KEGG   PATHWAY: aju05034
Entry
aju05034                    Pathway                                
Name
Alcoholism - Acinonyx jubatus (cheetah)
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
aju05034  Alcoholism
aju05034

Other DBs
GO: 0045471
Organism
Acinonyx jubatus (cheetah) [GN:aju]
Gene
106971078  tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
106968187  aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:4.1.1.28 4.1.1.105]
106974109  synaptic vesicular amine transporter [KO:K08155]
106971854  chromaffin granule amine transporter [KO:K08155]
106972520  amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
106972743  amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
106985115  sodium-dependent dopamine transporter [KO:K05036]
106989187  glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
106989347  glutamate receptor ionotropic, NMDA 2A [KO:K05209]
106965657  glutamate receptor ionotropic, NMDA 2B [KO:K05210]
106987730  glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
106986956  glutamate receptor ionotropic, NMDA 2D [KO:K05212]
106972048  glutamate receptor ionotropic, NMDA 3A [KO:K05213]
113596369  glutamate receptor ionotropic, NMDA 3B isoform X2 [KO:K05214]
106968918  histone deacetylase 2 isoform X1 [KO:K06067] [EC:3.5.1.98]
106982428  histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
106967267  histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
106967107  histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
106974278  histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
106989010  histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
106969353  histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
106982392  histone deacetylase 8 isoform X8 [KO:K11405] [EC:3.5.1.98]
106984149  histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
106987623  polyamine deacetylase HDAC10 isoform X3 [KO:K18671] [EC:3.5.1.98]
106978633  histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
128311497  histone H2A-Bbd type 2/3-like [KO:K11251]
128313973  histone H2A type 2-A [KO:K11251]
128315723  histone H2A type 1-B [KO:K11251]
128315724  histone H2A type 1-E [KO:K11251]
128315725  histone H2A type 1-H-like [KO:K11251]
128315747  histone H2A type 1-E [KO:K11251]
106968229  histone H2A.V isoform X2 [KO:K11251]
106967157  core histone macro-H2A.2 [KO:K11251]
106965661  histone H2A.J [KO:K11251]
106989149  core histone macro-H2A.1 isoform X1 [KO:K11251]
106988025  histone H2A type 1-E-like [KO:K11251]
106988033  histone H2A type 2-A [KO:K11251]
106988039  histone H2A type 1-C [KO:K11251]
106988045  histone H2A-beta, sperm-like [KO:K11251]
106988058  histone H2A type 1-B [KO:K11251]
106985217  histone H2A type 3 [KO:K11251]
106978991  histone H2A.Z [KO:K11251]
106989769  histone H2A-beta, sperm-like [KO:K11251]
106976312  histone H2A type 1-E [KO:K11251]
106976318  histone H2A type 1-E-like [KO:K11251]
106976324  histone H2A type 1-J [KO:K11251]
113597355  histone H2A-Bbd type 2/3 [KO:K11251]
113597356  histone H2A-Bbd type 2/3 [KO:K11251]
106986678  histone H2A type 2-B [KO:K11251]
113597922  histone H2A type 2-C [KO:K11251]
113598029  histone H2A-beta, sperm-like [KO:K11251]
113593208  histone H2AX [KO:K11251]
106989349  histone H2A-IV [KO:K11251]
113593972  histone H2A type 1-E-like [KO:K11251]
106988070  histone H2A type 1-H-like [KO:K11251]
106988057  histone H2A type 1-B [KO:K11251]
106976326  histone H2A type 1-E [KO:K11251]
106988063  histone H2B type 1-C/E/F/G/I [KO:K11252]
128313974  histone H2B type 2-E-like [KO:K11252]
128313981  histone H2B type 2-E-like [KO:K11252]
128315726  histone H2B type 1-M [KO:K11252]
128315728  histone H2B type 1-B [KO:K11252]
128315729  histone H2B type 1-C/E/F/G/I [KO:K11252]
128315730  histone H2B type 1-K-like [KO:K11252]
128315731  histone H2B type 1-C/E/F/G/I [KO:K11252]
128315732  histone H2B type 1-C/E/F/G/I [KO:K11252]
128315748  histone H2B type 1-C/E/F/G/I [KO:K11252]
106969569  histone H2B type 2-K1 [KO:K11252]
106988040  histone H2B type 1-C/E/F/G/I [KO:K11252]
106988062  histone H2B type 1-M [KO:K11252]
106988064  histone H2B type 1-K [KO:K11252]
106988066  histone H2B type 1-C/E/F/G/I [KO:K11252]
106988082  histone H2B type 1-A-like [KO:K11252]
106974815  histone H2B subacrosomal variant-like [KO:K11252]
106989350  histone H2B type 1-A [KO:K11252]
106985218  histone H2B type 3-B [KO:K11252]
106986679  histone H2B type 2-E [KO:K11252]
106982106  histone H2B type 2-F [KO:K11252]
106976313  histone H2B type 1-K [KO:K11252]
106985210  LOW QUALITY PROTEIN: uncharacterized protein LOC106985210 [KO:K11252]
113597270  histone H2B type 1-C/E/F/G/I [KO:K11252]
113592690  histone H2A.N [KO:K11252]
113593971  histone H2B type 1-C/E/F/G/I [KO:K11252]
106988080  histone H2B type 1-J [KO:K11252]
128315721  histone H2B type 1-C/E/F/G/I-like [KO:K11252]
128315790  uncharacterized protein LOC128315790 [KO:K11253]
128315791  uncharacterized protein LOC128315791 [KO:K11253]
106968593  histone H3.3A [KO:K11253]
106988026  uncharacterized protein LOC106988026 [KO:K11253]
106988055  histone H3.1 [KO:K11253]
106985220  H3-4; LOW QUALITY PROTEIN: histone H3.1t [KO:K11253]
106974444  histone H3.3A-like [KO:K11253]
106987747  histone H3.3A [KO:K11253]
113597382  histone H3-like [KO:K11253]
113593970  histone H3.1 [KO:K11253]
113593854  LOW QUALITY PROTEIN: uncharacterized protein LOC113593854 [KO:K11253]
106988076  histone H3.1 [KO:K11253]
106965662  uncharacterized protein LOC106965662 isoform X1 [KO:K11254]
106988031  histone H4 [KO:K11254]
106988053  histone H4 [KO:K11254]
106988073  histone H4 [KO:K11254]
106988075  histone H4 [KO:K11254]
106988077  histone H4 [KO:K11254]
106982111  histone H4 [KO:K11254]
106976329  histone H4 [KO:K11254]
106988032  histone H4 [KO:K11254]
113593855  histone H4 [KO:K11254]
106987902  histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
106975386  D(1A) dopamine receptor [KO:K04144]
106969942  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
106969924  neuroendocrine secretory protein 55 [KO:K04632]
106980600  D(2) dopamine receptor [KO:K04145]
106977809  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
106982494  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
106973284  guanine nucleotide-binding protein G(o) subunit alpha isoform X2 [KO:K04534]
106984654  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
106987417  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
106965344  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
106973885  guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
106967264  guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
106981966  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
113593204  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3-like [KO:K04540]
106981725  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
106982557  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 isoform X3 [KO:K04541]
106970626  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
106973348  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
106989697  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
113593434  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
113592841  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
106969997  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
106985197  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
113596552  putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 isoform X3 [KO:K04347]
106977369  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X1 [KO:K04547]
106969996  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
106985188  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X1 [KO:K04549]
106967169  equilibrative nucleoside transporter 3 [KO:K15014]
106973955  equilibrative nucleoside transporter 1 [KO:K15014]
106971203  equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
106979687  adenosine receptor A2a isoform X3 [KO:K04266]
106981421  adenosine receptor A2b [KO:K04267]
106984082  adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
106973352  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
106985791  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
106967098  cyclic AMP-responsive element-binding protein 1 isoform X3 [KO:K05870]
106988085  cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
106979942  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
106981255  cyclic AMP-responsive element-binding protein 3 [KO:K09048]
106970423  cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
106987262  cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
106975473  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
106978069  cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
106987665  cyclic AMP-responsive element-binding protein 5 isoform X6 [KO:K09047]
106983500  cyclic AMP-dependent transcription factor ATF-6 beta isoform X4 [KO:K09049]
106979769  corticoliberin [KO:K05256]
106982832  pro-neuropeptide Y [KO:K05232]
106970278  LOW QUALITY PROTEIN: brain-derived neurotrophic factor [KO:K04355]
106978572  BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
106988382  SHC-transforming protein 1 isoform X1 [KO:K06279]
106978092  SHC-transforming protein 2 isoform X1 [KO:K17447]
106987970  SHC-transforming protein 3 [KO:K17448]
106967221  SHC-transforming protein 4 isoform X1 [KO:K17449]
106987795  growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
106978987  son of sevenless homolog 1 isoform X1 [KO:K03099]
106989073  son of sevenless homolog 2 isoform X1 [KO:K03099]
106987957  GTPase HRas isoform X1 [KO:K02833]
106968778  GTPase KRas isoform X1 [KO:K07827]
106969596  GTPase NRas [KO:K07828]
106972677  serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
106970441  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
106977129  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
106980282  dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
106969232  mitogen-activated protein kinase 3 isoform X2 [KO:K04371] [EC:2.7.11.24]
106990008  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
106985991  proenkephalin-B [KO:K15840]
106980445  LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
106987911  calmodulin-1 [KO:K02183]
106977221  calmodulin-2 [KO:K02183]
106984637  calmodulin-like protein 6 isoform X1 [KO:K02183]
106973635  calmodulin-3 [KO:K02183]
106988136  calmodulin-like protein 3 [KO:K02183]
106988135  calmodulin-like [KO:K02183]
106987368  calcium/calmodulin-dependent protein kinase kinase 1 isoform X3 [KO:K00908] [EC:2.7.11.17]
106967543  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
106975674  calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
106973595  protein FosB isoform X1 [KO:K09029]
106980464  protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
106967586  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
106967920  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
106971182  serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
106984933  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
aju04010  MAPK signaling pathway
aju04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

DBGET integrated database retrieval system