KEGG   PATHWAY: ko05034
Entry
ko05034                     Pathway                                

Name
Alcoholism
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
ko05034  Alcoholism
ko05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Orthology
K00501  tyrosine 3-monooxygenase [EC:1.14.16.2]
K01593  aromatic-L-amino-acid/L-tryptophan decarboxylase [EC:4.1.1.28 4.1.1.105]
K08155  MFS transporter, DHA1 family, solute carrier family 18 (vesicular amine transporter), member 1/2
K00274  monoamine oxidase [EC:1.4.3.4]
K05036  solute carrier family 6 (neurotransmitter transporter, dopamine) member 3
K05208  glutamate receptor ionotropic, NMDA 1
K05209  glutamate receptor ionotropic, NMDA 2A
K05210  glutamate receptor ionotropic, NMDA 2B
K05211  glutamate receptor ionotropic, NMDA 2C
K05212  glutamate receptor ionotropic, NMDA 2D
K05213  glutamate receptor ionotropic, NMDA 3A
K05214  glutamate receptor ionotropic, NMDA 3B
K06067  histone deacetylase 1/2 [EC:3.5.1.98]
K11404  histone deacetylase 3 [EC:3.5.1.98]
K11406  histone deacetylase 4/5 [EC:3.5.1.98]
K11407  histone deacetylase 6 [EC:3.5.1.98]
K11408  histone deacetylase 7 [EC:3.5.1.98]
K11405  histone deacetylase 8 [EC:3.5.1.98]
K11409  histone deacetylase 9 [EC:3.5.1.98]
K18671  histone deacetylase 10 [EC:3.5.1.98]
K11418  histone deacetylase 11 [EC:3.5.1.98]
K11251  histone H2A
K11252  histone H2B
K11253  histone H3
K11254  histone H4
K11303  histone acetyltransferase 1 [EC:2.3.1.48]
K04144  dopamine receptor D1
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K04145  dopamine receptor D2
K04630  guanine nucleotide-binding protein G(i) subunit alpha
K04534  guanine nucleotide-binding protein G(o) subunit alpha
K04536  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K07825  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K04538  guanine nucleotide-binding protein subunit beta-4
K04539  guanine nucleotide-binding protein subunit beta-5
K07826  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K04540  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04347  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04547  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548  guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K15014  solute carrier family 29 (equilibrative nucleoside transporter), member 1/2/3
K04266  adenosine receptor A2a
K04267  adenosine receptor A2b
K08045  adenylate cyclase 5 [EC:4.6.1.1]
K04345  protein kinase A [EC:2.7.11.11]
K05870  cyclic AMP-responsive element-binding protein 1
K04450  cyclic AMP-dependent transcription factor ATF-2
K04374  cyclic AMP-dependent transcription factor ATF-4
K09048  cyclic AMP-responsive element-binding protein 3
K09047  cyclic AMP-responsive element-binding protein 5
K09049  cyclic AMP-dependent transcription factor ATF-6 beta
K05256  corticotropin-releasing hormone
K05232  neuropeptide Y
K04355  brain-derived neurotrophic factor
K04360  neurotrophic tyrosine kinase receptor type 2 [EC:2.7.10.1]
K06279  SHC-transforming protein 1
K17447  SHC-transforming protein 2
K17448  SHC-transforming protein 3
K17449  SHC-transforming protein 4
K04364  growth factor receptor-binding protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K15840  proenkephalin B (prodynorphin)
K02183  calmodulin
K00908  calcium/calmodulin-dependent protein kinase kinase 1 [EC:2.7.11.17]
K07359  calcium/calmodulin-dependent protein kinase kinase 2 [EC:2.7.11.17]
K05869  calcium/calmodulin-dependent protein kinase IV [EC:2.7.11.17]
K09029  protein FosB
K15494  protein phosphatase 1 regulatory subunit 1B
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K15985  cAMP-dependent protein kinase inhibitor alpha
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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  Authors
Lovinger DM
  Title
NMDA receptors lose their inhibitions.
  Journal
Nat Neurosci 5:614-6 (2002)
DOI:10.1038/nn0702-614
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
ko04010  MAPK signaling pathway
ko04728  Dopaminergic synapse
LinkDB

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