KEGG   PATHWAY: ncar05034
Entry
ncar05034                   Pathway                                
Name
Alcoholism - Sciurus carolinensis (gray squirrel)
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
ncar05034  Alcoholism
ncar05034

Other DBs
GO: 0045471
Organism
Sciurus carolinensis (gray squirrel) [GN:ncar]
Gene
124958984  tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
124990854  aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:4.1.1.28 4.1.1.105]
124984605  synaptic vesicular amine transporter [KO:K08155]
124983739  chromaffin granule amine transporter-like [KO:K08155]
124971911  amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
124972466  LOW QUALITY PROTEIN: amine oxidase [flavin-containing] A-like [KO:K00274] [EC:1.4.3.4]
124987217  sodium-dependent dopamine transporter [KO:K05036]
124964369  glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
124970656  LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2A-like [KO:K05209]
124983215  glutamate receptor ionotropic, NMDA 2B [KO:K05210]
124979849  glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
124966828  glutamate receptor ionotropic, NMDA 2D [KO:K05212]
124963937  glutamate receptor ionotropic, NMDA 3A [KO:K05213]
124968675  glutamate receptor ionotropic, NMDA 3B-like [KO:K05214]
124988795  histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
124960595  histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
124992800  LOW QUALITY PROTEIN: histone deacetylase 3-like [KO:K11404] [EC:3.5.1.98]
124986785  histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
124979133  histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
124979663  histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
124972407  LOW QUALITY PROTEIN: histone deacetylase 6-like [KO:K11407] [EC:3.5.1.98]
124982548  histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
124972184  histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
124990268  histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
124982437  polyamine deacetylase HDAC10-like isoform X1 [KO:K18671] [EC:3.5.1.98]
124971047  histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
124986554  core histone macro-H2A.1 isoform X1 [KO:K11251]
124958840  histone H2AX [KO:K11251]
124992932  histone H2A type 2-B [KO:K11251]
124992938  histone H2A type 2-C [KO:K11251]
124994795  histone H2A.V-like [KO:K11251]
124995056  histone H2A.Z [KO:K11251]
124988074  histone H2A type 1-A-like [KO:K11251]
124988098  histone H2A type 1-C [KO:K11251]
124988099  histone H2A type 1-B [KO:K11251]
124988100  histone H2A type 1-B [KO:K11251]
124988101  histone H2A type 1-B [KO:K11251]
124988124  histone H2A type 1-H-like [KO:K11251]
124988209  histone H2A type 1-E [KO:K11251]
124988210  histone H2A type 1-E [KO:K11251]
124988211  histone H2A type 1-E-like [KO:K11251]
124988212  histone H2A type 1-E [KO:K11251]
124988213  histone H2A type 1 [KO:K11251]
124988214  histone H2A type 1-J [KO:K11251]
124988215  histone H2A type 1-J [KO:K11251]
124988532  histone H2A.V-like isoform X1 [KO:K11251]
124989477  histone H2A type 1-like [KO:K11251]
124990207  histone H2A.V [KO:K11251]
124959587  histone H2A.V-like [KO:K11251]
124985130  core histone macro-H2A.2 [KO:K11251]
124979208  histone H2A type 2-A [KO:K11251]
124979213  histone H2A type 2-A [KO:K11251]
124971727  histone H2A-Bbd type 2/3-like [KO:K11251]
124971733  histone H2A-Bbd type 2/3-like [KO:K11251]
124972606  histone H2A-Bbd type 2/3-like [KO:K11251]
124973190  histone H2A.Z-like [KO:K11251]
124973336  histone H2A.V-like [KO:K11251]
124975089  histone H2A type 3 [KO:K11251]
124983655  histone H2A.J [KO:K11251]
124971420  histone H2A-Bbd type 1-like [KO:K11251]
124986632  histone H2B subacrosomal variant-like [KO:K11252]
124988075  histone H2B type 1-A [KO:K11252]
124988102  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988103  histone H2B type 1-M-like [KO:K11252]
124988104  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988105  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988106  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988107  histone H2B type 1-B-like [KO:K11252]
124988123  histone H2B type 1-C/E/F/G/I-like isoform X1 [KO:K11252]
124988125  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988216  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988217  histone H2B type 1-C/E/F/G/I [KO:K11252]
124988219  histone H2B type 1-K [KO:K11252]
124988220  histone H2B type 1-K [KO:K11252]
124988221  histone H2B type 1-K [KO:K11252]
124988222  histone H2B type 1-K-like [KO:K11252]
124989435  late histone H2B.L4-like [KO:K11252]
124990563  histone H2B type 2-K1-like [KO:K11252]
124979222  histone H2B type 2-E [KO:K11252]
124979224  histone H2B type 2-F [KO:K11252]
124979226  histone H2B type 2-E [KO:K11252]
124971584  late histone H2B.L4-like [KO:K11252]
124971587  histone H2B-like [KO:K11252]
124971589  histone H2B-like [KO:K11252]
124971590  late histone H2B.L4-like [KO:K11252]
124971592  late histone H2B.L4-like [KO:K11252]
124971593  histone H2B-like [KO:K11252]
124964446  histone H2B type 2-E [KO:K11252]
124975090  histone H2B type 3-B [KO:K11252]
124975096  H2B.U histone 2 [KO:K11252]
124985795  histone H3.3A-like [KO:K11253]
124987349  histone H3.3A-like [KO:K11253]
124988128  histone H3.1-like [KO:K11253]
124988205  histone H3.1-like [KO:K11253]
124988206  histone H3.1 [KO:K11253]
124988208  histone H3.1 [KO:K11253]
124988559  histone H3.1 [KO:K11253]
124991216  histone H3.3A-like [KO:K11253]
124984693  histone H3.3A-like [KO:K11253]
124961536  histone H3.3A [KO:K11253]
124970608  histone H3.3A-like [KO:K11253]
124964422  histone H3.3A-like [KO:K11253]
124965647  histone H3.3A-like [KO:K11253]
124975622  histone H3.3A-like [KO:K11253]
124979254  histone H3 [KO:K11253]
124988094  histone H3 [KO:K11253]
124988095  histone H3 [KO:K11253]
124988097  histone H3 [KO:K11253]
124979127  histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
124987160  LOW QUALITY PROTEIN: D(1A) dopamine receptor-like [KO:K04144]
124978161  neuroendocrine secretory protein 55 [KO:K04632]
124975134  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
124959858  D(2) dopamine receptor [KO:K04145]
124992673  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
124988012  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
124991078  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
124967520  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
124976089  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
124969987  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
124993231  guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
124978030  guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
124960444  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
124961969  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
124978139  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
124961463  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
124961876  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
124965653  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
124968657  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
124967414  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
124970655  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
124964520  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
124975713  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
124991054  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
124993726  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
124969192  putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
124990131  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
124980134  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X1 [KO:K04549]
124989511  equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
124984359  equilibrative nucleoside transporter 3-like isoform X1 [KO:K15014]
124960466  equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
124990229  LOW QUALITY PROTEIN: adenosine receptor A2a-like [KO:K04266]
124980873  adenosine receptor A2b [KO:K04267]
124992559  adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
124985819  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
124969119  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
124979032  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
124979831  LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2-like [KO:K04450]
124984025  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
124991113  cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
124958938  cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
124984689  cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
124969564  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
124964377  cyclic AMP-responsive element-binding protein 3-like isoform X1 [KO:K09048]
124991182  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
124988573  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
124962701  corticoliberin-like [KO:K05256]
124991809  pro-neuropeptide Y [KO:K05232]
124964245  BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
124982298  SHC-transforming protein 1 isoform X1 [KO:K06279]
124975378  SHC-transforming protein 2-like [KO:K17447]
124965516  SHC-transforming protein 3 isoform X1 [KO:K17448]
124978227  SHC-transforming protein 4 [KO:K17449]
124980188  growth factor receptor-bound protein 2 [KO:K04364]
124977045  son of sevenless homolog 2 [KO:K03099]
124963384  son of sevenless homolog 1 isoform X1 [KO:K03099]
124974041  LOW QUALITY PROTEIN: son of sevenless homolog 2-like [KO:K03099]
124958599  GTPase HRas isoform X1 [KO:K02833]
124991017  GTPase KRas-like [KO:K07827]
124982118  GTPase KRas isoform X1 [KO:K07827]
124962389  GTPase NRas [KO:K07828]
124971762  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
124990234  LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf-like [KO:K04365] [EC:2.7.11.1]
124971006  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
124977990  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
124990635  LOW QUALITY PROTEIN: mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
124970294  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
124971818  proenkephalin-B-like [KO:K15840]
124976834  LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
124967357  calmodulin-1 [KO:K02183]
124967948  calmodulin-like protein 6 [KO:K02183]
124962006  calmodulin-like [KO:K02183]
124962112  calmodulin-A-like [KO:K02183]
124962222  calmodulin-like protein 3 [KO:K02183]
124963056  calmodulin-1 [KO:K02183]
124976085  calmodulin-1 [KO:K02183]
124979083  calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
124990307  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
124987181  calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
124967280  protein FosB isoform X1 [KO:K09029]
124981061  protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
124991738  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
124960013  serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
124963007  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
124963034  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
ncar04010  MAPK signaling pathway
ncar04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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