KEGG   PATHWAY: ocu05034
Entry
ocu05034                    Pathway                                
Name
Alcoholism - Oryctolagus cuniculus (rabbit)
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
ocu05034  Alcoholism
ocu05034

Other DBs
GO: 0045471
Organism
Oryctolagus cuniculus (rabbit) [GN:ocu]
Gene
100355492  aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
100340936  chromaffin granule amine transporter [KO:K08155]
100351780  synaptic vesicular amine transporter [KO:K08155]
100357007  amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
100345623  amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
127486893  glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
100337889  glutamate receptor ionotropic, NMDA 2A [KO:K05209]
100353266  glutamate receptor ionotropic, NMDA 2B isoform X1 [KO:K05210]
100356338  glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
103346363  LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2D [KO:K05212]
100343526  glutamate receptor ionotropic, NMDA 3A [KO:K05213]
127489904  glutamate receptor ionotropic, NMDA 3B isoform X1 [KO:K05214]
100355156  histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
100354595  histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
100338458  histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
100358981  histone deacetylase 5 isoform X2 [KO:K11406] [EC:3.5.1.98]
103347301  histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
100354982  histone deacetylase 6 isoform X2 [KO:K11407] [EC:3.5.1.98]
103345620  nucleolar complex protein 4 homolog isoform X1 [KO:K11407] [EC:3.5.1.98]
100355860  histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
100352038  histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
100345764  histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
100352120  polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
100352253  histone deacetylase 11 isoform X6 [KO:K11418] [EC:3.5.1.98]
100358742  histone H2AX [KO:K11251]
100344695  histone H2A type 1-H [KO:K11251]
103345138  histone H2A type 1 [KO:K11251]
100345205  histone H2A type 1 [KO:K11251]
100347019  histone H2A type 1-H [KO:K11251]
100346499  histone H2A type 1 [KO:K11251]
100347535  histone H2A type 1 [KO:K11251]
100348415  histone H2A.Z [KO:K11251]
100328558  H2AZ2; histone H2A.V [KO:K11251]
100341677  core histone macro-H2A.1 isoform X1 [KO:K11251]
100350997  histone H2A.J [KO:K11251]
100338182  histone H2A-Bbd type 1 [KO:K11251]
100340697  histone H2A-Bbd type 1-like [KO:K11251]
100357425  histone H2A-Bbd type 1 [KO:K11251]
103351788  histone H2A-Bbd type 1 [KO:K11251]
100350918  histone H2A type 2-B [KO:K11251]
100357913  histone H2A type 2-C [KO:K11251]
100353691  histone H2A type 2-A [KO:K11251]
100342635  histone H2A type 1-E [KO:K11251]
100348485  histone H2A type 1-E [KO:K11251]
100348744  histone H2A type 1-B [KO:K11251]
100346975  histone H2A type 1-C [KO:K11251]
100345939  histone H2A type 1-E [KO:K11251]
100345168  histone H2A type 1-B [KO:K11251]
100344660  histone H2A type 1-E [KO:K11251]
100350091  histone H2A type 1-A [KO:K11251]
100343925  core histone macro-H2A.2 [KO:K11251]
127490210  histone H2A type 3 [KO:K11251]
100350750  histone H2B type 1-A [KO:K11252]
100342662  histone H2B subacrosomal variant [KO:K11252]
100344442  histone H2B type 1-H [KO:K11252]
100344952  histone H2B type 1-C/E/F/G/I [KO:K11252]
100343938  histone H2B type 1-H [KO:K11252]
100346241  histone H2B type 1-C/E/F/G/I [KO:K11252]
100347785  histone H2B type 1-C/E/F/G/I [KO:K11252]
100353468  late histone H2B.L4 [KO:K11252]
100352707  late histone H2B.L4 [KO:K11252]
103351930  histone H2B type F-M-like [KO:K11252]
100351672  histone H2B type 2-E [KO:K11252]
100355462  histone H2B type 2-F [KO:K11252]
100343141  histone H2B type 1-C/E/F/G/I [KO:K11252]
100342379  histone H2B type 1-C/E/F/G/I [KO:K11252]
103349694  histone H2B type 1-B [KO:K11252]
100347239  histone H2B type 1-C/E/F/G/I [KO:K11252]
100346716  histone H2B type 1-H [KO:K11252]
100344914  histone H2B type 1-C/E/F/G/I [KO:K11252]
100348578  histone H2B type 1-C/E/F/G/I [KO:K11252]
100352266  histone H2B type 2-K1 [KO:K11252]
108176081  H2B.U histone 2 [KO:K11252]
100346201  histone H2B type 1-C/E/F/G/I [KO:K11252]
127490211  histone H2B type 3-B [KO:K11252]
100343399  histone H3.1 [KO:K11253]
100328923  H3-3A; histone H3.3 [KO:K11253]
100353127  uncharacterized protein LOC100353127 [KO:K11253]
100341225  histone H3.3A [KO:K11253]
100346558  histone H3.3A [KO:K11253]
103350067  LOW QUALITY PROTEIN: histone H3 [KO:K11253]
100357927  histone H3.3A-like [KO:K11253]
100345683  histone H3.1 [KO:K11253]
100345425  histone H3.1 [KO:K11253]
100344410  histone H3.1 [KO:K11253]
100354792  histone H3.3A-like [KO:K11253]
100354195  histone H3.v1 [KO:K11253]
100347117  H3-4; histone H3.1 [KO:K11253]
100341005  histone H3.3A-like [KO:K11253]
100349246  histone H3.1 [KO:K11253]
100354620  histone H3-like [KO:K11253]
127490226  histone H3.3A [KO:K11253]
100344192  histone H4 [KO:K11254]
100346758  histone H3.1 [KO:K11254]
100345719  LOW QUALITY PROTEIN: histone H4 [KO:K11254]
100351746  LOW QUALITY PROTEIN: histone H4 [KO:K11254]
100340438  histone H4-like [KO:K11254]
100353786  histone H4-like [KO:K11254]
100354956  histone H4 [KO:K11254]
100340305  histone H4 [KO:K11254]
100343903  histone H4 [KO:K11254]
100349756  histone H4 [KO:K11254]
100347744  histone H4 [KO:K11254]
100346459  histone H4 [KO:K11254]
100352498  histone H4-like [KO:K11254]
100347401  histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
100008915  DRD1; D(1A) dopamine receptor [KO:K04144]
100008904  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
100346323  neuroendocrine secretory protein 55 [KO:K04632]
100347371  D(2) dopamine receptor isoform X1 [KO:K04145]
100338391  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100359147  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100339066  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100342283  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100337783  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
127489280  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100356799  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100346625  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
100338332  guanine nucleotide-binding protein subunit beta-4 isoform X2 [KO:K04538]
100008941  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100352954  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100348350  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X2 [KO:K04540]
103350926  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
108178480  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
100355417  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
108177128  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100342201  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
108176185  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
103350153  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
127489712  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100342450  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
108178552  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100357908  equilibrative nucleoside transporter 1 [KO:K15014]
100009420  SLC29A2; equilibrative nucleoside transporter 2 [KO:K15014]
100338173  equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
100339944  adenosine receptor A2a [KO:K04266]
100008951  ADORA2B; adenosine receptor A2b [KO:K04267]
100009315  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100008815  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100342212  cAMP-dependent protein kinase catalytic subunit beta isoform X3 [KO:K04345] [EC:2.7.11.11]
100351999  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100355367  cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100339383  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100358175  cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100343130  cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X2 [KO:K09048]
100345475  cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100357876  cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100357483  cyclic AMP-responsive element-binding protein 5 isoform X3 [KO:K09047]
100357489  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
127493063  cyclic AMP-dependent transcription factor ATF-6 beta-like isoform X1 [KO:K09049]
100301553  CRH; corticoliberin precursor [KO:K05256]
100301542  NPY; neuropeptide Y precursor [KO:K05232]
100356949  LOW QUALITY PROTEIN: brain-derived neurotrophic factor [KO:K04355]
100352548  BDNF/NT-3 growth factors receptor isoform X2 [KO:K04360] [EC:2.7.10.1]
100342812  SHC-transforming protein 1 isoform X2 [KO:K06279]
100353992  SHC-transforming protein 3 isoform X2 [KO:K17448]
100350676  SHC-transforming protein 4 isoform X2 [KO:K17449]
100342500  growth factor receptor-bound protein 2 [KO:K04364]
100356615  son of sevenless homolog 1 isoform X1 [KO:K03099]
100346391  son of sevenless homolog 2 isoform X1 [KO:K03099]
127486605  GTPase HRas isoform X1 [KO:K02833]
100347487  GTPase KRas isoform X1 [KO:K07827]
127489236  GTPase KRas-like [KO:K07827]
100344241  GTPase NRas [KO:K07828]
100340437  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
100351964  serine/threonine-protein kinase B-raf isoform X6 [KO:K04365] [EC:2.7.11.1]
100347407  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100009316  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
127489461  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:2.7.12.2]
100347345  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100348561  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100341339  proenkephalin-B [KO:K15840]
103345165  LOW QUALITY PROTEIN: calmodulin-like protein 3 [KO:K02183]
100347856  calmodulin-like protein 3 [KO:K02183]
100354905  calmodulin-3 [KO:K02183]
100352392  CALM2; calmodulin [KO:K02183]
100350107  calmodulin-1 [KO:K02183]
100345526  calmodulin-like protein 4 isoform X1 [KO:K02183]
100350843  calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
100350689  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
127488422  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
103345118  calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
100355399  protein phosphatase 1 regulatory subunit 1B [KO:K15494]
100009587  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100009298  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100353054  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100343293  cAMP-dependent protein kinase inhibitor alpha isoform X3 [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
ocu04010  MAPK signaling pathway
ocu04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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