KEGG   PATHWAY: mmf05034
Entry
mmf05034                    Pathway                                
Name
Alcoholism - Molossus molossus (Pallas's mastiff 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
mmf05034  Alcoholism
mmf05034

Other DBs
GO: 0045471
Organism
Molossus molossus (Pallas's mastiff bat) [GN:mmf]
Gene
118628135  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
118620035  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
118615752  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
118632491  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
118620895  LOW QUALITY PROTEIN: amine oxidase [flavin-containing] B-like [KO:K00274] [EC:1.4.3.4]
118635850  MAOB; amine oxidase [flavin-containing] B [KO:K00274] [EC:1.4.3.4]
118636146  MAOA; amine oxidase [flavin-containing] A [KO:K00274] [EC:1.4.3.4]
118641782  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
118629438  GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208]
118641796  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
118623871  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
118634176  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
118639222  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
118629696  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
118643921  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
118626632  HDAC1; histone deacetylase 1 isoform X1 [KO:K06067] [EC:3.5.1.98]
118621643  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
118624162  histone deacetylase 2-like [KO:K06067] [EC:3.5.1.98]
118615784  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
118633816  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
118625264  HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
118635893  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
118624663  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
118635895  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
118619779  histone deacetylase 9 isoform X1 [KO:K11409] [EC:3.5.1.98]
118641179  HDAC10; polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
118617340  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
118619389  histone H2A.V-like [KO:K11251]
118620312  histone H2A.V [KO:K11251]
118628201  histone H2AX [KO:K11251]
118635690  histone H2A-Bbd type 2/3 [KO:K11251]
118636622  histone H2A-Bbd type 2/3-like [KO:K11251]
118636638  histone H2A-Bbd type 2/3-like [KO:K11251]
118637163  histone H2A type 1-H-like [KO:K11251]
118637168  histone H2A type 1 [KO:K11251]
118637169  histone H2A type 1-D [KO:K11251]
118637170  histone H2A type 1 [KO:K11251]
118637171  histone H2A type 1 [KO:K11251]
118637172  histone H2A type 1-D [KO:K11251]
118637173  histone H2A type 1 [KO:K11251]
118637174  histone H2A type 1 [KO:K11251]
118637175  histone H2A type 1 [KO:K11251]
118637176  histone H2A type 1 [KO:K11251]
118637177  histone H2A type 1-H [KO:K11251]
118637196  histone H2A type 1-like [KO:K11251]
118637411  histone H2A type 1-A-like [KO:K11251]
118637619  core histone macro-H2A.1-like [KO:K11251]
118630504  histone H2A.Z [KO:K11251]
118638005  histone H2A type 2-A [KO:K11251]
118638007  histone H2A type 2-A [KO:K11251]
118638008  histone H2A type 2-B [KO:K11251]
118638009  histone H2A type 2-C [KO:K11251]
118616024  core histone macro-H2A.1 isoform X1 [KO:K11251]
118624572  histone H2A.J [KO:K11251]
118632310  core histone macro-H2A.2 [KO:K11251]
118641463  histone H2B subacrosomal variant-like [KO:K11252]
118619915  histone H2B type 2-E1 [KO:K11252]
118637164  histone H2B type 1-K-like [KO:K11252]
118637165  histone H2B type 1-M [KO:K11252]
118637180  histone H2B type 1-K [KO:K11252]
118637181  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637182  histone H2B type 1-H [KO:K11252]
118637183  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637184  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637185  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637186  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637187  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637188  histone H2B type 1-K [KO:K11252]
118637189  histone H2B type 1-C/E/F/G/I [KO:K11252]
118637191  histone H2B type 1-B [KO:K11252]
118637192  histone H2B type 2-E [KO:K11252]
118637193  histone H2B type 1-H-like [KO:K11252]
118637348  histone H2B type 1-A [KO:K11252]
118637410  histone H2B type 1-A-like isoform X1 [KO:K11252]
118637847  histone H2B type 2-F [KO:K11252]
118638010  histone H2B type 2-E [KO:K11252]
118638011  histone H2B type 2-E [KO:K11252]
118638373  histone H2B 1/2-like [KO:K11252]
118625702  histone H3.3A-like [KO:K11253]
118640520  histone H3.3A [KO:K11253]
118633745  histone H3.3A [KO:K11253]
118634059  histone H3.3A-like [KO:K11253]
118621044  histone H3.3A-like [KO:K11253]
118636230  histone H3.3A-like [KO:K11253]
118637166  histone H3.1 [KO:K11253]
118637167  histone H3.1 [KO:K11253]
118637202  LOW QUALITY PROTEIN: uncharacterized protein LOC118637202 [KO:K11253]
118637203  histone H3.1-like [KO:K11253]
118637255  histone H3.1-like [KO:K11253]
118637620  uncharacterized protein LOC118637620 [KO:K11253]
118643815  histone H3.3A-like [KO:K11253]
118623257  histone H3.3A-like [KO:K11253]
118637624  uncharacterized protein LOC118637624 [KO:K11253]
118638004  histone H3 [KO:K11253]
118638014  histone H3-like [KO:K11253]
118638015  histone H3-like [KO:K11253]
118624560  histone H3.3A-like [KO:K11253]
118637194  histone H4 [KO:K11254]
118637195  histone H4 [KO:K11254]
118637197  histone H4 [KO:K11254]
118637198  histone H4 [KO:K11254]
118638012  histone H4 [KO:K11254]
118625801  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
118615645  DRD1; D(1A) dopamine receptor [KO:K04144]
118618303  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
118618304  neuroendocrine secretory protein 55-like [KO:K04632]
118628052  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
118632994  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
118620140  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
118637975  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
118639180  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
118643409  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
118641555  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
118624402  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
118616885  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
118617165  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
118629739  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
118627522  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
118640651  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
118626418  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
118638371  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
118615888  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
118639405  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
118621254  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
118629801  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
118619968  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
118626713  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
118616113  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
118642671  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
118620007  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
118634527  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
118620985  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
118628854  SLC29A2; equilibrative nucleoside transporter 2 [KO:K15014]
118632482  SLC29A3; equilibrative nucleoside transporter 3 [KO:K15014]
118640000  ADORA2A; adenosine receptor A2a [KO:K04266]
118641250  ADORA2B; adenosine receptor A2b [KO:K04267]
118617134  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
118626166  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
118615793  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
118624959  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
118625175  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
118623538  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
118620417  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
118628166  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
118629628  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
118637511  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
118615816  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
118620061  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
118621725  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
118631735  CRH; corticoliberin [KO:K05256]
118620213  NPY; pro-neuropeptide Y [KO:K05232]
118628031  BDNF; brain-derived neurotrophic factor isoform X1 [KO:K04355]
118629607  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
118637475  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118615745  SHC2; SHC-transforming protein 2 [KO:K17447]
118629877  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
118631532  SHC4; SHC-transforming protein 4 [KO:K17449]
118633806  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
118630966  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
118616724  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118643162  HRAS; GTPase HRas isoform X1 [KO:K02833]
118624619  KRAS; GTPase KRas isoform X1 [KO:K07827]
118637822  NRAS; GTPase NRas [KO:K07828]
118635666  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
118619570  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
118633343  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118628434  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
118640210  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
118642307  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
118618696  PDYN; proenkephalin-B [KO:K15840]
118640095  calmodulin-like [KO:K02183]
118640172  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
118617946  CALM1; calmodulin-1 [KO:K02183]
118619605  calmodulin-1 [KO:K02183]
118627560  calmodulin-like [KO:K02183]
118628169  calmodulin-1-like [KO:K02183]
118636313  calmodulin-1-like [KO:K02183]
118643424  CALML6; calmodulin-like protein 6 [KO:K02183]
118630484  CALM2; calmodulin-2 [KO:K02183]
118638252  CALM3; calmodulin-3 [KO:K02183]
118631897  calmodulin-like protein 3 [KO:K02183]
118634466  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:2.7.11.17]
118640013  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
118641608  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
118639216  FOSB; protein fosB isoform X1 [KO:K09029]
118634429  PPP1R1B; protein phosphatase 1 regulatory subunit 1B isoform X1 [KO:K15494]
118627965  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
118630486  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
118639818  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
118631794  PKIA; cAMP-dependent protein kinase inhibitor alpha [KO:K15985]
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
mmf04010  MAPK signaling pathway
mmf04728  Dopaminergic synapse
KO pathway
ko05034   
LinkDB

DBGET integrated database retrieval system