KEGG   PATHWAY: pon05034Help
Entry
pon05034                    Pathway                                

Name
Alcoholism - Pongo abelii (Sumatran orangutan)
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
BRITE hierarchy
Pathway map
Alcoholism
pon05034

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BSID: 
GO: 
Organism
Pongo abelii (Sumatran orangutan) [GN:pon]
Gene
TH; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
DDC; dopa decarboxylase (aromatic L-amino acid decarboxylase) [KO:K01593] [EC:4.1.1.28]
chromaffin granule amine transporter-like; K08155 MFS transporter, DHA1 family, solute carrier family 18 (vesicular amine transporter), member 1/2 [KO:K08155]
SLC18A2; solute carrier family 18 (vesicular monoamine), member 2 [KO:K08155]
MAOA; monoamine oxidase A [KO:K00274] [EC:1.4.3.4]
MAOB; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
sodium-dependent dopamine transporter-like; K05036 solute carrier family 6 (neurotransmitter transporter, dopamine) member 3 [KO:K05036]
sodium-dependent dopamine transporter-like; K05036 solute carrier family 6 (neurotransmitter transporter, dopamine) member 3 [KO:K05036]
GRIN1; glutamate receptor, ionotropic, N-methyl D-aspartate 1 [KO:K05208]
GRIN2A; glutamate receptor, ionotropic, N-methyl D-aspartate 2A [KO:K05209]
GRIN2B; glutamate receptor, ionotropic, N-methyl D-aspartate 2B [KO:K05210]
GRIN2C; glutamate receptor, ionotropic, N-methyl D-aspartate 2C [KO:K05211]
GRIN3A; glutamate receptor, ionotropic, N-methyl-D-aspartate 3A [KO:K05213]
GRIN3B; glutamate receptor, ionotropic, N-methyl-D-aspartate 3B [KO:K05214]
HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
HDAC5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
histone deacetylase 4-like; K11406 histone deacetylase 4/5 [EC:3.5.1.98] [KO:K11406] [EC:3.5.1.98]
HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
HDAC10; histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
HDAC7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
HDAC9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
histone H2A type 1-like; K11251 histone H2A [KO:K11251]
histone H2A.J-like; K11251 histone H2A [KO:K11251]
histone H2A.Z-like; K11251 histone H2A [KO:K11251]
histone H2A type 2-A-like; K11251 histone H2A [KO:K11251]
H2AFZ; H2A histone family, member Z [KO:K11251]
histone H2A type 1-A-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-B/E-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-C-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-J-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-like; K11251 histone H2A [KO:K11251]
histone H2A type 2-B-like; K11251 histone H2A [KO:K11251]
histone H2A.x-like; K11251 histone H2A [KO:K11251]
H2AFY2; H2A histone family, member Y2 [KO:K11251]
histone H2A type 3-like; K11251 histone H2A [KO:K11251]
core histone macro-H2A.1-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-B/E-like; K11251 histone H2A [KO:K11251]
histone H2A type 4-like; K11251 histone H2A [KO:K11251]
histone H2B type 1-A-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-B-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-H-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-K-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-F/J/L-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-M-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-O-like; K11252 histone H2B [KO:K11252]
histone H2B type W-T-like; K11252 histone H2B [KO:K11252]
histone H2B type W-T-like; K11252 histone H2B [KO:K11252]
HIST1H2BC; histone cluster 1, H2bc [KO:K11252]
histone H2B type 1-B-like; K11252 histone H2B [KO:K11252]
histone H2B type 3-B-like; K11252 histone H2B [KO:K11252]
histone H2B type F-M-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-N-like; K11252 histone H2B [KO:K11252]
histone H2B type 1-D-like; K11252 histone H2B [KO:K11252]
histone H2B type 2-F-like; K11252 histone H2B [KO:K11252]
histone H3.1-like; K11253 histone H3 [KO:K11253]
histone H3.2-like; K11253 histone H3 [KO:K11253]
histone H3.3-like; K11253 histone H3 [KO:K11253]
histone H3.1t-like; K11253 histone H3 [KO:K11253]
histone H3.2-like; K11253 histone H3 [KO:K11253]
histone H3.1-like; K11253 histone H3 [KO:K11253]
histone H3.1-like; K11253 histone H3 [KO:K11253]
uncharacterized LOC100436122; K11253 histone H3 [KO:K11253]
histone H3.1-like; K11253 histone H3 [KO:K11253]
histone H3.2-like; K11253 histone H3 [KO:K11253]
histone H4-like protein type G-like; K11254 histone H4 [KO:K11254]
Histone H4; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
uncharacterized LOC100439702; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
HAT1; histone acetyltransferase 1 [KO:K11303] [EC:2.3.1.48]
DRD1; dopamine receptor D1 [KO:K04144]
GNAS; GNAS complex locus [KO:K04632]
DRD2; dopamine receptor D2 [KO:K04145]
GNAI3; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 [KO:K04630]
GNAI1; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 [KO:K04630]
GNAI2; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2 [KO:K04630]
GNAO1; guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O [KO:K04534]
GNB1; guanine nucleotide binding protein (G protein), beta polypeptide 1 [KO:K04536]
GNB2; guanine nucleotide binding protein (G protein), beta polypeptide 2 [KO:K04537]
GNB3; guanine nucleotide binding protein (G protein), beta polypeptide 3 [KO:K07825]
GNB4; guanine nucleotide binding protein (G protein), beta polypeptide 4 [KO:K04538]
GNB5; guanine nucleotide binding protein (G protein), beta 5 [KO:K04539]
GNG2; guanine nucleotide binding protein (G protein), gamma 2 [KO:K07826]
GNG3; guanine nucleotide binding protein (G protein), gamma 3 [KO:K04540]
GNG4; guanine nucleotide binding protein (G protein), gamma 4 [KO:K04541]
GNG5; guanine nucleotide binding protein (G protein), gamma 5 [KO:K04542]
GNG7; guanine nucleotide binding protein (G protein), gamma 7 [KO:K04543]
GNG10; guanine nucleotide binding protein (G protein), gamma 10 [KO:K04545]
GNG11; guanine nucleotide binding protein (G protein), gamma 11 [KO:K04546]
GNG12; guanine nucleotide binding protein (G protein), gamma 12 [KO:K04347]
guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12-like; K04347 guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
GNG13; guanine nucleotide binding protein (G protein), gamma 13 [KO:K04547]
GNGT1; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 [KO:K04548]
GNGT2; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 2 [KO:K04549]
ADORA2A; adenosine A2a receptor [KO:K04266]
ADORA2B; adenosine A2b receptor [KO:K04267]
ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
CREB1; cAMP responsive element binding protein 1 [KO:K05870]
ATF4; activating transcription factor 4 (tax-responsive enhancer element B67) [KO:K04374]
CREB3L1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
CREB3L4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
CREB3; cAMP responsive element binding protein 3 [KO:K09048]
CREB3L2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
CREB3L3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
CREB5; cAMP responsive element binding protein 5 [KO:K09047]
ATF6B; activating transcription factor 6 beta [KO:K09049]
CRH; corticotropin releasing hormone [KO:K05256]
NPY; neuropeptide Y [KO:K05232]
BDNF; brain-derived neurotrophic factor [KO:K04355]
NTRK2; neurotrophic tyrosine kinase, receptor, type 2 [KO:K04360] [EC:2.7.10.1]
SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
SHC-transforming protein 2-like; K17447 SHC- transforming protein 2 [KO:K17447]
SHC-transforming protein 2-like; K17447 SHC- transforming protein 2 [KO:K17447]
SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K17448]
SHC4; SHC (Src homology 2 domain containing) family, member 4 [KO:K17449]
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
HRAS; v-Ha-ras Harvey rat sarcoma viral oncogene homolog [KO:K02833]
GTPase KRas-like; K07827 GTPase KRas [KO:K07827]
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
ARAF; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
BRAF; v-raf murine sarcoma viral oncogene homolog B1 [KO:K04365] [EC:2.7.11.1]
RAF1; v-raf-1 murine leukemia viral oncogene homolog 1 [KO:K04366] [EC:2.7.11.1]
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
PDYN; prodynorphin [KO:K15840]
calmodulin-like protein 5-like; K02183 calmodulin [KO:K02183]
calmodulin-like protein 3-like; K02183 calmodulin [KO:K02183]
calmodulin-like protein 6-like; K02183 calmodulin [KO:K02183]
CALM1; calmodulin 1 (phosphorylase kinase, delta) [KO:K02183]
CALM2; calmodulin 2 (phosphorylase kinase, delta) [KO:K02183]
CALM3; calmodulin 3 (phosphorylase kinase, delta) [KO:K02183]
CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1, alpha [KO:K07359] [EC:2.7.11.17]
CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:2.7.11.17]
CAMK4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
FOSB; FBJ murine osteosarcoma viral oncogene homolog B [KO:K09029]
PPP1R1B; protein phosphatase 1, regulatory (inhibitor) subunit 1B [KO:K15494]
PPP1CB; protein phosphatase 1, catalytic subunit, beta isozyme [KO:K06269] [EC:3.1.3.16]
PPP1CA; protein phosphatase 1, catalytic subunit, alpha isozyme [KO:K06269] [EC:3.1.3.16]
PPP1CC; protein phosphatase 1, catalytic subunit, gamma isozyme [KO:K06269] [EC:3.1.3.16]
PKIA; protein kinase (cAMP-dependent, catalytic) 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
  Authors
Spanagel R
  Title
Alcoholism: a systems approach from molecular physiology to addictive behavior.
  Journal
Physiol Rev 89:649-705 (2009)
Reference
  Authors
Newton PM, Messing RO
  Title
Intracellular signaling pathways that regulate behavioral responses to ethanol.
  Journal
Pharmacol Ther 109:227-37 (2006)
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)
Reference
  Authors
Ron D, Jurd R
  Title
The "ups and downs" of signaling cascades in addiction.
  Journal
Sci STKE 2005:re14 (2005)
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)
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)
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)
Reference
  Authors
Zhang TA, Maldve RE, Morrisett RA
  Title
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
  Journal
Biochem Pharmacol 72:919-27 (2006)
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)
Reference
  Authors
Lovinger DM
  Title
NMDA receptors lose their inhibitions.
  Journal
Nat Neurosci 5:614-6 (2002)
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)
Reference
  Authors
Berke JD, Hyman SE
  Title
Addiction, dopamine, and the molecular mechanisms of memory.
  Journal
Neuron 25:515-32 (2000)
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)
Reference
  Authors
Lee AM, Messing RO
  Title
Protein kinases and addiction.
  Journal
Ann N Y Acad Sci 1141:22-57 (2008)
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)
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)
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)
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)
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)
KO pathway
 

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