KEGG   PATHWAY: sfum05034
Entry
sfum05034                   Pathway                                
Name
Alcoholism - Sorex fumeus (smoky shrew)
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
sfum05034  Alcoholism
sfum05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Sorex fumeus (smoky shrew) [GN:sfum]
Gene
130015763  NRAS; GTPase NRas [KO:K07828]
130015978  [KO:K11253]
130016027  [KO:K11253]
130016161  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
130016426  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
130016515  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
130016670  GRIN2A; glutamate receptor ionotropic, NMDA 2A [KO:K05209]
130016791  [KO:K11251]
130016873  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
130017010  [KO:K11253]
130017086  [KO:K11253]
130017278  [KO:K11253]
130017394  [KO:K04632]
130017428  [KO:K04632]
130017606  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
130018121  [KO:K11253]
130018221  [KO:K11253]
130018300  [KO:K04538]
130019368  [KO:K11251]
130019369  CRH; corticoliberin [KO:K05256]
130019636  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
130019652  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
130019771  [KO:K04546]
130019956  [KO:K11253]
130019967  [KO:K11253]
130019988  PKIA; cAMP-dependent protein kinase inhibitor alpha [KO:K15985]
130020314  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
130020597  [KO:K11253]
130020611  [KO:K11253]
130020648  [KO:K02183]
130020896  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
130021165  [KO:K11253]
130021168  [KO:K11253]
130021512  DRD1; D(1A) dopamine receptor [KO:K04144]
130021537  [KO:K11251]
130021538  [KO:K11252]
130021539  [KO:K11252]
130021701  [KO:K11252]
130021960  [KO:K11251]
130022114  SHC2; SHC-transforming protein 2 [KO:K17447]
130022232  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
130022460  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
130022616  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
130022692  [KO:K11251]
130022732  [KO:K11251]
130022928  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
130023599  [KO:K11251]
130024040  [KO:K02183]
130024076  [KO:K02183]
130024696  [KO:K11253]
130024717  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
130024986  GRIN2B; glutamate receptor ionotropic, NMDA 2B isoform X1 [KO:K05210]
130025123  [KO:K11253]
130026301  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
130026323  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
130026327  CALM2; calmodulin-2 [KO:K02183]
130026468  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
130026857  [KO:K11253]
130027115  [KO:K11253]
130027169  HDAC7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
130027313  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
130027358  HDAC9; histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
130027449  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
130027581  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
130027678  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
130027689  NPY; pro-neuropeptide Y [KO:K05232]
130028068  [KO:K11251]
130028177  [KO:K11251]
130028328  [KO:K06269] [EC:3.1.3.16]
130028381  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
130028400  [KO:K11252]
130028691  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
130028776  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
130028912  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
130029757  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
130029772  ADORA2A; adenosine receptor A2a [KO:K04266]
130029929  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
130030012  [KO:K11252]
130030236  [KO:K11253]
130030475  PDYN; proenkephalin-B [KO:K15840]
130030478  [KO:K11253]
130030655  [KO:K11253]
130030687  [KO:K11251]
130030984  [KO:K11253]
130031010  [KO:K11253]
130031274  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
130031452  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
130031638  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
130031711  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
130031893  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
130032069  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
130032444  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
130032457  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
130032791  [KO:K11251]
130032807  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
130033392  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
130033536  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
130034131  [KO:K11253]
130034139  [KO:K11252]
130034141  [KO:K11253]
130034541  SLC29A1; equilibrative nucleoside transporter 1 [KO:K15014]
130034692  [KO:K11253]
130034740  [KO:K11253]
130034941  [KO:K11253]
130034999  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
130035119  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
130035187  SHC3; SHC-transforming protein 3 [KO:K17448]
130035238  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
130035331  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
130035345  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
130035498  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
130035875  CALML4; calmodulin-like protein 4 [KO:K02183]
130035963  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
130036116  [KO:K11253]
130036507  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
130036575  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
130036732  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
130036768  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
130036909  [KO:K11253]
130037521  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
130037581  [KO:K11253]
130037632  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
130037797  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
130038120  [KO:K11253]
130038161  HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
130038218  [KO:K11251]
130038384  [KO:K11253]
130038388  [KO:K11252]
130038751  [KO:K11253]
130038759  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
130038985  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
130039305  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
130039340  [KO:K00274] [EC:1.4.3.4]
130039368  [KO:K11253]
130039770  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
130039856  TH; LOW QUALITY PROTEIN: tyrosine 3-monooxygenase [KO:K00501] [EC:1.14.16.2]
130039909  HRAS; GTPase HRas isoform X1 [KO:K02833]
130039968  SLC29A2; equilibrative nucleoside transporter 2 [KO:K15014]
130040057  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
130040146  [KO:K11253]
130040148  [KO:K11254]
130040248  [KO:K11251]
130040249  [KO:K11251]
130040250  [KO:K11251]
130040251  [KO:K11252]
130040252  [KO:K11252]
130040253  [KO:K11253]
130040254  [KO:K11253]
130040272  [KO:K11253]
130040273  [KO:K11253]
130040274  [KO:K11251]
130040275  [KO:K11251]
130040276  [KO:K11251]
130040277  [KO:K11251]
130040279  [KO:K11251]
130040280  [KO:K11252]
130040281  [KO:K11252]
130040282  [KO:K11252]
130040283  [KO:K11252]
130040284  [KO:K11252]
130040285  [KO:K11252]
130040286  [KO:K11254]
130040287  [KO:K11254]
130040288  [KO:K11254]
130040290  [KO:K11254]
130040291  [KO:K11253]
130040293  [KO:K11251]
130040297  [KO:K11251]
130040306  [KO:K11251]
130040307  [KO:K11251]
130040308  [KO:K11251]
130040309  [KO:K11251]
130040310  [KO:K11252]
130040311  [KO:K11252]
130040312  [KO:K11252]
130040313  [KO:K11252]
130040314  [KO:K11252]
130040315  [KO:K11254]
130040316  [KO:K11254]
130040318  [KO:K11251]
130040319  [KO:K11252]
130040328  [KO:K11252]
130040329  [KO:K11252]
130040650  [KO:K11253]
130040713  [KO:K11251]
130040871  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
130041273  [KO:K11253]
130041799  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
130041980  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
130042005  CALM1; calmodulin-1 [KO:K02183]
130042418  [KO:K11253]
130042425  [KO:K11253]
130042439  KRAS; GTPase KRas isoform X1 [KO:K07827]
130042440  [KO:K11251]
130042909  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
130043087  [KO:K11253]
130043108  SHC4; SHC-transforming protein 4 [KO:K17449]
130043296  [KO:K11253]
130043326  [KO:K11253]
130043441  ADORA2B; adenosine receptor A2b [KO:K04267]
130043822  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
130043857  FOSB; protein FosB isoform X1 [KO:K09029]
130043923  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
130044366  CALM3; calmodulin-3 [KO:K02183]
130044369  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
130044395  [KO:K11253]
130044417  GRIN2D; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 2D [KO:K05212]
130044847  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
130045166  [KO:K11253]
130045178  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
130045226  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
130045240  [KO:K11253]
130045490  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
130045948  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
130046085  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
130046135  [KO:K11253]
130046184  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
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
sfum04010  MAPK signaling pathway
sfum04728  Dopaminergic synapse
KO pathway
ko05034   

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