KEGG   PATHWAY: pps05034
Entry
pps05034                    Pathway                                
Name
Alcoholism - Pan paniscus (bonobo)
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
pps05034  Alcoholism
pps05034

Other DBs
GO: 0045471
Organism
Pan paniscus (bonobo) [GN:pps]
Gene
100967895  TH; tyrosine 3-monooxygenase isoform X2 [KO:K00501] [EC:1.14.16.2]
100971531  DDC; aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:4.1.1.28 4.1.1.105]
100967958  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
100986598  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
100984839  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
134730363  SLC6A3; sodium-dependent dopamine transporter isoform X1 [KO:K05036]
100987673  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
100977852  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X2 [KO:K05209]
100974219  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
100989438  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
100977548  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
100973890  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
100980497  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
100978715  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
100978769  HDAC3; histone deacetylase 3 isoform X2 [KO:K11404] [EC:3.5.1.98]
100970870  HDAC4; histone deacetylase 4 isoform X6 [KO:K11406] [EC:3.5.1.98]
100985135  HDAC5; histone deacetylase 5 isoform X3 [KO:K11406] [EC:3.5.1.98]
100979180  HDAC6; histone deacetylase 6 isoform X4 [KO:K11407] [EC:3.5.1.98]
100980355  HDAC7; histone deacetylase 7 isoform X4 [KO:K11408] [EC:3.5.1.98]
100988053  HDAC8; histone deacetylase 8 isoform X3 [KO:K11405] [EC:3.5.1.98]
100967488  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
100973483  HDAC10; polyamine deacetylase HDAC10 isoform X6 [KO:K18671] [EC:3.5.1.98]
100967730  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
100984913  histone H2A-Bbd type 2/3 [KO:K11251]
100975117  histone H2A type 3 [KO:K11251]
100990167  histone H2A type 1-C [KO:K11251]
100992822  histone H2A-Bbd type 2/3 [KO:K11251]
100982169  histone H2A type 1 [KO:K11251]
100982497  histone H2A type 1-H [KO:K11251]
100985779  histone H2A type 2-B [KO:K11251]
100994157  uncharacterized protein LOC100994157 isoform X1 [KO:K11251]
100978953  histone H2A type 1-A [KO:K11251]
100986643  histone H2A type 1 [KO:K11251]
100988670  histone H2A type 1 [KO:K11251]
100989678  histone H2A type 1 [KO:K11251]
103783475  histone H2A type 1 [KO:K11251]
100985121  histone H2A type 1-H-like [KO:K11251]
100976242  histone H2A.J [KO:K11251]
100973544  histone H2A type 2-A [KO:K11251]
103784359  histone H2A type 2-A [KO:K11251]
100974647  core histone macro-H2A.2 [KO:K11251]
117977735  histone H2A-Bbd type 2/3 [KO:K11251]
100974858  core histone macro-H2A.1 isoform X1 [KO:K11251]
117981575  histone H2A.Z-like [KO:K11251]
100990022  histone H2A type 1-J [KO:K11251]
100974682  histone H2A.V isoform X2 [KO:K11251]
100974973  histone H2A.Z [KO:K11251]
100980195  histone H2A type 1-B [KO:K11251]
100992550  histone H2A type 1-B [KO:K11251]
103785886  histone H2A type 2-C [KO:K11251]
100977261  histone H2B type 1-C/E/F/G/I [KO:K11252]
100992900  histone H2B type 1-B [KO:K11252]
100984497  histone H2B type 2-F isoform X4 [KO:K11252]
100981154  histone H2B type 1-K [KO:K11252]
100969533  histone H2B type W-T [KO:K11252]
100985433  histone H2B type 2-E [KO:K11252]
100979289  histone H2B type 1-A [KO:K11252]
100986973  histone H2B type 1-F/J/L [KO:K11252]
100987642  histone H2B type 1-O [KO:K11252]
100989331  histone H2B type 1-M [KO:K11252]
100988917  histone H2B type W-T-like [KO:K11252]
100988594  LOW QUALITY PROTEIN: histone H2B type F-M [KO:K11252]
103785481  histone H2B type 2-K1 [KO:K11252]
100981494  histone H2B type 1-J [KO:K11252]
100979499  histone H2B type 1-H [KO:K11252]
100975795  H2B.U histone 2-like [KO:K11252]
100981885  histone H2B type 1-C/E/F/G/I [KO:K11252]
100985638  histone H2B type 1-N isoform X1 [KO:K11252]
100979846  histone H2B type 1-C/E/F/G/I [KO:K11252]
100985450  histone H2B type 1-C/E/F/G/I [KO:K11252]
100989841  histone H2B type 1-C/E/F/G/I [KO:K11252]
130540440  histone H2B type 3-B [KO:K11252]
134730579  histone H2B type 1-M [KO:K11252]
100974795  H3-4; histone H3.1t [KO:K11253]
100992611  histone H3.3A-like [KO:K11253]
100986301  histone H3.1-like [KO:K11253]
100990354  histone H3.1-like [KO:K11253]
100982184  histone H3.3A-like [KO:K11253]
100983097  histone H3.3A-like [KO:K11253]
100976209  LOW QUALITY PROTEIN: histone H3.3A [KO:K11253]
103784504  histone H3.1-like [KO:K11253]
100978834  histone H3.3A-like [KO:K11253]
100970414  histone H3.3A [KO:K11253]
100988671  histone H3.3A [KO:K11253]
100970485  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
100988335  DRD1; D(1A) dopamine receptor [KO:K04144]
100990650  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X2 [KO:K04632]
117974231  neuroendocrine secretory protein 55 [KO:K04632]
100980993  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
100968961  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100974334  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
100985590  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X3 [KO:K04630]
100991540  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100978523  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100982509  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100968267  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
100967770  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100990010  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100970547  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100995028  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
100980807  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100973322  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
117975026  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
100983091  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
100987458  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
112437196  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100978647  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 isoform X2 [KO:K04545]
100976735  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100992242  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
112437428  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100977074  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
100994102  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100983531  SLC29A3; equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
100973873  SLC29A1; equilibrative nucleoside transporter 1 isoform X5 [KO:K15014]
100970048  SLC29A2; equilibrative nucleoside transporter 2 isoform X2 [KO:K15014]
100970926  ADORA2A; adenosine receptor A2a [KO:K04266]
100994290  ADORA2B; adenosine receptor A2b [KO:K04267]
100989177  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
100982589  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
100970917  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100968237  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100974672  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X2 [KO:K05870]
100985706  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100980724  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
100988487  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100986194  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100981063  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100977804  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100989680  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100977358  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
100973232  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
100993334  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100992287  CRH; corticoliberin [KO:K05256]
100988735  NPY; pro-neuropeptide Y [KO:K05232]
100983866  BDNF; brain-derived neurotrophic factor isoform X3 [KO:K04355]
100994887  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
100993361  SHC1; SHC-transforming protein 1 isoform X9 [KO:K06279]
100974798  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
100972624  SHC3; SHC-transforming protein 3 isoform X2 [KO:K17448]
100991042  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
100993451  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100972953  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100980038  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
100993386  HRAS; GTPase HRas isoform X1 [KO:K02833]
100990801  KRAS; GTPase KRas isoform X1 [KO:K07827]
100970465  NRAS; GTPase NRas isoform X2 [KO:K07828]
100990590  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
100971666  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100972902  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100988422  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100979542  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100995567  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100993260  PDYN; proenkephalin-B [KO:K15840]
100990459  CALML5; calmodulin-like protein 5 [KO:K02183]
100990795  CALML3; calmodulin-like protein 3 [KO:K02183]
100996176  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
100976055  calmodulin-2-like [KO:K02183]
100979074  CALML6; calmodulin-like protein 6 [KO:K02183]
100968473  CALM1; calmodulin-1 isoform X2 [KO:K02183]
100977014  CALM3; calmodulin-3 [KO:K02183]
100980454  CALM2; calmodulin-2 isoform X1 [KO:K02183]
100994214  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
100989349  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
100970371  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
100989480  FOSB; protein FosB isoform X1 [KO:K09029]
100980284  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X2 [KO:K15494]
100992486  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100974889  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100978326  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
134730135  serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269] [EC:3.1.3.16]
134730136  serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269] [EC:3.1.3.16]
100987657  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X2 [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
pps04010  MAPK signaling pathway
pps04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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