KEGG   PATHWAY: tmu05034
Entry
tmu05034                    Pathway                                
Name
Alcoholism - Trichechus manatus latirostris (Florida manatee)
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
tmu05034  Alcoholism
tmu05034

Other DBs
GO: 0045471
Organism
Trichechus manatus latirostris (Florida manatee) [GN:tmu]
Gene
101347132  tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
101348227  aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
101351670  synaptic vesicular amine transporter isoform X1 [KO:K08155]
101346156  LOW QUALITY PROTEIN: chromaffin granule amine transporter [KO:K08155]
101360324  amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
101351235  amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
101341243  sodium-dependent dopamine transporter [KO:K05036]
101349517  glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
101353799  glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
101340402  glutamate receptor ionotropic, NMDA 2B [KO:K05210]
101355341  glutamate receptor ionotropic, NMDA 2C [KO:K05211]
101358510  glutamate receptor ionotropic, NMDA 2D [KO:K05212]
101355075  glutamate receptor ionotropic, NMDA 3A [KO:K05213]
101349451  LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 3B [KO:K05214]
101342476  histone deacetylase 2 isoform X1 [KO:K06067] [EC:3.5.1.98]
101357779  histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
101356648  histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
101352004  histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
101346948  histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
101347918  histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
101344245  histone deacetylase 7 isoform X2 [KO:K11408] [EC:3.5.1.98]
101343522  histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
101352452  histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
101347092  histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
101342448  histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
101348798  histone H2A.V [KO:K11251]
101344492  histone H2A type 3 [KO:K11251]
101357180  histone H2A type 2-B [KO:K11251]
101357936  histone H2A type 2-C-like [KO:K11251]
101344812  histone H2AX [KO:K11251]
101361644  histone H2A type 1 [KO:K11251]
101361903  histone H2A type 1-D [KO:K11251]
101340334  histone H2A type 1-H [KO:K11251]
101340592  histone H2A type 1 [KO:K11251]
101340859  histone H2A type 1-D [KO:K11251]
105756982  histone H2A-Bbd type 2/3 [KO:K11251]
101349824  histone H2A type 1-D [KO:K11251]
101350083  histone H2A type 1-D [KO:K11251]
101352393  histone H2A type 1-B/E [KO:K11251]
101352653  histone H2A type 1-B/E-like [KO:K11251]
101353937  histone H2A type 1-C [KO:K11251]
101355468  histone H2A type 1 [KO:K11251]
101353686  histone H2A-Bbd type 1-like [KO:K11251]
101348834  LOW QUALITY PROTEIN: histone H2A type 1-H [KO:K11251]
101349604  histone H2A type 1 isoform X1 [KO:K11251]
101346422  core histone macro-H2A.1 isoform X1 [KO:K11251]
101343723  histone H2A type 3-like [KO:K11251]
101341184  histone H2A.J [KO:K11251]
101357385  histone H2A.Z [KO:K11251]
101357246  core histone macro-H2A.2 [KO:K11251]
101361070  histone H2A-Bbd type 2/3-like [KO:K11251]
101358207  histone H2A-beta, sperm-like [KO:K11251]
101354080  histone H2A-Bbd type 1-like [KO:K11251]
101343981  histone H2B type 3-B-like [KO:K11252]
101344247  histone H2B type 3-B [KO:K11252]
101357429  histone H2B type 2-E [KO:K11252]
101358454  histone H2B type 2-F [KO:K11252]
101341109  histone H2B type 1-H [KO:K11252]
101341608  histone H2B type 1-F/J/L [KO:K11252]
101342368  histone H2B type 1-N-like [KO:K11252]
101342628  histone H2B type 1-J-like [KO:K11252]
101352913  histone H2B type 1 [KO:K11252]
101353177  histone H2B type 1-M [KO:K11252]
101353427  histone H2B type 1 [KO:K11252]
101353680  histone H2B type 1-H [KO:K11252]
101354453  histone H2B type 1 [KO:K11252]
101354703  histone H2B type 1-B [KO:K11252]
101355214  histone H2B type 1 [KO:K11252]
101355724  histone H2B type 1-like [KO:K11252]
101349091  histone H2B type 1-K [KO:K11252]
101349865  histone H2B type 1-J [KO:K11252]
101353949  histone H2B type 1-N [KO:K11252]
101361893  histone H2B type 1-A [KO:K11252]
101340322  histone H2B type 1-A-like [KO:K11252]
101341643  histone H2B subacrosomal variant-like [KO:K11252]
111822869  histone H2B type 1-A-like [KO:K11252]
101350587  histone H3.1-like [KO:K11253]
101344738  histone H3.1 [KO:K11253]
101357682  histone H3 [KO:K11253]
101358200  histone H3-like [KO:K11253]
101360146  histone H3.3-like [KO:K11253]
105756681  histone H3.1 [KO:K11253]
101353922  histone H3.3-like [KO:K11253]
101341098  histone H3.1-like [KO:K11253]
101357033  histone H3.3 [KO:K11253]
101354212  histone H3.1 [KO:K11253]
101345123  histone H3.3-like [KO:K11253]
101359098  histone H3.3 [KO:K11253]
101348538  histone H3.1 [KO:K11253]
111821397  histone H3.3-like [KO:K11253]
101349047  histone H3.1 [KO:K11253]
101348789  uncharacterized protein LOC101348789 [KO:K11253]
101343646  LOW QUALITY PROTEIN: uncharacterized protein LOC101343646 [KO:K11253]
101355988  histone H4 [KO:K11254]
101358177  histone H4 [KO:K11254]
111819284  histone H4 [KO:K11254]
111822625  LOW QUALITY PROTEIN: histone H4 [KO:K11254]
111821913  histone H4 [KO:K11254]
111821914  histone H4 [KO:K11254]
101343768  histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
101349260  D(1A) dopamine receptor [KO:K04144]
101361837  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas [KO:K04632]
101348142  neuroendocrine secretory protein 55 [KO:K04632]
101349901  D(2) dopamine receptor isoform X1 [KO:K04145]
101341952  guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
101346092  guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101343271  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101357613  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
101350742  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
101345319  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
101355136  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
101348280  guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
101341327  guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
101352593  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X1 [KO:K07826]
101342107  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
101357541  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
101345326  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
101347845  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 isoform X2 [KO:K04543]
111821467  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
111819711  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
101341777  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
101351188  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
111819060  putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
101351136  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
101342034  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
101360148  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
101342434  equilibrative nucleoside transporter 3 [KO:K15014]
101353936  equilibrative nucleoside transporter 2 [KO:K15014]
101343519  equilibrative nucleoside transporter 1 [KO:K15014]
101346688  adenosine receptor A2a [KO:K04266]
101358749  adenosine receptor A2b [KO:K04267]
101346041  adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101342638  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101348995  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101356881  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101359884  cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
101345357  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101355964  cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
101349137  cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101344337  cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
101344076  cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101352607  cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101345798  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
101359783  cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
101344702  corticoliberin [KO:K05256]
101360409  pro-neuropeptide Y [KO:K05232]
101350169  brain-derived neurotrophic factor isoform X1 [KO:K04355]
101342178  BDNF/NT-3 growth factors receptor isoform X5 [KO:K04360] [EC:2.7.10.1]
101358105  SHC-transforming protein 1 isoform X1 [KO:K06279]
101359726  SHC-transforming protein 2 [KO:K17447]
101360084  SHC-transforming protein 3 [KO:K17448]
101355900  SHC-transforming protein 4 [KO:K17449]
101359012  growth factor receptor-bound protein 2 [KO:K04364]
101359592  son of sevenless homolog 1 isoform X1 [KO:K03099]
101347392  son of sevenless homolog 2 isoform X1 [KO:K03099]
101342804  GTPase HRas isoform X2 [KO:K02833]
101347525  GTPase KRas isoform X3 [KO:K07827]
101344230  GTPase NRas isoform X1 [KO:K07828]
101351589  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101353421  serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
101357840  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101343332  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101340589  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101358526  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101361630  proenkephalin-B [KO:K15840]
101347126  calmodulin-2 isoform X2 [KO:K02183]
101361121  LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
101358846  LOW QUALITY PROTEIN: calmodulin-like protein 3 [KO:K02183]
101346240  calmodulin-3 [KO:K02183]
101358487  calmodulin [KO:K02183]
101346473  calmodulin-like protein 4 [KO:K02183]
101359111  calmodulin-like [KO:K02183]
101354334  calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
101347848  LOW QUALITY PROTEIN: calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
101343253  calcium/calmodulin-dependent protein kinase type IV isoform X3 [KO:K05869] [EC:2.7.11.17]
101355201  protein fosB [KO:K09029]
101353914  protein phosphatase 1 regulatory subunit 1B [KO:K15494]
101346316  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
101344889  serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
101345455  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
101343128  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
tmu04010  MAPK signaling pathway
tmu04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

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