KEGG   PATHWAY: mthb05034
Entry
mthb05034                   Pathway                                
Name
Alcoholism - Macaca thibetana thibetana (Pere David's 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
mthb05034  Alcoholism
mthb05034

Other DBs
GO: 0045471
Organism
Macaca thibetana thibetana (Pere David's macaque) [GN:mthb]
Gene
126935834  tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
126951474  aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
126961455  LOW QUALITY PROTEIN: chromaffin granule amine transporter [KO:K08155]
126962692  synaptic vesicular amine transporter [KO:K08155]
126945545  amine oxidase [flavin-containing] A-like [KO:K00274] [EC:1.4.3.4]
126945577  amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:1.4.3.4]
126957406  sodium-dependent dopamine transporter [KO:K05036]
126936897  glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
126944576  glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
126930739  glutamate receptor ionotropic, NMDA 2B [KO:K05210]
126939160  glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
126943541  glutamate receptor ionotropic, NMDA 2D [KO:K05212]
126937764  glutamate receptor ionotropic, NMDA 3A [KO:K05213]
126942934  glutamate receptor ionotropic, NMDA 3B [KO:K05214]
126957492  histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
126952258  histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
126957249  histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
126932547  histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
126938665  histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
126945539  histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
126930151  histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
126946245  histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
126950000  histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
126929449  polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
126947740  histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
126936072  histone H2AX [KO:K11251]
126936901  histone H2A type 3 [KO:K11251]
126955216  histone H2A.Z [KO:K11251]
126962516  core histone macro-H2A.2 [KO:K11251]
126931343  histone H2A.J [KO:K11251]
126955997  core histone macro-H2A.1 isoform X1 [KO:K11251]
126932652  histone H2A type 2-A [KO:K11251]
126932661  histone H2A type 2-A [KO:K11251]
126932666  histone H2A type 2-B [KO:K11251]
126932672  histone H2A type 2-C [KO:K11251]
126950191  histone H2A.V isoform X1 [KO:K11251]
126945510  histone H2A-Bbd type 2/3-like [KO:K11251]
126945511  histone H2A-Bbd type 2/3-like [KO:K11251]
126945513  histone H2A-Bbd type 2/3-like [KO:K11251]
126958195  histone H2A.Z [KO:K11251]
126952994  histone H2A type 1-A [KO:K11251]
126953518  histone H2A type 1-C [KO:K11251]
126953520  histone H2A type 1 [KO:K11251]
126953521  histone H2A type 1 [KO:K11251]
126953522  histone H2A type 1 [KO:K11251]
126953523  histone H2A type 1-D [KO:K11251]
126953524  histone H2A type 1-H-like [KO:K11251]
126953525  histone H2A type 1-B [KO:K11251]
126953526  histone H2A type 1-B [KO:K11251]
126953527  histone H2A type 1 [KO:K11251]
126953528  histone H2A type 1-J [KO:K11251]
126953529  histone H2A type 1-H [KO:K11251]
126946352  LOW QUALITY PROTEIN: histone H2A-like 3 [KO:K11251]
126945736  LOW QUALITY PROTEIN: histone H2A-like 3 [KO:K11251]
126936916  histone H2B type 3-B [KO:K11252]
126936921  H2B.U histone 2 [KO:K11252]
126956617  histone H2B type 1-K-like [KO:K11252]
126932605  histone H2B type 2-F isoform X1 [KO:K11252]
126932680  histone H2B type 2-E [KO:K11252]
126946028  histone H2B type F-M-like [KO:K11252]
126946037  histone H2B type W-T [KO:K11252]
126946038  histone H2B type W-T-like [KO:K11252]
126946039  histone H2B type W-T-like [KO:K11252]
126946045  histone H2B type F-M [KO:K11252]
126946046  histone H2B type F-M [KO:K11252]
126951645  histone H2B type 2-K1 [KO:K11252]
126952995  histone H2B type 1-A-like [KO:K11252]
126952996  histone H2B type 1-A [KO:K11252]
126953513  histone H2B type 1-M-like [KO:K11252]
126953531  histone H2B type 1-K [KO:K11252]
126953532  histone H2B type 1-O [KO:K11252]
126953533  histone H2B type 1-M [KO:K11252]
126953534  histone H2B type 1-J [KO:K11252]
126953535  histone H2B type 1-C/E/F/G/I [KO:K11252]
126953536  histone H2B type 1-F/J/L-like [KO:K11252]
126953537  histone H2B type 1-C/E/F/G/I [KO:K11252]
126953538  histone H2B type 1-B [KO:K11252]
126953539  histone H2B type 1-C/E/F/G/I [KO:K11252]
126953540  histone H2B type 1-C/E/F/G/I-like [KO:K11252]
126953542  histone H2B type 1-C/E/F/G/I [KO:K11252]
126953543  histone H2B type 1-F/J/L [KO:K11252]
126929757  histone H3.3A-like [KO:K11253]
126936887  histone H3.1t [KO:K11253]
126962053  histone H3.3A-like [KO:K11253]
126930844  histone H3.3A [KO:K11253]
126937204  histone H3.3A [KO:K11253]
126956436  histone H3.Y [KO:K11253]
126949879  histone H3.3A-like [KO:K11253]
126939277  histone H3.3A [KO:K11253]
126946311  histone H3.3A-like [KO:K11253]
126946704  histone H3.3A-like [KO:K11253]
126952817  histone H3.3C-like [KO:K11253]
126941981  histone H3.3C-like [KO:K11253]
126953340  histone H3.1-like [KO:K11253]
126953515  histone H3.1 [KO:K11253]
126953516  histone H3.1 [KO:K11253]
126953517  histone H3.1 [KO:K11253]
126953554  histone H3.1t-like [KO:K11253]
126953555  histone H3.1-like [KO:K11253]
126953613  histone H3.3A-like [KO:K11253]
126932604  histone H3 [KO:K11253]
126932489  histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
126956339  D(1A) dopamine receptor [KO:K04144]
126929358  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
126929369  neuroendocrine secretory protein 55 [KO:K04632]
126935923  D(2) dopamine receptor [KO:K04145]
126929846  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
126949885  guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
126948709  guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
126943869  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
126952008  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
126950415  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
126930448  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
126947562  guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
126959042  guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
126958548  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
126935530  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X1 [KO:K04540]
126942604  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
126955333  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
126963646  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
126951422  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
126935723  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
126942881  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
126943523  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
126937751  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
126949943  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
126942836  putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
126939573  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
126944893  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
126949942  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
126939894  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
126962513  equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
126952402  equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
126935364  equilibrative nucleoside transporter 2 [KO:K15014]
126929656  adenosine receptor A2a [KO:K04266]
126938806  adenosine receptor A2b [KO:K04267]
126949094  adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
126942437  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
126937647  cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
126963591  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
126933094  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
126932678  cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
126963745  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
126942639  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
126938066  cyclic AMP-responsive element-binding protein 3 [KO:K09048]
126951142  cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
126934237  cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
126935751  cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
126950050  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
126953217  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
126961526  corticoliberin [KO:K05256]
126950035  pro-neuropeptide Y [KO:K05232]
126934686  brain-derived neurotrophic factor isoform X1 [KO:K04355]
126937627  BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
126933571  SHC-transforming protein 1 isoform X1 [KO:K06279]
126942949  SHC-transforming protein 2 [KO:K17447]
126937656  SHC-transforming protein 3 [KO:K17448]
126958692  SHC-transforming protein 4 [KO:K17449]
126939255  growth factor receptor-bound protein 2 [KO:K04364]
126933534  son of sevenless homolog 1 isoform X1 [KO:K03099]
126958499  son of sevenless homolog 2 isoform X1 [KO:K03099]
126935869  GTPase HRas isoform X1 [KO:K02833]
126931572  GTPase KRas [KO:K07827]
126930824  GTPase NRas [KO:K07828]
126945567  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
126949633  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
126949054  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
126957976  dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
126944456  mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
126929669  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
126929103  proenkephalin-B [KO:K15840]
126961592  calmodulin-1-like [KO:K02183]
126962311  calmodulin-like protein 5 [KO:K02183]
126962328  calmodulin-like protein 3 [KO:K02183]
126943484  calmodulin-3 isoform X1 [KO:K02183]
126958173  LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
126951481  calmodulin-1-like [KO:K02183]
126934255  calmodulin-2 [KO:K02183]
126952282  calmodulin-like protein 6 [KO:K02183]
126959699  calmodulin-1 isoform X1 [KO:K02183]
126939943  calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
126930629  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
126956231  calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
126943490  protein FosB isoform X1 [KO:K09029]
126938566  protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
126931492  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
126933834  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
126935389  serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
126961714  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
mthb04010  MAPK signaling pathway
mthb04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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