KEGG   PATHWAY: dle05034
Entry
dle05034                    Pathway                                
Name
Alcoholism - Delphinapterus leucas (beluga 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
dle05034  Alcoholism
dle05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Delphinapterus leucas (beluga whale) [GN:dle]
Gene
111162931  [KO:K11253]
111163022  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
111163034  ADORA2A; adenosine receptor A2a [KO:K04266]
111163530  GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
111163963  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
111164170  [KO:K11253]
111164599  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
111164824  [KO:K06067] [EC:3.5.1.98]
111164829  [KO:K06067] [EC:3.5.1.98]
111165310  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
111165532  MAOB; amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:1.4.3.4]
111165554  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
111165559  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
111166195  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
111166309  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
111166488  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
111166674  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
111166783  GNG14; LOW QUALITY PROTEIN: putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
111166804  NTRK2; BDNF/NT-3 growth factors receptor isoform X2 [KO:K04360] [EC:2.7.10.1]
111166890  DRD2; D(2) dopamine receptor [KO:K04145]
111167062  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
111167181  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
111167415  [KO:K11251]
111167641  SHC3; SHC-transforming protein 3 [KO:K17448]
111167746  ADORA2B; adenosine receptor A2b isoform X1 [KO:K04267]
111167944  [KO:K11253]
111168441  [KO:K11253]
111168442  [KO:K11251]
111168443  [KO:K11251]
111168444  [KO:K11251]
111168445  [KO:K11252]
111168446  [KO:K11252]
111168448  [KO:K11252]
111168449  [KO:K11252]
111168460  [KO:K11252]
111168481  [KO:K11253]
111168485  [KO:K11253]
111168512  [KO:K11251]
111168514  [KO:K11251]
111168515  [KO:K11253]
111168516  [KO:K11253]
111168517  [KO:K11251]
111168518  [KO:K11252]
111168519  [KO:K11251]
111168520  [KO:K11251]
111168521  [KO:K11251]
111168523  [KO:K11252]
111168524  [KO:K11252]
111168525  [KO:K11252]
111168526  [KO:K11252]
111168527  [KO:K11252]
111168528  [KO:K11252]
111168529  [KO:K11252]
111168530  [KO:K11252]
111168535  [KO:K11254]
111168539  [KO:K11253]
111168543  [KO:K11253]
111168544  [KO:K11252]
111168549  [KO:K11252]
111168550  [KO:K11251]
111168809  HDAC11; histone deacetylase 11 isoform X2 [KO:K11418] [EC:3.5.1.98]
111168973  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
111168991  SLC18A1; chromaffin granule amine transporter [KO:K08155]
111169299  [KO:K11253]
111169314  [KO:K11251]
111169315  [KO:K11252]
111169522  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
111169704  [KO:K11253]
111169736  [KO:K11252]
111169737  [KO:K11253]
111169747  [KO:K11251]
111169748  [KO:K11251]
111169749  [KO:K11252]
111170127  [KO:K02183]
111170186  HDAC5; histone deacetylase 5 isoform X2 [KO:K11406] [EC:3.5.1.98]
111170340  HRAS; GTPase HRas isoform X1 [KO:K02833]
111170444  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
111170472  GRIN3B; glutamate receptor ionotropic, NMDA 3B isoform X1 [KO:K05214]
111170483  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
111170741  [KO:K11251]
111170918  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
111170946  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
111171120  [KO:K11252]
111171154  [KO:K11251]
111171155  [KO:K11252]
111171291  [KO:K11253]
111171650  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
111171769  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
111171987  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
111172270  SLC18A2; synaptic vesicular amine transporter isoform X1 [KO:K08155]
111172865  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
111172890  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
111173161  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
111173177  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
111173318  [KO:K11253]
111173828  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
111174072  HDAC7; histone deacetylase 7 isoform X2 [KO:K11408] [EC:3.5.1.98]
111174368  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
111174794  CALM2; calmodulin-2 [KO:K02183]
111174855  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
111174925  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
111175514  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
111176162  CALM1; calmodulin-1 [KO:K02183]
111176690  [KO:K07825]
111176694  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
111176743  [KO:K11252]
111176787  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
111176794  [KO:K11251]
111176851  KRAS; GTPase KRas [KO:K07827]
111176991  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
111177332  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
111177525  [KO:K11253]
111177624  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
111177653  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
111177745  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
111177758  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
111177962  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
111178375  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
111178380  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
111178437  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
111178539  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
111178870  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
111179105  [KO:K11251]
111179820  BDNF; LOW QUALITY PROTEIN: brain-derived neurotrophic factor [KO:K04355]
111179996  NRAS; GTPase NRas [KO:K07828]
111180070  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
111180225  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
111180666  GRIN2D; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2D [KO:K05212]
111180709  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
111180711  CALM3; calmodulin-3 [KO:K02183]
111180737  FOSB; protein fosB isoform X1 [KO:K09029]
111181049  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
111181617  SHC4; SHC-transforming protein 4 [KO:K17449]
111181827  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
111181977  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
111182181  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
111182462  [KO:K11251]
111182816  [KO:K11253]
111182833  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
111182859  GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
111182990  NPY; pro-neuropeptide Y [KO:K05232]
111183021  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
111183022  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
111183465  [KO:K11251]
111183483  SLC29A3; equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
111183676  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
111183709  SLC29A2; equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
111183716  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
111183856  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
111183987  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
111184074  TH; tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
111184364  PDYN; proenkephalin-B [KO:K15840]
111184525  [KO:K11251]
111184555  DDC; aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:4.1.1.28 4.1.1.105]
111185128  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
111185456  DRD1; D(1A) dopamine receptor [KO:K04144]
111185582  CRH; corticoliberin [KO:K05256]
111185899  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
111186212  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X1 [KO:K04374]
111186360  HDAC10; polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
111186741  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
111186746  [KO:K04632]
111186858  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
111186906  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
111187055  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
111187200  CALML6; calmodulin-like protein 6 [KO:K02183]
111188007  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
111188066  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
115802015  [KO:K11253]
115802482  [KO:K11253]
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
dle04010  MAPK signaling pathway
dle04728  Dopaminergic synapse
KO pathway
ko05034   

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