KEGG   PATHWAY: mlf05034
Entry
mlf05034                    Pathway                                
Name
Alcoholism - Myotis lucifugus (little brown bat)
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
mlf05034  Alcoholism
mlf05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Myotis lucifugus (little brown bat) [GN:mlf]
Gene
102416978  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X2 [KO:K09048]
102417051  [KO:K11251]
102417363  [KO:K11253]
102417411  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
102417633  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102417681  [KO:K11251]
102417755  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102417800  [KO:K11251]
102417912  [KO:K02183]
102417960  PRKACA; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102418119  [KO:K11252]
102418405  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
102418432  [KO:K11251]
102418533  [KO:K11251]
102418736  [KO:K11253]
102418844  [KO:K11252]
102418951  [KO:K11251]
102419013  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
102419061  [KO:K11254]
102419271  [KO:K11251]
102419369  [KO:K11253]
102419493  [KO:K02183]
102419677  [KO:K11251]
102419808  [KO:K02183]
102419892  [KO:K11253]
102420164  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
102420203  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
102420309  [KO:K11252]
102420416  [KO:K11253]
102420431  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
102420482  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
102420628  [KO:K11252]
102420735  [KO:K11254]
102420799  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
102420945  [KO:K11252]
102421027  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
102421075  CRH; corticoliberin [KO:K05256]
102421214  [KO:K11252]
102421241  [KO:K11251]
102421340  [KO:K11251]
102421841  CAMKK2; LOW QUALITY PROTEIN: calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
102421847  [KO:K11254]
102421849  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
102422152  [KO:K11252]
102422236  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102422450  [KO:K11251]
102422498  [KO:K04545]
102424094  HDAC7; histone deacetylase 7 isoform X8 [KO:K11408] [EC:3.5.1.98]
102424579  [KO:K11254]
102424769  [KO:K11253]
102424893  [KO:K11253]
102424965  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
102425000  [KO:K11251]
102425254  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102425260  [KO:K11252]
102425449  HDAC5; histone deacetylase 5 isoform X2 [KO:K11406] [EC:3.5.1.98]
102425604  GRIN3B; glutamate receptor ionotropic, NMDA 3B isoform X1 [KO:K05214]
102425617  HDAC2; histone deacetylase 2 isoform X1 [KO:K06067] [EC:3.5.1.98]
102425880  [KO:K11254]
102426193  [KO:K11253]
102426207  [KO:K11253]
102426310  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
102426513  [KO:K11251]
102426645  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
102426790  [KO:K11251]
102426825  [KO:K11251]
102426842  NTRK2; BDNF/NT-3 growth factors receptor [KO:K04360] [EC:2.7.10.1]
102427147  [KO:K11252]
102427151  [KO:K11405] [EC:3.5.1.98]
102427186  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
102427230  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102427259  DRD1; D(1A) dopamine receptor [KO:K04144]
102427425  NPY; pro-neuropeptide Y [KO:K05232]
102427447  [KO:K11252]
102427705  [KO:K11253]
102427857  [KO:K11253]
102428001  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
102428066  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
102428247  [KO:K11253]
102428334  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
102428458  FOSB; protein fosB [KO:K09029]
102428494  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
102428502  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms short isoform X11 [KO:K04632]
102428529  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102428756  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
102428864  [KO:K11253]
102428918  [KO:K11251]
102429402  MAOA; LOW QUALITY PROTEIN: amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
102429560  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
102429580  [KO:K04630]
102429594  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
102429703  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
102429724  [KO:K11251]
102429857  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X2 [KO:K06269] [EC:3.1.3.16]
102430334  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
102430561  HAT1; histone acetyltransferase type B catalytic subunit isoform X1 [KO:K11303] [EC:2.3.1.48]
102430744  NRAS; GTPase NRas [KO:K07828]
102430787  CALM2; calmodulin-2 isoform X1 [KO:K02183]
102430817  GRIN3A; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 3A [KO:K05213]
102431250  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
102431273  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
102431535  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
102431548  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
102431576  PDYN; proenkephalin-B [KO:K15840]
102431853  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
102431999  KRAS; GTPase KRas isoform X1 [KO:K07827]
102432445  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
102432478  HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
102432571  [KO:K11252]
102432599  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
102432692  [KO:K04548]
102432910  [KO:K04546]
102432911  HDAC9; histone deacetylase 9 isoform X5 [KO:K11409] [EC:3.5.1.98]
102433108  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
102433506  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
102433989  [KO:K04632]
102434453  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102434796  [KO:K11252]
102434863  CALM1; calmodulin-1 [KO:K02183]
102435103  [KO:K11253]
102435241  BRAF; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
102435382  SHC3; LOW QUALITY PROTEIN: SHC-transforming protein 3 [KO:K17448]
102435386  [KO:K11251]
102435413  [KO:K11252]
102435777  SLC29A2; equilibrative nucleoside transporter 2 isoform X2 [KO:K15014]
102436175  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
102436383  [KO:K06269] [EC:3.1.3.16]
102436564  ADORA2A; adenosine receptor A2a [KO:K04266]
102436951  HDAC3; histone deacetylase 3 isoform X1 [KO:K11404] [EC:3.5.1.98]
102437107  [KO:K11251]
102437203  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102437531  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
102437551  [KO:K11253]
102437773  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102437833  PPP1R1B; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
102437886  [KO:K11252]
102438182  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X2 [KO:K00908] [EC:2.7.11.17]
102438532  [KO:K11253]
102438598  [KO:K04534]
102438613  HDAC10; LOW QUALITY PROTEIN: histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
102438871  SLC18A1; chromaffin granule amine transporter [KO:K08155]
102438995  SLC18A2; synaptic vesicular amine transporter isoform X1 [KO:K08155]
102439458  [KO:K11251]
102439466  ADORA2B; adenosine receptor A2b [KO:K04267]
102439961  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
102440307  [KO:K11251]
102440332  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
102440407  [KO:K02183]
102440469  [KO:K11252]
102440574  [KO:K11251]
102440620  [KO:K11251]
102440705  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
102440781  [KO:K11252]
102441181  [KO:K11251]
102441490  [KO:K11252]
102441698  [KO:K11252]
102441802  [KO:K11252]
102441805  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
102441904  PKIA; cAMP-dependent protein kinase inhibitor alpha [KO:K15985]
102441909  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
102442019  [KO:K11254]
102442325  [KO:K11251]
102442437  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
102442926  SOS1; son of sevenless homolog 1 [KO:K03099]
102442948  [KO:K11251]
102443063  HDAC11; histone deacetylase 11 isoform X6 [KO:K11418] [EC:3.5.1.98]
102443067  [KO:K11252]
102443136  [KO:K02183]
102443216  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
102443276  [KO:K11252]
106694910  [KO:K11253]
106694955  [KO:K11254]
106697041  [KO:K04545]
106698231  [KO:K11254]
106699200  [KO:K11252]
111825549  [KO:K11252]
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
mlf04010  MAPK signaling pathway
mlf04728  Dopaminergic synapse
KO pathway
ko05034   

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