KEGG   PATHWAY: efus05034
Entry
efus05034                   Pathway                                
Name
Alcoholism - Eptesicus fuscus (big brown bat)
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
efus05034  Alcoholism
efus05034

Other DBs
GO: 0045471
Organism
Eptesicus fuscus (big brown bat) [GN:efus]
Gene
103303267  TH; tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
103294197  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
103288590  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
103299499  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
103296426  MAOB; amine oxidase [flavin-containing] B isoform X1 [KO:K00274] [EC:1.4.3.4]
103296427  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
103305117  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
103295972  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
103286119  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
129149821  glutamate receptor ionotropic, NMDA 2B [KO:K05210]
103298309  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
103297786  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
103286379  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
103294432  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
103300141  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
103303280  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
103293384  LOW QUALITY PROTEIN: histone deacetylase 1-like [KO:K06067] [EC:3.5.1.98]
103285668  HDAC3; histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
103293040  HDAC5; histone deacetylase 5 isoform X3 [KO:K11406] [EC:3.5.1.98]
103283239  HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
103301287  HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
103285232  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
103285834  histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
103300732  HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
103292188  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
103298706  HDAC10; polyamine deacetylase HDAC10 isoform X3 [KO:K18671] [EC:3.5.1.98]
103301567  HDAC11; histone deacetylase 11 isoform X3 [KO:K11418] [EC:3.5.1.98]
103285110  histone H2A.J [KO:K11251]
103286545  core histone macro-H2A.1 isoform X1 [KO:K11251]
103289503  core histone macro-H2A.2 [KO:K11251]
103291108  histone H2A type 1 [KO:K11251]
103293719  histone H2AX [KO:K11251]
103298952  histone H2A type 2-C [KO:K11251]
103299794  histone H2A.Z [KO:K11251]
103304022  histone H2A type 1-H-like [KO:K11251]
103304828  histone H2A-Bbd type 2/3-like [KO:K11251]
129147936  histone H2A type 1-H-like [KO:K11251]
129147937  histone H2A type 1-like [KO:K11251]
129147941  histone H2A type 1 [KO:K11251]
129147942  histone H2A type 1 [KO:K11251]
103291093  histone H2A type 1-D [KO:K11251]
129147943  histone H2A type 1 [KO:K11251]
129147944  histone H2A type 1 [KO:K11251]
103291102  histone H2A type 1 [KO:K11251]
103304027  histone H2A type 1-like [KO:K11251]
129147954  histone H2A type 1 [KO:K11251]
103303598  histone H2A.V isoform X1 [KO:K11251]
129148535  histone H2A-Bbd type 2/3 [KO:K11251]
129149626  histone H2A-Bbd type 2/3-like [KO:K11251]
129147865  histone H2A type 2-A [KO:K11251]
129147866  histone H2A type 2-A [KO:K11251]
103291092  histone H2B type 1-C/E/F/G/I [KO:K11252]
103291096  histone H2B type 1-C/E/F/G/I [KO:K11252]
103291097  histone H2B type 1-C/E/F/G/I-like [KO:K11252]
103291110  histone H2B type 1-A [KO:K11252]
103298950  histone H2B type 2-E [KO:K11252]
103305335  histone H2B subacrosomal variant-like [KO:K11252]
103298948  histone H2B type 2-F isoform X1 [KO:K11252]
114228786  histone H2B type 2-K1 [KO:K11252]
103304023  histone H2B type 1-C/E/F/G/I [KO:K11252]
129147070  histone H2B type 1-C/E/F/G/I [KO:K11252]
129147945  histone H2B type 1-C/E/F/G/I [KO:K11252]
129147946  histone H2B type 1-C/E/F/G/I [KO:K11252]
129147947  histone H2B type 1-C/E/F/G/I [KO:K11252]
129147948  histone H2B type 1-C/E/F/G/I [KO:K11252]
129147949  histone H2B type 1-C/E/F/G/I-like [KO:K11252]
114233575  histone H2B type 1-M-like [KO:K11252]
129147950  histone H2B type 1-B-like [KO:K11252]
103291109  histone H2B type 1-A-like [KO:K11252]
129147867  histone H2B type 2-E [KO:K11252]
129147868  histone H2B type 2-E [KO:K11252]
129147878  histone H2B type 1-C/E/F/G/I [KO:K11252]
103291198  histone H3.3A-like [KO:K11253]
103298279  histone H3.3A [KO:K11253]
129147938  histone H3.1 [KO:K11253]
129147939  histone H3.1 [KO:K11253]
129147940  histone H3.1 [KO:K11253]
103291094  uncharacterized protein LOC103291094 [KO:K11253]
103293443  histone H3.3A [KO:K11253]
129147863  histone H3 isoform X1 [KO:K11253]
103283317  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
103291538  DRD1; D(1A) dopamine receptor [KO:K04144]
103285782  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X4 [KO:K04632]
103285922  neuroendocrine secretory protein 55-like [KO:K04632]
103293788  DRD2; D(2) dopamine receptor isoform X2 [KO:K04145]
103291154  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
103293295  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
103298642  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
103295848  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X3 [KO:K04534]
103295279  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform X3 [KO:K04536]
103285992  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
103289027  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
103286752  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
103287561  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
103283745  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
103303734  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X1 [KO:K04540]
103293513  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
103284162  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
103286474  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103299657  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103297851  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103292609  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
129150929  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
103294263  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
114227350  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
103286557  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
103292756  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
103301022  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
103284108  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
103300750  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
114234933  guanine nucleotide-binding protein G(T) subunit gamma-T1-like [KO:K04548]
103297082  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
103290955  SLC29A2; equilibrative nucleoside transporter 2 isoform X2 [KO:K15014]
103296622  SLC29A1; equilibrative nucleoside transporter 1 [KO:K15014]
103289589  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
103300381  ADORA2A; adenosine receptor A2a [KO:K04266]
103299369  ADORA2B; adenosine receptor A2b [KO:K04267]
103298761  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
103300989  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X2 [KO:K04345] [EC:2.7.11.11]
103284158  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103289363  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
103283488  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
103288848  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
103286442  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
103290849  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
103294106  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
103298930  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
103294228  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
103291632  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
103300452  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
103293970  CRH; corticoliberin isoform X2 [KO:K05256]
103291908  NPY; pro-neuropeptide Y [KO:K05232]
103292699  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
103286498  NTRK2; BDNF/NT-3 growth factors receptor [KO:K04360] [EC:2.7.10.1]
103298913  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
103294446  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
103297925  SHC3; SHC-transforming protein 3 [KO:K17448]
103287410  SHC4; SHC-transforming protein 4 [KO:K17449]
103298291  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
103283761  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
103305666  SOS1; son of sevenless homolog 1 [KO:K03099]
103302548  HRAS; GTPase HRas isoform X1 [KO:K02833]
103285154  KRAS; GTPase KRas isoform X1 [KO:K07827]
103291212  NRAS; GTPase NRas [KO:K07828]
103296401  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
103294085  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
103295757  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
103283794  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
103287001  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
103296283  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103285610  PDYN; proenkephalin-B isoform X2 [KO:K15840]
103292236  CALM1; calmodulin-1 isoform X2 [KO:K02183]
103298572  CALML5; calmodulin-like protein 5 [KO:K02183]
103304916  calmodulin-1-like [KO:K02183]
103305414  CALM2; calmodulin-2 [KO:K02183]
103297693  CALM3; calmodulin-3 isoform X1 [KO:K02183]
103298573  calmodulin-like protein 3 [KO:K02183]
103293186  calmodulin-1-like [KO:K02183]
129148572  calmodulin-1-like [KO:K02183]
103283955  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
129150189  CALML6; calmodulin-like protein 6 [KO:K02183]
103299891  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
103287031  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
103288726  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
103301383  FOSB; protein FosB isoform X1 [KO:K09029]
103297138  PPP1R1B; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
103287049  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X2 [KO:K06269] [EC:3.1.3.16]
103290927  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
103297381  serine/threonine-protein phosphatase PP1-gamma catalytic subunit B-like isoform X2 [KO:K06269] [EC:3.1.3.16]
103305499  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
103283859  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
efus04010  MAPK signaling pathway
efus04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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