KEGG   PATHWAY: pon05034Help
pon05034                    Pathway                                

Alcoholism - Pongo abelii (Sumatran orangutan)
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.
Human Diseases; Substance dependence
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Pongo abelii (Sumatran orangutan) [GN:pon]
TH; tyrosine hydroxylase [KO:K00501] [EC:]
DDC; dopa decarboxylase [KO:K01593] [EC:]
chromaffin granule amine transporter-like [KO:K08155]
SLC18A2; solute carrier family 18 member A2 [KO:K08155]
MAOA; monoamine oxidase A [KO:K00274] [EC:]
MAOB; monoamine oxidase B [KO:K00274] [EC:]
sodium-dependent dopamine transporter-like [KO:K05036]
sodium-dependent dopamine transporter-like [KO:K05036]
GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
GRIN2C; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
GRIN2D; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
GRIN3A; glutamate ionotropic receptor NMDA type subunit 3A [KO:K05213]
GRIN3B; glutamate ionotropic receptor NMDA type subunit 3B [KO:K05214]
HDAC1; histone deacetylase 1 [KO:K06067] [EC:]
HDAC2; histone deacetylase 2 [KO:K06067] [EC:]
HDAC3; histone deacetylase 3 [KO:K11404] [EC:]
HDAC5; histone deacetylase 5 [KO:K11406] [EC:]
histone deacetylase 4 [KO:K11406] [EC:]
HDAC6; histone deacetylase 6 [KO:K11407] [EC:]
HDAC7; histone deacetylase 7 [KO:K11408] [EC:]
HDAC8; histone deacetylase 8 [KO:K11405] [EC:]
HDAC9; histone deacetylase 9 [KO:K11409] [EC:]
HDAC10; histone deacetylase 10 [KO:K18671] [EC:]
HDAC11; histone deacetylase 11 [KO:K11418] [EC:]
histone H2A.J [KO:K11251]
histone H2A type 2-A [KO:K11251]
H2AFZ; H2A histone family, member Z [KO:K11251]
histone H2A type 1-A [KO:K11251]
histone H2A type 1 [KO:K11251]
histone H2A type 1-C [KO:K11251]
histone H2A type 1-J-like [KO:K11251]
histone H2A type 1 [KO:K11251]
histone H2A type 2-B [KO:K11251]
histone H2AX [KO:K11251]
H2AFY2; core histone macro-H2A.2 [KO:K11251]
histone H2A type 3 [KO:K11251]
core histone macro-H2A.1 [KO:K11251]
histone H2A type 1-H [KO:K11251]
histone H2A type 1 [KO:K11251]
histone H2A type 1 [KO:K11251]
histone H2A type 1 [KO:K11251]
histone H2A type 1 [KO:K11251]
histone H2A type 1-like [KO:K11251]
histone H2A type 2-C [KO:K11251]
histone H2A.V [KO:K11251]
histone H2A type 1-D [KO:K11251]
histone H2B type 1-A [KO:K11252]
histone H2B type 1-B [KO:K11252]
histone H2B type 1-H [KO:K11252]
histone H2B type 1-K [KO:K11252]
histone H2B type 1-F/J/L [KO:K11252]
histone H2B type 1-M [KO:K11252]
histone H2B type 1-O [KO:K11252]
histone H2B type W-T-like [KO:K11252]
histone H2B type W-T [KO:K11252]
HIST1H2BC; histone cluster 1, H2bc [KO:K11252]
histone H2B type 3-A-like [KO:K11252]
histone H2B type 3-B [KO:K11252]
histone H2B type F-M-like [KO:K11252]
histone H2B type 1-like [KO:K11252]
histone H2B type 1 [KO:K11252]
histone H2B type 1 [KO:K11252]
late histone H2B.L4-like [KO:K11252]
histone H2B type 1-N [KO:K11252]
histone H2B type 1-M-like [KO:K11252]
histone H2B type 2-F [KO:K11252]
histone H2B type 1 [KO:K11252]
histone H2B type F-M [KO:K11252]
histone H3 [KO:K11253]
H3F3A; H3 histone, family 3A [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.1 [KO:K11253]
histone H3 [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.1-like [KO:K11253]
uncharacterized LOC100443987 [KO:K11254]
Histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
uncharacterized LOC100935714 [KO:K11254]
histone H4 [KO:K11254]
HAT1; histone acetyltransferase 1 [KO:K11303] [EC:]
DRD1; dopamine receptor D1 [KO:K04144]
GNAS; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
DRD2; dopamine receptor D2 [KO:K04145]
GNAI3; G protein subunit alpha i3 [KO:K04630]
GNAI1; G protein subunit alpha i1 [KO:K04630]
GNAI2; G protein subunit alpha i2 [KO:K04630]
GNAO1; G protein subunit alpha o1 [KO:K04534]
GNB1; G protein subunit beta 1 [KO:K04536]
GNB2; G protein subunit beta 2 [KO:K04537]
GNB3; G protein subunit beta 3 [KO:K07825]
GNB4; G protein subunit beta 4 [KO:K04538]
GNB5; G protein subunit beta 5 [KO:K04539]
GNG2; G protein subunit gamma 2 [KO:K07826]
GNG3; G protein subunit gamma 3 [KO:K04540]
GNG4; G protein subunit gamma 4 [KO:K04541]
GNG5; G protein subunit gamma 5 [KO:K04542]
GNG10; G protein subunit gamma 10 [KO:K04545]
GNG11; G protein subunit gamma 11 [KO:K04546]
GNG12; G protein subunit gamma 12 [KO:K04347]
GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
ADORA2A; adenosine A2a receptor [KO:K04266]
ADORA2B; adenosine A2b receptor [KO:K04267]
ADCY5; adenylate cyclase 5 [KO:K08045] [EC:]
CREB1; cAMP responsive element binding protein 1 [KO:K05870]
ATF2; activating transcription factor 2 [KO:K04450]
ATF4; activating transcription factor 4 [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; cyclic AMP-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 receptor tyrosine kinase 2 [KO:K04360] [EC:]
SHC1; SHC adaptor protein 1 [KO:K06279]
SHC-transforming protein 2-like [KO:K17447]
SHC-transforming protein 2 [KO:K17447]
SHC3; SHC adaptor protein 3 [KO:K17448]
SHC4; SHC adaptor protein 4 [KO:K17449]
GRB2; growth factor receptor bound protein 2 [KO:K04364]
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
HRAS; HRas proto-oncogene, GTPase [KO:K02833]
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:]
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:]
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
PDYN; prodynorphin [KO:K15840]
CALML5; calmodulin like 5 [KO:K02183]
CALML3; calmodulin like 3 [KO:K02183]
CALML6; calmodulin like 6 [KO:K02183]
CALM1; calmodulin 1 [KO:K02183]
CALM2; calmodulin 2 [KO:K02183]
CALM3; calmodulin 3 [KO:K02183]
CALML4; calmodulin like 4 [KO:K02183]
CAMKK1; calcium/calmodulin dependent protein kinase kinase 1 [KO:K00908] [EC:]
CAMKK2; calcium/calmodulin dependent protein kinase kinase 2 [KO:K07359] [EC:]
CAMK4; calcium/calmodulin dependent protein kinase IV [KO:K05869] [EC:]
FOSB; FosB proto-oncogene, AP-1 transcription factor subunit [KO:K09029]
PPP1R1B; protein phosphatase 1 regulatory inhibitor subunit 1B [KO:K15494]
PPP1CB; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:]
PPP1CA; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:]
PPP1CC; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:]
PKIA; cAMP-dependent protein kinase inhibitor alpha [KO:K15985]
Hydrogen peroxide
Calcium cation
3',5'-Cyclic AMP
Spanagel R
Alcoholism: a systems approach from molecular physiology to addictive behavior.
Physiol Rev 89:649-705 (2009)
Newton PM, Messing RO
Intracellular signaling pathways that regulate behavioral responses to ethanol.
Pharmacol Ther 109:227-37 (2006)
Mailliard WS, Diamond I
Recent advances in the neurobiology of alcoholism: the role of adenosine.
Pharmacol Ther 101:39-46 (2004)
Ron D, Jurd R
The "ups and downs" of signaling cascades in addiction.
Sci STKE 2005:re14 (2005)
Diana M, Brodie M, Muntoni A, Puddu MC, Pillolla G, Steffensen S, Spiga S, Little HJ
Enduring effects of chronic ethanol in the CNS: basis for alcoholism.
Alcohol Clin Exp Res 27:354-61 (2003)
Moonat S, Starkman BG, Sakharkar A, Pandey SC
Neuroscience of alcoholism: molecular and cellular mechanisms.
Cell Mol Life Sci 67:73-88 (2010)
Pandey SC
The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction.
Pharmacol Ther 104:47-58 (2004)
Zhang TA, Maldve RE, Morrisett RA
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
Biochem Pharmacol 72:919-27 (2006)
Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA
DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens.
Nat Neurosci 5:641-8 (2002)
Lovinger DM
NMDA receptors lose their inhibitions.
Nat Neurosci 5:614-6 (2002)
Hyman SE, Malenka RC, Nestler EJ
Neural mechanisms of addiction: the role of reward-related learning and memory.
Annu Rev Neurosci 29:565-98 (2006)
Berke JD, Hyman SE
Addiction, dopamine, and the molecular mechanisms of memory.
Neuron 25:515-32 (2000)
Clapp P, Bhave SV, Hoffman PL
How Adaptation of the Brain to Alcohol Leads to Dependence: A Pharmacological Perspective.
Alcohol Res Health 31:310-339 (2008)
Jeanes ZM, Buske TR, Morrisett RA
In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell.
J Pharmacol Exp Ther 336:155-64 (2011)
Lee AM, Messing RO
Protein kinases and addiction.
Ann N Y Acad Sci 1141:22-57 (2008)
Repunte-Canonigo V, Lutjens R, van der Stap LD, Sanna PP
Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.
Brain Res 1138:48-56 (2007)
Logrip ML, Janak PH, Ron D
Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.
FASEB J 22:2393-404 (2008)
Shukla SD, Velazquez J, French SW, Lu SC, Ticku MK, Zakhari S
Emerging role of epigenetics in the actions of alcohol.
Alcohol Clin Exp Res 32:1525-34 (2008)
Pascual M, Boix J, Felipo V, Guerri C
Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.
J Neurochem 108:920-31 (2009)
Li J, Cheng Y, Bian W, Liu X, Zhang C, Ye JH
Region-specific induction of FosB/DeltaFosB by voluntary alcohol intake: effects of naltrexone.
Alcohol Clin Exp Res 34:1742-50 (2010)
KO pathway

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