X1 [KO:K04541]
105289068  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
105310269  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
111744611  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
105307968  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105294373  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
105307158  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
105295886  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
105303281  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X4 [KO:K04547]
105294383  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
105307274  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
105288495  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
105297942  SLC29A2; equilibrative nucleoside transporter 2 isoform X5 [KO:K15014]
105300127  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
105289354  ADORA2A; adenosine receptor A2a isoform X1 [KO:K04266]
105291304  ADORA2B; adenosine receptor A2b [KO:K04267]
105288850  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105289063  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105308501  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
105298404  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
105290195  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
105298070  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
105296460  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
105306745  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
105290070  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
105306466  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
105291624  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
105293217  cyclic AMP-responsive element-binding protein 5 [KO:K09047]
105305286  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
105295071  CRH; corticoliberin [KO:K05256]
105311096  NPY; pro-neuropeptide Y [KO:K05232]
105293721  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
105300054  NTRK2; BDNF/NT-3 growth factors receptor [KO:K04360] [EC:2.7.10.1]
105296379  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
105302278  SHC2; SHC-transforming protein 2 [KO:K17447]
105300265  SHC3; SHC-transforming protein 3 [KO:K17448]
105288811  SHC4; SHC-transforming protein 4 [KO:K17449]
105293353  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
105292949  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105309535  SOS2; son of sevenless homolog 2 [KO:K03099]
105305933  HRAS; GTPase HRas isoform X1 [KO:K02833]
105294059  KRAS; GTPase KRas isoform X2 [KO:K07827]
105296550  NRAS; GTPase NRas isoform X1 [KO:K07828]
105305459  ARAF; serine/threonine-protein kinase A-Raf isoform X8 [KO:K08845] [EC:2.7.11.1]
105291659  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
105299021  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105309827  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
105289326  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
105304566  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
105298209  PDYN; proenkephalin-B [KO:K15840]
105297322  CALM3; calmodulin-3 [KO:K02183]
105290127  CALM1; calmodulin-1 [KO:K02183]
105299180  calmodulin [KO:K02183]
105292913  CALM2; calmodulin-2 isoform X1 [KO:K02183]
105309689  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
105303606  CALML6; calmodulin-like protein 6 [KO:K02183]
105291809  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
105289204  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X3 [KO:K07359] [EC:2.7.11.17]
105295473  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
105297343  FOSB; protein fosB [KO:K09029]
105307493  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
105289220  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105299132  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
105309924  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
105302948  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
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
pvp04010  MAPK signaling pathway
pvp04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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