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 3-monooxygenase isoform X6 [KO:K00501] [EC:]
DDC; aromatic-L-amino-acid decarboxylase isoform X1 [KO:K01593] [EC:]
SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
SLC18A2; synaptic vesicular amine transporter [KO:K08155]
MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:]
MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:]
SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
GRIN2C; glutamate receptor ionotropic, NMDA 2C isoform X1 [KO:K05211]
GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
GRIN3B; glutamate receptor ionotropic, NMDA 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 isoform X1 [KO:K11406] [EC:]
HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:]
HDAC6; histone deacetylase 6 [KO:K11407] [EC:]
HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:]
HDAC8; histone deacetylase 8 isoform X2 [KO:K11405] [EC:]
HDAC9; histone deacetylase 9 [KO:K11409] [EC:]
HDAC10; histone deacetylase 10 isoform X1 [KO:K18671] [EC:]
HDAC11; histone deacetylase 11 isoform X2 [KO:K11418] [EC:]
histone H2A.J [KO:K11251]
histone H2A type 2-A [KO:K11251]
H2AFZ; histone H2A.Z [KO:K11251]
histone H2A type 1-A [KO:K11251]
histone H2A type 1-B/E [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]
core histone macro-H2A.2 [KO:K11251]
histone H2A type 3 [KO:K11251]
core histone macro-H2A.1 isoform X1 [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-B/E [KO:K11251]
histone H2A type 1-like [KO:K11251]
histone H2A type 2-C [KO:K11251]
histone H2A.V isoform X1 [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 [KO:K11252]
HIST1H2BC; histone H2B type 1 [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 isoform X1 [KO:K11252]
histone H2B type 1 [KO:K11252]
LOW QUALITY PROTEIN: histone H2B type F-M [KO:K11252]
uncharacterized protein LOC100439748 [KO:K11253]
histone H3.3 [KO:K11253]
histone H3.1 [KO:K11253]
histone H3.1 isoform X2 [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 protein LOC100443987 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
histone H4 [KO:K11254]
HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:]
DRD1; D(1A) dopamine receptor [KO:K04144]
GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X3 [KO:K04632]
DRD2; D(2) dopamine receptor [KO:K04145]
GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 isoform X1 [KO:K04537]
GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 precursor [KO:K07826]
GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 precursor [KO:K04541]
GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 precursor [KO:K04542]
GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 isoform X2 [KO:K04546]
GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 precursor [KO:K04347]
GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 isoform X3 [KO:K04548]
GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
ADORA2A; adenosine receptor A2a [KO:K04266]
ADORA2B; adenosine receptor A2b [KO:K04267]
ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:]
CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
CRH; corticoliberin [KO:K05256]
NPY; pro-neuropeptide Y [KO:K05232]
BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
NTRK2; BDNF/NT-3 growth factors receptor isoform X2 [KO:K04360] [EC:]
SHC1; SHC-transforming protein 1 [KO:K06279]
SHC2; SHC-transforming protein 2 [KO:K17447]
SHC3; SHC-transforming protein 3 [KO:K17448]
SHC4; SHC-transforming protein 4 [KO:K17449]
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
HRAS; GTPase HRas [KO:K02833]
KRAS; GTPase KRas isoform X1 [KO:K07827]
NRAS; GTPase NRas precursor [KO:K07828]
ARAF; serine/threonine-protein kinase A-Raf isoform X4 [KO:K08845] [EC:]
BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:]
MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:]
PDYN; proenkephalin-B [KO:K15840]
CALML5; calmodulin-like protein 5 [KO:K02183]
CALML3; calmodulin-like protein 3 [KO:K02183]
CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
CALM1; calmodulin [KO:K02183]
CALM2; calmodulin [KO:K02183]
CALM3; calmodulin [KO:K02183]
CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:]
CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:]
CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:]
FOSB; protein fosB isoform X1 [KO:K09029]
PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:]
PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:]
PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [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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