KEGG   PATHWAY: pcad05034
Entry
pcad05034                   Pathway                                
Name
Alcoholism - Physeter macrocephalus (sperm whale)
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
pcad05034  Alcoholism
pcad05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Physeter macrocephalus (sperm whale) [GN:pcad]
Gene
102974274  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
102974315  SHC2; SHC-transforming protein 2 [KO:K17447]
102974369  ATF2; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
102974409  NPY; pro-neuropeptide Y isoform X2 [KO:K05232]
102975387  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
102975548  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
102975738  HDAC5; histone deacetylase 5 isoform X2 [KO:K11406] [EC:3.5.1.98]
102975750  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
102976132  [KO:K11252]
102976421  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
102976424  [KO:K11251]
102976460  [KO:K11252]
102976485  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
102976671  CALM1; calmodulin-1 [KO:K02183]
102976718  [KO:K11254]
102976719  HDAC8; histone deacetylase 8 isoform X3 [KO:K11405] [EC:3.5.1.98]
102976986  [KO:K11254]
102977125  KRAS; GTPase KRas isoform X1 [KO:K07827]
102977174  GRIN3B; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 3B [KO:K05214]
102977243  HDAC10; polyamine deacetylase HDAC10 isoform X4 [KO:K18671] [EC:3.5.1.98]
102977259  [KO:K11251]
102977311  HDAC6; histone deacetylase 6 isoform X2 [KO:K11407] [EC:3.5.1.98]
102977456  SHC3; SHC-transforming protein 3 [KO:K17448]
102977506  [KO:K02183]
102977542  [KO:K11251]
102977845  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
102977934  BDNF; brain-derived neurotrophic factor isoform X6 [KO:K04355]
102978069  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X3 [KO:K15985]
102978131  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
102978667  [KO:K11251]
102978728  SLC18A1; chromaffin granule amine transporter [KO:K08155]
102978925  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
102978947  [KO:K11252]
102978983  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
102979220  [KO:K11253]
102979676  [KO:K11254]
102980154  [KO:K11251]
102980340  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
102980522  HDAC3; histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
102980648  HDAC4; histone deacetylase 4 isoform X4 [KO:K11406] [EC:3.5.1.98]
102980685  [KO:K11251]
102980707  FOSB; protein FosB isoform X1 [KO:K09029]
102981091  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102981111  [KO:K11252]
102981323  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X2 [KO:K07826]
102981359  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102981389  [KO:K11251]
102981677  [KO:K03099]
102981726  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
102981740  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
102981900  [KO:K11251]
102981944  [KO:K11252]
102982318  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
102982478  [KO:K11251]
102982641  NRAS; LOW QUALITY PROTEIN: GTPase NRas [KO:K07828]
102982687  [KO:K11254]
102983319  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102983767  [KO:K11251]
102984020  SLC29A3; equilibrative nucleoside transporter 3 isoform X2 [KO:K15014]
102984042  [KO:K11252]
102984157  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
102984294  [KO:K11252]
102984305  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102984487  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
102984570  [KO:K11251]
102984704  PDYN; proenkephalin-B [KO:K15840]
102984954  DRD2; D(2) dopamine receptor [KO:K04145]
102985182  H3-4; LOW QUALITY PROTEIN: histone H3.1t [KO:K11253]
102985272  [KO:K11253]
102985635  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X3 [KO:K09047]
102985702  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
102985729  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
102986055  [KO:K11252]
102986070  [KO:K11253]
102986078  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X3 [KO:K09048]
102986172  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
102986231  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
102986440  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
102986522  [KO:K11253]
102986539  SLC29A2; equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
102986543  [KO:K11252]
102986621  ADORA2B; adenosine receptor A2b isoform X1 [KO:K04267]
102986813  [KO:K11251]
102986837  [KO:K04450]
102986916  BRAF; serine/threonine-protein kinase B-raf isoform X3 [KO:K04365] [EC:2.7.11.1]
102987032  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
102987057  [KO:K11253]
102987194  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
102987258  [KO:K04632]
102987354  [KO:K11251]
102987376  [KO:K11254]
102987558  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
102987662  [KO:K11251]
102987685  [KO:K11252]
102987866  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
102987948  [KO:K11252]
102987969  [KO:K11252]
102988232  [KO:K02183]
102988309  CALM3; calmodulin-3 [KO:K02183]
102988341  [KO:K04632]
102988406  [KO:K11251]
102988652  SHC4; SHC-transforming protein 4 isoform X2 [KO:K17449]
102988654  DDC; aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:4.1.1.28 4.1.1.105]
102988681  [KO:K11252]
102988727  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
102988799  [KO:K11251]
102988970  [KO:K11253]
102989074  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102989082  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102989093  [KO:K11252]
102989262  [KO:K11253]
102989391  DRD1; D(1A) dopamine receptor [KO:K04144]
102989541  [KO:K11251]
102989808  [KO:K11252]
102990164  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
102991367  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
102991486  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102991639  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102991645  CRH; corticoliberin [KO:K05256]
102991829  HDAC9; histone deacetylase 9 isoform X14 [KO:K11409] [EC:3.5.1.98]
102992015  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
102992191  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102992218  [KO:K11251]
102992255  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
102992365  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
102992419  [KO:K11251]
102992439  [KO:K07828]
102992497  [KO:K11251]
102992526  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
102992677  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X2 [KO:K15494]
102992781  [KO:K11252]
102992858  [KO:K11251]
102992996  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102993067  [KO:K11252]
102993128  [KO:K11252]
102993267  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X2 [KO:K04632]
102993313  [KO:K11252]
102993331  [KO:K11252]
102993605  [KO:K11252]
102993731  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
102993806  HDAC2; histone deacetylase 2 isoform X3 [KO:K06067] [EC:3.5.1.98]
102993890  [KO:K11254]
102994134  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
102994172  [KO:K11251]
102994418  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
102994440  [KO:K11252]
102994621  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
102994715  HRAS; GTPase HRas isoform X2 [KO:K02833]
102994718  [KO:K11251]
102994740  [KO:K11253]
102994991  [KO:K11253]
102995267  ADORA2A; adenosine receptor A2a [KO:K04266]
102995361  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
102995518  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
102995656  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
102996618  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102996666  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
102996827  TH; tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
102996886  [KO:K02183]
102997009  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
112062012  [KO:K04542]
112062230  [KO:K11253]
112062231  [KO:K11251]
112062401  [KO:K11251]
112062576  [KO:K11252]
112062577  [KO:K11252]
112062578  [KO:K11252]
112062579  [KO:K11252]
112062778  [KO:K11252]
112062779  [KO:K11252]
112063837  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
112063854  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
112064328  [KO:K11253]
112064343  [KO:K11251]
112064344  [KO:K11251]
112064346  [KO:K11252]
112064782  [KO:K04542]
112066479  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
112066563  GNGT2; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
112066902  [KO:K11251]
112067178  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
112067655  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
114483947  [KO:K04364]
114484194  [KO:K11253]
114484270  [KO:K11253]
114484271  [KO:K11254]
114484273  [KO:K11253]
114484675  [KO:K11251]
114485274  [KO:K11253]
129391322  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
129392645  [KO:K02183]
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
pcad04010  MAPK signaling pathway
pcad04728  Dopaminergic synapse
KO pathway
ko05034   

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