KEGG   PATHWAY: lve05034
Entry
lve05034                    Pathway                                
Name
Alcoholism - Lipotes vexillifer (Yangtze River dolphin)
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
lve05034  Alcoholism
lve05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Lipotes vexillifer (Yangtze River dolphin) [GN:lve]
Gene
103068403  [KO:K11252]
103068413  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
103068676  [KO:K11252]
103068686  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
103068734  NRAS; GTPase NRas [KO:K07828]
103068747  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
103068824  HDAC9; histone deacetylase 9-like isoform X1 [KO:K11409] [EC:3.5.1.98]
103069101  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
103069141  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
103069235  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform X1 [KO:K04536]
103069308  [KO:K11253]
103069500  [KO:K04542]
103069787  [KO:K04360] [EC:2.7.10.1]
103070161  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
103070260  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
103070274  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
103070340  [KO:K11252]
103070550  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
103070598  [KO:K11251]
103070672  PDYN; proenkephalin-B [KO:K15840]
103070776  [KO:K11253]
103070885  [KO:K11251]
103071163  [KO:K11252]
103071198  [KO:K11251]
103071433  [KO:K11253]
103071696  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
103071706  [KO:K11251]
103071935  [KO:K11253]
103071989  [KO:K11252]
103072092  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
103072156  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
103072537  [KO:K11251]
103072994  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
103073360  [KO:K11253]
103073535  PPP1R1B; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
103073628  NPY; pro-neuropeptide Y [KO:K05232]
103073637  [KO:K11251]
103073911  [KO:K11252]
103074048  [KO:K11254]
103074112  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
103074332  FOSB; protein fosB isoform X1 [KO:K09029]
103074387  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
103074541  [KO:K02183]
103074668  HDAC6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
103074679  [KO:K11252]
103074817  CALML5; calmodulin-like protein 5 [KO:K02183]
103074885  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
103074978  [KO:K11254]
103074989  PKIA; cAMP-dependent protein kinase inhibitor alpha isoform X1 [KO:K15985]
103075046  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
103075068  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
103075277  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
103075492  [KO:K04542]
103075543  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103075748  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
103075978  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
103076043  HRAS; GTPase HRas isoform X1 [KO:K02833]
103076354  [KO:K11254]
103076372  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
103076424  [KO:K11253]
103076444  [KO:K11253]
103076624  [KO:K11252]
103076637  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
103076694  ADORA2A; adenosine receptor A2a [KO:K04266]
103076737  SLC29A2; equilibrative nucleoside transporter 2 [KO:K15014]
103076743  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
103076829  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
103076894  [KO:K11252]
103077170  [KO:K11251]
103077256  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
103077308  GNAI2; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
103077443  [KO:K11251]
103077464  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103077579  KRAS; GTPase KRas [KO:K07827]
103077666  DRD1; D(1A) dopamine receptor [KO:K04144]
103077708  [KO:K11253]
103077804  HDAC10; histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
103078017  ADORA2B; adenosine receptor A2b [KO:K04267]
103078122  SHC3; SHC-transforming protein 3 [KO:K17448]
103078231  HDAC8; histone deacetylase 8-like isoform X1 [KO:K11405] [EC:3.5.1.98]
103078258  [KO:K11252]
103078828  [KO:K11251]
103079101  [KO:K11252]
103079120  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
103079242  SOS1; son of sevenless homolog 1 [KO:K03099]
103079256  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
103079324  [KO:K11251]
103079661  HDAC4; LOW QUALITY PROTEIN: histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
103079766  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
103079884  [KO:K11251]
103079886  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
103079915  CALML6; calmodulin-like protein 6 [KO:K02183]
103079983  [KO:K11251]
103080157  [KO:K11252]
103080185  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
103080383  [KO:K11253]
103080427  [KO:K11252]
103080471  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
103080538  CRH; corticoliberin [KO:K05256]
103080634  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
103080666  [KO:K11252]
103080676  [KO:K11251]
103080710  [KO:K11251]
103080762  CALM1; calmodulin isoform X1 [KO:K02183]
103080928  [KO:K11251]
103080941  [KO:K11254]
103080975  [KO:K11254]
103081084  SOS2; son of sevenless homolog 2-like [KO:K03099]
103081119  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
103081210  [KO:K11253]
103081255  [KO:K11252]
103081367  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
103081391  [KO:K11253]
103081667  [KO:K11254]
103081704  [KO:K11252]
103081811  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
103081931  [KO:K11253]
103081970  [KO:K11251]
103082097  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
103082207  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
103082240  [KO:K11251]
103082659  [KO:K11254]
103082805  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
103082839  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
103082925  [KO:K11252]
103083197  [KO:K11251]
103083306  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
103083673  [KO:K11251]
103084206  SLC18A1; chromaffin granule amine transporter [KO:K08155]
103084472  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
103084962  [KO:K11251]
103085069  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
103085162  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
103085385  [KO:K04632]
103085711  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
103085965  [KO:K11252]
103086024  TH; tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
103086084  [KO:K06269] [EC:3.1.3.16]
103086171  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
103086246  [KO:K11251]
103086377  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
103086451  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
103086526  [KO:K11254]
103086798  [KO:K11252]
103087008  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
103087068  [KO:K11251]
103087479  CALM2; calmodulin [KO:K02183]
103087626  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
103087933  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
103088169  [KO:K11252]
103088445  [KO:K11251]
103088833  SHC2; SHC-transforming protein 2 [KO:K17447]
103088900  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
103088923  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
103089051  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas-like [KO:K04632]
103089070  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
103089247  [KO:K11254]
103089645  [KO:K11251]
103089724  [KO:K04548]
103089745  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
103089752  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
103089763  [KO:K11253]
103090018  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
103090099  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
103090141  [KO:K11252]
103090400  [KO:K11252]
103090666  [KO:K11251]
103091025  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
103091030  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
103091114  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
103091169  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
103091269  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
103091573  SLC29A1; equilibrative nucleoside transporter 1 [KO:K15014]
103091655  CALM3; calmodulin [KO:K02183]
103091670  GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
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
lve04010  MAPK signaling pathway
lve04728  Dopaminergic synapse
KO pathway
ko05034   

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