KEGG   PATHWAY: uar05034
Entry
uar05034                    Pathway                                
Name
Alcoholism - Ursus americanus (American black bear)
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
uar05034  Alcoholism
uar05034

Other DBs
GO: 0045471
Organism
Ursus americanus (American black bear) [GN:uar]
Gene
123775491  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
123786262  DDC; aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:4.1.1.28 4.1.1.105]
123795992  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
123789908  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
123786636  LOW QUALITY PROTEIN: amine oxidase [flavin-containing] B-like [KO:K00274] [EC:1.4.3.4]
123786638  amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
123799122  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
123796318  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
123783633  GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
123781746  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
123803192  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
123776356  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
123781021  GRIN3A; glutamate receptor ionotropic, NMDA 3A isoform X1 [KO:K05213]
123793962  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
123792970  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
123782225  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
123790221  HDAC3; histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
123803228  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
123790010  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
123790885  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
123794809  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
123791742  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
123789200  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
123803774  HDAC10; polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
123802026  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
123792645  histone H2AX [KO:K11251]
123786649  histone H2A-Bbd type 2/3-like [KO:K11251]
123786650  LOW QUALITY PROTEIN: histone H2A-Bbd type 2/3-like [KO:K11251]
123786663  histone H2A-Bbd type 2/3 [KO:K11251]
123794128  histone H2A type 1 [KO:K11251]
123794155  LOW QUALITY PROTEIN: histone H2A type 1-A [KO:K11251]
123794176  histone H2A type 1 [KO:K11251]
123794177  histone H2A type 1-E [KO:K11251]
123794178  histone H2A type 1 [KO:K11251]
123794180  histone H2A type 1 [KO:K11251]
123794181  histone H2A type 1-E-like [KO:K11251]
123794182  histone H2A type 1-H [KO:K11251]
123794216  histone H2A type 1-B-like [KO:K11251]
123794217  histone H2A type 1-C [KO:K11251]
123794218  histone H2A type 1-E [KO:K11251]
123794219  histone H2A type 1-B [KO:K11251]
123794220  histone H2A type 1-B [KO:K11251]
123794221  histone H2A type 1-D-like [KO:K11251]
123794243  histone H2A type 1-H-like [KO:K11251]
123787645  histone H2A-Bbd type 1-like [KO:K11251]
123781754  histone H2A.J [KO:K11251]
123788846  histone H2A.Z [KO:K11251]
123796492  LOW QUALITY PROTEIN: histone H2A type 1-H [KO:K11251]
123789471  histone H2A.V [KO:K11251]
123782934  core histone macro-H2A.2 [KO:K11251]
123790332  core histone macro-H2A.1 isoform X1 [KO:K11251]
123778388  histone H2A-Bbd type 1-like [KO:K11251]
123779208  histone H2A type 2-B [KO:K11251]
123779209  histone H2A type 2-C [KO:K11251]
123779211  histone H2A type 2-A [KO:K11251]
123779213  histone H2A type 2-A [KO:K11251]
123797232  histone H2A-like [KO:K11251]
123800260  histone H2B subacrosomal variant-like [KO:K11252]
123794127  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794183  histone H2B type 1-K [KO:K11252]
123794184  histone H2B type 1-J [KO:K11252]
123794185  histone H2B type 1-K [KO:K11252]
123794187  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794188  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794189  histone H2B type 1-N [KO:K11252]
123794190  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794192  histone H2B type 1-C/E/F/G/I-like [KO:K11252]
123794222  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794223  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794225  histone H2B type 1-M-like [KO:K11252]
123794226  histone H2B type 2-E-like [KO:K11252]
123794227  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794228  histone H2B type 1-C/E/F/G/I [KO:K11252]
123794229  histone H2B type 1-B [KO:K11252]
123794230  histone H2B type 1-L [KO:K11252]
123794244  histone H2B type 1-A [KO:K11252]
123794245  histone H2B type 1-A [KO:K11252]
123780463  late histone H2B.L4-like [KO:K11252]
123780471  late histone H2B.L4-like [KO:K11252]
123787926  late histone H2B.L4-like [KO:K11252]
123796494  histone H2B type 3-B-like [KO:K11252]
123796496  histone H2B type 3-B [KO:K11252]
123779210  histone H2B type 2-E [KO:K11252]
123779214  histone H2B type 2-E [KO:K11252]
123779215  histone H2B type 2-E [KO:K11252]
123779216  histone H2B type 2-F-like [KO:K11252]
123776190  late histone H2B.L4-like [KO:K11252]
123776191  late histone H2B.L4-like [KO:K11252]
123794147  histone H3.1-like [KO:K11253]
123794175  histone H3.1 [KO:K11253]
123794199  histone H3.1 [KO:K11253]
123794212  uncharacterized protein LOC123794212 [KO:K11253]
123794213  histone H3.1 [KO:K11253]
123794215  histone H3.1 [KO:K11253]
123794236  uncharacterized protein LOC123794236 [KO:K11253]
123803075  histone H3.3A [KO:K11253]
123796493  histone H3.1 [KO:K11253]
123789706  histone H3.3C-like [KO:K11253]
123791793  histone H3.3A isoform X1 [KO:K11253]
123779227  histone H3-like centromeric protein CSE4 [KO:K11253]
123779223  histone H3 [KO:K11253]
123779217  histone H4 [KO:K11254]
123781722  histone H4 [KO:K11254]
123794193  histone H4 [KO:K11254]
123794194  histone H4 [KO:K11254]
123794195  histone H4 [KO:K11254]
123794196  histone H4 [KO:K11254]
123794231  histone H4 [KO:K11254]
123794232  histone H4 [KO:K11254]
123794233  histone H4 [KO:K11254]
123780738  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
123796326  DRD1; D(1A) dopamine receptor [KO:K04144]
123803297  neuroendocrine secretory protein 55 [KO:K04632]
123803290  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas-like [KO:K04632]
123792366  DRD2; D(2) dopamine receptor [KO:K04145]
123795104  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
123789354  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
123798684  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
123798421  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
123796116  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
123777259  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
123781583  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
123786411  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
123801797  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
123800611  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
123789819  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
123783123  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
123787748  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
123795269  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
123793984  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
123778756  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
123803383  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
123776695  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
123789281  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
123795327  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
123777697  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
123783660  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
123789282  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
123802847  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
123795016  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
123782881  SLC29A3; LOW QUALITY PROTEIN: equilibrative nucleoside transporter 3 [KO:K15014]
123778469  SLC29A2; equilibrative nucleoside transporter 2 [KO:K15014]
123795611  ADORA2A; LOW QUALITY PROTEIN: adenosine receptor A2a [KO:K04266]
123779774  ADORA2B; adenosine receptor A2b [KO:K04267]
123802178  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
123801768  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
123795272  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
123798247  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
123794100  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
123780649  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
123799579  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
123781164  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
123788905  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
123796787  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
123783374  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
123789128  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
123790975  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
123786694  CRH; corticoliberin [KO:K05256]
123789581  NPY; pro-neuropeptide Y [KO:K05232]
123799466  BDNF; brain-derived neurotrophic factor [KO:K04355]
123781399  BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
123783413  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
123794070  LOW QUALITY PROTEIN: SHC-transforming protein 2-like [KO:K17447]
123776524  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
123801854  SHC4; SHC-transforming protein 4 [KO:K17449]
123802938  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
123799809  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
123793291  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
123775506  HRAS; GTPase HRas isoform X1 [KO:K02833]
123801699  KRAS; GTPase KRas isoform X1 [KO:K07827]
123795037  NRAS; GTPase NRas [KO:K07828]
123786515  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
123788872  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
123802053  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
123800861  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
123795639  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
123784602  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
123800499  PDYN; proenkephalin-B [KO:K15840]
123785908  CALM2; calmodulin-2 [KO:K02183]
123800842  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
123802291  calmodulin-like [KO:K02183]
123802321  CALML3; calmodulin-like protein 3 [KO:K02183]
123796079  CALML6; calmodulin-like protein 6 [KO:K02183]
123798898  CALM1; calmodulin-1 [KO:K02183]
123778741  CALM3; calmodulin-3 [KO:K02183]
123777017  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
123779287  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
123779312  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
123800024  FOSB; LOW QUALITY PROTEIN: protein fosB [KO:K09029]
123779548  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
123799882  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
123795174  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
123778467  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
123779126  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
123797946  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X1 [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
uar04010  MAPK signaling pathway
uar04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

DBGET integrated database retrieval system