KEGG   PATHWAY: mni05034
Entry
mni05034                    Pathway                                
Name
Alcoholism - Macaca nemestrina (pig-tailed macaque)
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
mni05034  Alcoholism
mni05034

Other DBs
GO: 0045471
Organism
Macaca nemestrina (pig-tailed macaque) [GN:mni]
Gene
105469782  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
105492377  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
105467456  SLC18A2; synaptic vesicular amine transporter isoform X1 [KO:K08155]
105482119  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
105463379  amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
105463385  MAOB; amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:1.4.3.4]
105464564  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
105471967  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
105467787  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
105481967  GRIN2B; glutamate receptor ionotropic, NMDA 2B isoform X1 [KO:K05210]
105469137  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X2 [KO:K05211]
105478638  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
105480993  GRIN3A; glutamate receptor ionotropic, NMDA 3A isoform X1 [KO:K05213]
105487302  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
105499715  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
105494637  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
105466979  HDAC3; histone deacetylase 3 isoform X3 [KO:K11404] [EC:3.5.1.98]
105473807  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
105469256  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
105493906  histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
105470063  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
105464741  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
105475646  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
105489760  HDAC10; histone deacetylase 10 isoform X1 [KO:K18671] [EC:3.5.1.98]
105477742  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
105476383  histone H2AX [KO:K11251]
105486359  histone H2A.Z [KO:K11251]
105497788  histone H2A type 2-C [KO:K11251]
105497790  histone H2A type 2-B [KO:K11251]
105466082  core histone macro-H2A.2 [KO:K11251]
105467125  core histone macro-H2A.1 isoform X1 [KO:K11251]
105478977  histone H2A type 2-A [KO:K11251]
105499684  histone H2A type 3 [KO:K11251]
105491635  histone H2A type 1 [KO:K11251]
105491640  histone H2A type 1-H-like [KO:K11251]
105491642  histone H2A type 1 [KO:K11251]
105491646  histone H2A type 1-J [KO:K11251]
105491648  histone H2A type 1 [KO:K11251]
105491664  histone H2A type 1-H [KO:K11251]
105491667  histone H2A type 1 [KO:K11251]
105481862  histone H2A.J [KO:K11251]
105482562  histone H2A type 1-A [KO:K11251]
105482571  histone H2A type 1-B/E [KO:K11251]
105482583  histone H2A type 1-C [KO:K11251]
105482591  histone H2A type 1-B/E [KO:K11251]
105482595  histone H2A type 1-D [KO:K11251]
105494223  histone H2A.V isoform X1 [KO:K11251]
105499037  histone H2A-Bbd type 1-like [KO:K11251]
105474913  late histone H2B.L4-like [KO:K11252]
105497787  histone H2B type 2-E [KO:K11252]
105466836  histone H2B type 1-J-like [KO:K11252]
105478979  histone H2B type 2-F-like isoform X2 [KO:K11252]
105499683  histone H2B type 3-B [KO:K11252]
105499692  histone H2B type W-T-like [KO:K11252]
105499693  histone H2B type F-M [KO:K11252]
105499746  histone H2B type W-T [KO:K11252]
105499747  histone H2B type F-M-like [KO:K11252]
105499748  histone H2B type W-T-like [KO:K11252]
105499682  histone H2B type 3-A [KO:K11252]
105491634  histone H2B type 1-O [KO:K11252]
105491643  histone H2B type 1-N [KO:K11252]
105491645  histone H2B type 1-M [KO:K11252]
105491649  histone H2B type 1-F/J/L [KO:K11252]
105491666  histone H2B type 1-K [KO:K11252]
105491668  histone H2B type 1-J [KO:K11252]
112422912  histone H2B type 1-F/J/L-like [KO:K11252]
105482560  histone H2B type 1-A-like [KO:K11252]
105482561  histone H2B type 1-A [KO:K11252]
105482570  histone H2B type 1-B [KO:K11252]
105482579  histone H2B type 1 [KO:K11252]
105482580  histone H2B type 1-M-like [KO:K11252]
105482585  histone H2B type 1-like [KO:K11252]
105482592  histone H2B type 1 [KO:K11252]
105482594  histone H2B type 1 [KO:K11252]
105482601  histone H2B type 1 [KO:K11252]
105464478  histone H3.3-like [KO:K11253]
105476302  histone H3.3-like [KO:K11253]
105478569  histone H3.3 [KO:K11253]
105498489  histone H3.3-like [KO:K11253]
105499677  histone H3.1 [KO:K11253]
105469173  histone H3.3 [KO:K11253]
105491636  histone H3.1 [KO:K11253]
105491641  uncharacterized protein LOC105491641 [KO:K11253]
105491644  histone H3.1t [KO:K11253]
112425312  histone H3.3C-like [KO:K11253]
112426763  histone H3.1 [KO:K11253]
105482638  histone H3.1 [KO:K11253]
105492091  histone H3.3-like [KO:K11253]
105492329  histone cluster 2, H3c pseudogene [KO:K11253]
105482572  histone H3.1 [KO:K11253]
105492949  LOW QUALITY PROTEIN: histone H3.3-like [KO:K11253]
105492952  histone H3.3C-like [KO:K11253]
112428906  histone H3.3C-like [KO:K11253]
105484470  histone H3.3 [KO:K11253]
105478976  histone H3 [KO:K11253]
105483239  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
105480914  DRD1; D(1A) dopamine receptor [KO:K04144]
105470579  neuroendocrine secretory protein 55 [KO:K04632]
105470577  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
105493586  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
105475385  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
105479273  GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105480474  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
105494072  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
105496719  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105497010  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
105484206  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
105489969  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
105490201  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105481826  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
105469457  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X1 [KO:K04540]
105474606  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
105463427  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
112426886  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
105485776  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
105478587  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
105481072  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105475520  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
105498434  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
112427422  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
105475518  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
105472342  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
105466059  SLC29A3; equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
105489543  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
105469632  SLC29A2; equilibrative nucleoside transporter 2 [KO:K15014]
105498492  ADORA2A; adenosine receptor A2a isoform X1 [KO:K04266]
105491088  ADORA2B; adenosine receptor A2b [KO:K04267]
105470270  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105498103  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
105491778  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
105482741  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105468005  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
105483203  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
105464416  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
105485736  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
105487183  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
105497957  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
105471318  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
105471659  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X3 [KO:K09048]
105475779  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
105497591  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
105482189  CRH; corticoliberin [KO:K05256]
105475705  NPY; pro-neuropeptide Y [KO:K05232]
105463281  BDNF; brain-derived neurotrophic factor isoform X2 [KO:K04355]
105498757  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
105497981  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
105486618  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
105498803  SHC3; SHC-transforming protein 3 [KO:K17448]
105490670  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
105469160  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
105465416  SOS1; son of sevenless homolog 1 [KO:K03099]
105481847  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
105494134  HRAS; GTPase HRas isoform X1 [KO:K02833]
105492133  KRAS; GTPase KRas isoform X1 [KO:K07827]
105479146  NRAS; GTPase NRas [KO:K07828]
105463916  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
105471274  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
105477727  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105488275  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105480656  MAPK1; LOW QUALITY PROTEIN: mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
105482882  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
105481630  PDYN; proenkephalin-B [KO:K15840]
105464979  CALM2; calmodulin-2 [KO:K02183]
105496718  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
105488029  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
105478585  CALM3; calmodulin-3 isoform X1 [KO:K02183]
105467562  CALM1; calmodulin-1 isoform X1 [KO:K02183]
105483519  calmodulin-like [KO:K02183]
105492388  calmodulin-like [KO:K02183]
105494378  CALML3; calmodulin-like protein 3 [KO:K02183]
105494380  CALML5; calmodulin-like protein 5 [KO:K02183]
105472037  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
105495499  CAMKK2; LOW QUALITY PROTEIN: calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
105471123  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
105478548  FOSB; protein fosB isoform X1 [KO:K09029]
105472249  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X2 [KO:K15494]
105479729  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
105469672  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
105493733  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105483553  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
mni04010  MAPK signaling pathway
mni04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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