KEGG   PATHWAY: mcc05034
Entry
mcc05034                    Pathway                                
Name
Alcoholism - Macaca mulatta (rhesus monkey)
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
mcc05034  Alcoholism
mcc05034

Other DBs
GO: 0045471
Organism
Macaca mulatta (rhesus monkey) [GN:mcc]
Gene
721137  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
693677  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
701133  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
705489  SLC18A1; chromaffin granule amine transporter isoform X2 [KO:K08155]
708371  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
708468  MAOB; amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:1.4.3.4]
574143  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
574380  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
100429880  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
698571  GRIN2B; glutamate receptor ionotropic, NMDA 2B isoform X1 [KO:K05210]
699216  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
717945  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
716892  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
721155  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
708441  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
694662  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
704467  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
710797  HDAC4; histone deacetylase 4 isoform X6 [KO:K11406] [EC:3.5.1.98]
711456  HDAC5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
711363  HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
718225  HDAC7; histone deacetylase 7 isoform X2 [KO:K11408] [EC:3.5.1.98]
699642  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
708314  HDAC9; histone deacetylase 9 isoform X18 [KO:K11409] [EC:3.5.1.98]
715698  HDAC10; polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
693537  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
701863  H2AFJ; histone H2A.J [KO:K11251]
704994  histone H2A type 1-H [KO:K11251]
705054  HIST2H2AC; histone H2A type 2-C [KO:K11251]
698239  HIST1H2AA; histone H2A type 1-A [KO:K11251]
693768  HIST3H2A; histone cluster 3, H2a [KO:K11251]
697235  HIST1H2AD; histone H2A type 1-D [KO:K11251]
697977  histone H2A type 1-B/E [KO:K11251]
701826  histone H2A type 1-H [KO:K11251]
704006  HIST1H2AK; histone H2A type 1 [KO:K11251]
704664  histone H2A type 1 [KO:K11251]
705469  histone H2A type 1 [KO:K11251]
695551  HIST1H2AE; histone H2A type 1-B/E [KO:K11251]
711836  H2AFY; H2A histone family, member Y [KO:K11251]
701962  histone H2A.Z [KO:K11251]
696463  histone H2A type 2-A [KO:K11251]
705170  HIST2H2AB; histone H2A type 2-B [KO:K11251]
705636  uncharacterized protein LOC705636 [KO:K11251]
709326  H2AFZ; H2A histone family, member Z [KO:K11251]
696629  HIST1H2AC; histone H2A type 1-C [KO:K11251]
703073  H2AFX; histone H2A.x [KO:K11251]
704127  HIST1H2AJ; histone cluster 1, H2aj [KO:K11251]
703044  H2AFB3; histone H2A-Bbd type 2/3 [KO:K11251]
711117  H2AFY2; core histone macro-H2A.2 [KO:K11251]
701574  histone H2A type 1 [KO:K11251]
106995531  histone H2A-Bbd type 2/3-like [KO:K11251]
114670854  histone H2A type 2-A [KO:K11251]
114675038  histone H2A-Bbd type 2/3-like [KO:K11251]
114677660  uncharacterized protein LOC114677660 [KO:K11251]
704780  histone H2B type 1-N [KO:K11252]
702227  HIST1H2BO; histone H2B type 1-O [KO:K11252]
699275  H2BFWT; histone H2B type W-T [KO:K11252]
698109  HIST1H2BA; histone H2B type 1-A [KO:K11252]
695657  histone H2B type 1-B [KO:K11252]
696506  histone H2B type 1 [KO:K11252]
704241  histone H2B type 1-F/J/L [KO:K11252]
701337  HIST1H2BJ; histone H2B type 1-J [KO:K11252]
714818  histone H2B type 2-E [KO:K11252]
701464  HIST1H2BK; histone H2B type 1-K [KO:K11252]
693635  HIST3H2BB; histone H2B type 3-B [KO:K11252]
693507  HIST1H2BD; histone H2B type 3-A [KO:K11252]
696996  histone H2B type 1 [KO:K11252]
697469  histone H2B type 1 [KO:K11252]
697857  histone H2B type 1 [KO:K11252]
698482  HIST1H2BH; histone H2B type 1-H [KO:K11252]
704452  HIST1H2BM; histone H2B type 1-M [KO:K11252]
714001  histone H2B type 1-K [KO:K11252]
698767  histone H2B type W-T [KO:K11252]
696808  histone H2B type 1 [KO:K11252]
106997853  histone H2B type 1-M [KO:K11252]
107000817  histone H2B type 2-F isoform X2 [KO:K11252]
698679  histone H2B type F-M [KO:K11252]
106995678  histone H2B type F-M-like [KO:K11252]
698430  histone H2B type F-M [KO:K11252]
106997735  late histone H2B.L4-like [KO:K11252]
106997851  histone H2B type 1-A-like [KO:K11252]
114673509  histone H2B type 2-E-like [KO:K11252]
114674721  histone H2B type F-M-like [KO:K11252]
114674719  histone H2B type W-T-like [KO:K11252]
114675561  histone H2B type 2-E-like [KO:K11252]
708899  histone H3.3 [KO:K11253]
710748  histone H3.3-like [KO:K11253]
695663  histone H3.3-like [KO:K11253]
699443  histone H3.3 [KO:K11253]
704104  histone H3.3 [KO:K11253]
695092  HIST1H3D; histone H3.1 [KO:K11253]
694024  HIST3H3; histone H3.1 [KO:K11253]
693887  histone H3.3 [KO:K11253]
695427  histone H3.1 [KO:K11253]
698105  histone H3.1 [KO:K11253]
703889  histone H3.1 [KO:K11253]
704845  HIST2H3A; uncharacterized protein HIST2H3A [KO:K11253]
705220  uncharacterized protein LOC705220 [KO:K11253]
718280  histone cluster 2, H3c pseudogene [KO:K11253]
693939  histone H3.3-like [KO:K11253]
694152  histone H3.3C-like [KO:K11253]
699015  histone H3.3C-like [KO:K11253]
708847  histone H3.3-like [KO:K11253]
709296  histone H3.3-like [KO:K11253]
100430668  histone H3.1 [KO:K11253]
114669830  histone H3 [KO:K11253]
107000233  histone H3.3-like [KO:K11253]
114677623  histone H3.3C-like [KO:K11253]
114677671  histone H3.1-like [KO:K11253]
695323  histone H4 [KO:K11254]
697115  histone H4 [KO:K11254]
697721  histone H4 [KO:K11254]
698354  histone H4 [KO:K11254]
699110  histone H4 [KO:K11254]
699317  histone H4 [KO:K11254]
704341  histone H4 [KO:K11254]
106996511  histone H4 [KO:K11254]
106997862  histone H4 [KO:K11254]
114677669  histone H4 [KO:K11254]
107000818  histone H4 [KO:K11254]
695933  HAT1; histone acetyltransferase type B catalytic subunit isoform X2 [KO:K11303] [EC:2.3.1.48]
697796  DRD1; D(1A) dopamine receptor [KO:K04144]
694289  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X2 [KO:K04632]
100424899  neuroendocrine secretory protein 55 [KO:K04632]
694181  DRD2; D(2) dopamine receptor [KO:K04145]
699310  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
703780  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
708940  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
574394  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
703399  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
719248  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
713913  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
709489  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
695441  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
710000  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100169972  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
718223  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
703336  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
710548  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
711335  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
114673987  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
708193  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
700606  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100424606  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
114673968  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
722398  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
700724  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
698840  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
709682  SLC29A3; equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
703031  SLC29A1; equilibrative nucleoside transporter 1 [KO:K15014]
720038  SLC29A2; equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
707865  ADORA2A; adenosine receptor A2a isoform X1 [KO:K04266]
696848  ADORA2B; adenosine receptor A2b [KO:K04267]
715897  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
709728  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
718632  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
700652  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
708717  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
699072  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
703965  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
714981  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
713391  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
696350  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
721825  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
715951  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
697718  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
717050  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
702877  CRH; corticoliberin [KO:K05256]
574114  NPY; pro-neuropeptide Y precursor [KO:K05232]
701245  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
709757  NTRK2; BDNF/NT-3 growth factors receptor precursor [KO:K04360] [EC:2.7.10.1]
718982  SHC1; SHC-transforming protein 1 [KO:K06279]
721021  SHC2; SHC-transforming protein 2 [KO:K17447]
574275  SHC3; SHC-transforming protein 3 [KO:K17448]
714611  SHC4; SHC-transforming protein 4 [KO:K17449]
702041  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
713777  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
705601  SOS2; son of sevenless homolog 2 [KO:K03099]
698830  HRAS; GTPase HRas [KO:K02833]
707977  KRAS; GTPase KRas [KO:K07827]
709089  NRAS; GTPase NRas [KO:K07828]
707169  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
693554  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
694725  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
710415  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
708938  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
698569  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
716341  PDYN; proenkephalin-B precursor [KO:K15840]
717686  calmodulin [KO:K02183]
698552  CALM1; calmodulin-1 isoform X1 [KO:K02183]
715270  CALM2; calmodulin-2 [KO:K02183]
703514  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
712159  CALML5; calmodulin-like protein 5 [KO:K02183]
722513  CALML3; calmodulin-like protein 3 [KO:K02183]
716584  CALM3; calmodulin-3 isoform X1 [KO:K02183]
693753  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
706351  calmodulin-like [KO:K02183]
707562  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
699685  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X3 [KO:K07359] [EC:2.7.11.17]
712322  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
715896  FOSB; protein fosB isoform X1 [KO:K09029]
574203  PPP1R1B; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
703302  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
709935  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
721735  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
698509  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
mcc04010  MAPK signaling pathway
mcc04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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