KEGG   PATHWAY: mmu05034
Entry
mmu05034                    Pathway                                
Name
Alcoholism - Mus musculus (house mouse)
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
mmu05034  Alcoholism
mmu05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Mus musculus (house mouse) [GN:mmu]
Gene
100039319  H2ab1; H2A.B variant histone 1 [KO:K11251]
100041230  H4c17; H4 clustered histone 17 [KO:K11254]
100042840  H2al2b; H2A histone family member L2B [KO:K11251]
100042922  H2al1a; H2A histone family member L1A [KO:K11251]
100042927  H2al1b; H2A histone family member L1B [KO:K11251]
100042929  H2al1c; H2A histone family member L1C [KO:K11251]
100042931  H2al1d; H2A histone family member L1D [KO:K11251]
100042939  H2al1f; H2A histone family member L1F [KO:K11251]
100042943  H2al1g; H2A histone family member L1G [KO:K11251]
100042944  H2al1h; H2A histone family member L1H [KO:K11251]
100042946  H2al1i; H2A histone family member L1I [KO:K11251]
100043318  Gng5c; G protein subunit gamma 5C [KO:K04542]
100503710  Gng14; G protein subunit gamma 14 [KO:K04347]
102633809  Gm3785; predicted gene 3785 [KO:K04542]
105242736  Gm6749; predicted pseudogene 6749 [KO:K11253]
107435  Hat1; histone aminotransferase 1 [KO:K11303] [EC:2.3.1.48]
109648  Npy; neuropeptide Y [KO:K05232]
109731  Maob; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
109880  Braf; Braf transforming gene [KO:K04365] [EC:2.7.11.1]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]
110877  Slc18a1; solute carrier family 18 (vesicular monoamine), member 1 [KO:K08155]
11540  Adora2a; adenosine A2a receptor [KO:K04266]
11541  Adora2b; adenosine A2b receptor [KO:K04267]
115488119  Gm47655; predicted gene, 47655 [KO:K11253]
115490335  Gm44180; predicted gene, 44180 [KO:K11253]
11836  Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
11909  Atf2; activating transcription factor 2 [KO:K04450]
11911  Atf4; activating transcription factor 4 [KO:K04374]
12064  Bdnf; brain derived neurotrophic factor [KO:K04355]
12313  Calm1; calmodulin 1 [KO:K02183]
12314  Calm2; calmodulin 2 [KO:K02183]
12315  Calm3; calmodulin 3 [KO:K02183]
12326  Camk4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
12912  Creb1; cAMP responsive element binding protein 1 [KO:K05870]
12913  Creb3; cAMP responsive element binding protein 3 [KO:K09048]
12915  Atf6b; activating transcription factor 6 beta [KO:K09049]
12918  Crh; corticotropin releasing hormone [KO:K05256]
13162  Slc6a3; solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 [KO:K05036]
13195  Ddc; dopa decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
13340  Slc29a2; solute carrier family 29 (nucleoside transporters), member 2 [KO:K15014]
13488  Drd1; dopamine receptor D1 [KO:K04144]
13489  Drd2; dopamine receptor D2 [KO:K04145]
14282  Fosb; FBJ osteosarcoma oncogene B [KO:K09029]
14677  Gnai1; G protein subunit alpha i1 [KO:K04630]
14678  Gnai2; G protein subunit alpha i2 [KO:K04630]
14679  Gnai3; G protein subunit alpha i3 [KO:K04630]
14681  Gnao1; guanine nucleotide binding protein, alpha O [KO:K04534]
14683  Gnas; GNAS complex locus [KO:K04632]
14688  Gnb1; guanine nucleotide binding protein (G protein), beta 1 [KO:K04536]
14693  Gnb2; guanine nucleotide binding protein (G protein), beta 2 [KO:K04537]
14695  Gnb3; guanine nucleotide binding protein (G protein), beta 3 [KO:K07825]
14696  Gnb4; guanine nucleotide binding protein (G protein), beta 4 [KO:K04538]
14697  Gnb5; guanine nucleotide binding protein (G protein), beta 5 [KO:K04539]
14699  Gngt1; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 [KO:K04548]
14700  Gng10; guanine nucleotide binding protein (G protein), gamma 10 [KO:K04545]
14701  Gng12; guanine nucleotide binding protein (G protein), gamma 12 [KO:K04347]
14702  Gng2; guanine nucleotide binding protein (G protein), gamma 2 [KO:K07826]
14704  Gng3; guanine nucleotide binding protein (G protein), gamma 3 [KO:K04540]
14706  Gng4; guanine nucleotide binding protein (G protein), gamma 4 [KO:K04541]
14707  Gng5; G protein subunit gamma 5 [KO:K04542]
14708  Gng7; guanine nucleotide binding protein (G protein), gamma 7 [KO:K04543]
14709  Gng8; guanine nucleotide binding protein (G protein), gamma 8 [KO:K04544]
14710  Gngt2; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 2 [KO:K04549]
14784  Grb2; growth factor receptor bound protein 2 [KO:K04364]
14810  Grin1; glutamate receptor, ionotropic, NMDA1 (zeta 1) [KO:K05208]
14811  Grin2a; glutamate receptor, ionotropic, NMDA2A (epsilon 1) [KO:K05209]
14812  Grin2b; glutamate receptor, ionotropic, NMDA2B (epsilon 2) [KO:K05210]
14813  Grin2c; glutamate receptor, ionotropic, NMDA2C (epsilon 3) [KO:K05211]
14814  Grin2d; glutamate receptor, ionotropic, NMDA2D (epsilon 4) [KO:K05212]
15077  H3c14; H3 clustered histone 14 [KO:K11253]
15078  H3f3a; H3.3 histone A [KO:K11253]
15081  H3f3b; H3.3 histone B [KO:K11253]
15182  Hdac2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
15183  Hdac3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
15184  Hdac5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
15185  Hdac6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
15267  H2ac18; H2A clustered histone 18 [KO:K11251]
15270  H2ax; H2A.X variant histone [KO:K11251]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
170483  Grin3b; glutamate receptor, ionotropic, NMDA3B [KO:K05214]
170787  Hdac10; histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
17161  Maoa; monoamine oxidase A [KO:K00274] [EC:1.4.3.4]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
18212  Ntrk2; neurotrophic tyrosine kinase, receptor, type 2 [KO:K04360] [EC:2.7.10.1]
18610  Pdyn; prodynorphin [KO:K15840]
18747  Prkaca; protein kinase, cAMP dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
18749  Prkacb; protein kinase, cAMP dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
18767  Pkia; protein kinase inhibitor, alpha [KO:K15985]
19045  Ppp1ca; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
19046  Ppp1cb; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
19047  Ppp1cc; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
19049  Ppp1r1b; protein phosphatase 1, regulatory inhibitor subunit 1B [KO:K15494]
20416  Shc1; src homology 2 domain-containing transforming protein C1 [KO:K06279]
20418  Shc3; src homology 2 domain-containing transforming protein C3 [KO:K17448]
20662  Sos1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
20663  Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
207565  Camkk2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:2.7.11.17]
208647  Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
208677  Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
208727  Hdac4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
214084  Slc18a2; solute carrier family 18 (vesicular monoamine), member 2 [KO:K08155]
216148  Shc2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
21823  Th; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
224129  Adcy5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
231991  Creb5; cAMP responsive element binding protein 5 [KO:K09047]
232232  Hdac11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
232440  H2aj; H2J.A histone [KO:K11251]
236663  H2al1j; H2A histone family member L1J [KO:K11251]
242443  Grin3a; glutamate receptor ionotropic, NMDA3A [KO:K05213]
260423  H3c7; H3 clustered histone 7 [KO:K11253]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
26427  Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
26914  Macroh2a1; macroH2A.1 histone [KO:K11251]
271849  Shc4; SHC (Src homology 2 domain containing) family, member 4 [KO:K17449]
319148  H3c3; H3 clustered histone 3 [KO:K11253]
319149  H3c4; H3 clustered histone 4 [KO:K11253]
319150  H3c2; H3 clustered histone 2 [KO:K11253]
319151  H3c6; H3 clustered histone 6 [KO:K11253]
319152  H3c10; H3 clustered histone 10 [KO:K11253]
319153  H3c11; H3 clustered histone 11 [KO:K11253]
319154  H3c13; H3 clustered histone 13 [KO:K11253]
319155  H4c3; H4 clustered histone 3 [KO:K11254]
319156  H4c4; H4 clustered histone 4 [KO:K11254]
319157  H4c6; H4 clustered histone 6 [KO:K11254]
319158  H4c9; H4 clustered histone 9 [KO:K11254]
319159  H4c11; H4 clustered histone 11 [KO:K11254]
319160  H4c12; H4 clustered histone 12 [KO:K11254]
319161  H4c18; H4 clustered histone 18 [KO:K11254]
319162  H2ac25; H2A clustered histone 25 [KO:K11251]
319163  H2ac1; H2A clustered histone 1 [KO:K11251]
319164  H2ac6; H2A clustered histone 6 [KO:K11251]
319165  H2ac7; H2A clustered histone 7 [KO:K11251]
319166  H2ac8; H2A clustered histone 8 [KO:K11251]
319167  H2ac11; H2A clustered histone 11 [KO:K11251]
319168  H2ac12; H2A clustered histone 12 [KO:K11251]
319169  H2ac15; H2A clustered histone 15 [KO:K11251]
319170  H2ac22; H2A clustered histone 22 [KO:K11251]
319171  H2ac24; H2A clustered histone 24 [KO:K11251]
319172  H2ac4; H2A clustered histone 4 [KO:K11251]
319173  H2ac10; H2A clustered histone 10 [KO:K11251]
319176  H2ac20; H2A clustered histone 20 [KO:K11251]
319177  H2bc1; H2B clustered histone 1 [KO:K11252]
319178  H2bc3; H2B clustered histone 3 [KO:K11252]
319179  H2bc6; H2B clustered histone 6 [KO:K11252]
319180  H2bc7; H2B clustered histone 7 [KO:K11252]
319181  H2bc8; H2B clustered histone 8 [KO:K11252]
319182  H2bc9; H2B clustered histone 9 [KO:K11252]
319183  H2bc11; H2B clustered histone 11 [KO:K11252]
319184  H2bc12; H2B clustered histone 12 [KO:K11252]
319185  H2bc13; H2B clustered histone 13 [KO:K11252]
319186  H2bc14; H2B clustered histone 14 [KO:K11252]
319187  H2bc15; H2B clustered histone 15 [KO:K11252]
319188  H2bc22; H2B clustered histone 22 [KO:K11252]
319189  H2bc18; H2B clustered histone 18 [KO:K11252]
319190  H2bc21; H2B clustered histone 21 [KO:K11252]
319191  H2ac13; H2A clustered histone 13 [KO:K11251]
319192  H2ac19; H2A clustered histone 19 [KO:K11251]
320332  H4c16; H4 histone 16 [KO:K11254]
326619  H4c1; H4 clustered histone 1 [KO:K11254]
326620  H4c2; H4 clustered histone 2 [KO:K11254]
333452  H2al1o; H2A histone family member L1O [KO:K11251]
360198  H3c1; H3 clustered histone 1 [KO:K11253]
382522  H2bc26; H2B clustered histone 26 [KO:K11252]
382523  H3f4; H3.4 histone, cluster member [KO:K11253]
385317  H2al3; H2A histone family member L3 [KO:K11251]
385328  H2al1n; H2A histone family member L1N [KO:K11251]
404634  Macroh2a2; macroH2A.2 histone [KO:K11251]
433759  Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
434233  Ppp1ccb; protein phosphatase 1 catalytic subunit gamma B [KO:K06269] [EC:3.1.3.16]
494124  Calm5; calmodulin 5 [KO:K02183]
51788  H2az1; H2A.Z variant histone 1 [KO:K11251]
547154  H2al1k; H2A histone family member L1K [KO:K11251]
547160  H2al1e; H2A histone family member L1E [KO:K11251]
547210  H2al2c; H2A histone family member L2C [KO:K11251]
55984  Camkk1; calcium/calmodulin-dependent protein kinase kinase 1, alpha [KO:K00908] [EC:2.7.11.17]
56233  Hdac7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
621893  H2ac21; H2A clustered histone 21 [KO:K11251]
624153  H2ab2; H2A.B variant histone 2 [KO:K11251]
624957  H2ab3; H2A.B variant histone 3 [KO:K11251]
625328  H3f3c; H3 histone, family 3C [KO:K11253]
63959  Slc29a1; solute carrier family 29 (nucleoside transporters), member 1 [KO:K15014]
64337  Gng13; guanine nucleotide binding protein (G protein), gamma 13 [KO:K04547]
66066  Gng11; guanine nucleotide binding protein (G protein), gamma 11 [KO:K04546]
665433  H2ac23; H2A clustered histone 23 [KO:K11251]
665596  H2bc23; H2B clustered histone 23 [KO:K11252]
665622  H2bc24; H2B clustered histone 24 [KO:K11252]
667250  H3f5; H3.5 histone [KO:K11253]
68024  H2bc4; H2B clustered histone 4 [KO:K11252]
68231  H2al2a; H2A histone family member L2A [KO:K11251]
69382  H2bl1; H2B.L histone variant 1 [KO:K11252]
69386  H4c8; H4 clustered histone 8 [KO:K11254]
69389  H2bw2; H2B.W histone 2 [KO:K11252]
70315  Hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
70405  Calml3; calmodulin-like 3 [KO:K02183]
71279  Slc29a3; solute carrier family 29 (nucleoside transporters), member 3 [KO:K15014]
75600  Calml4; calmodulin-like 4 [KO:K02183]
76383  H2al1m; H2A histone family member L1M [KO:K11251]
77605  H2az2; H2A.Z histone variant 2 [KO:K11251]
78284  Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
78303  H2bc27; H2B clustered histone 27 [KO:K11252]
79221  Hdac9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
80796  Calm4; calmodulin 4 [KO:K02183]
97114  H3c15; H3 clustered histone 15 [KO:K11253]
97122  H4c14; H4 clustered histone 14 [KO:K11254]
97908  H3c8; H3 clustered histone 8 [KO:K11253]
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
mmu04010  MAPK signaling pathway
mmu04728  Dopaminergic synapse
KO pathway
ko05034   

  All links  
No link information was found.
DBGET integrated database retrieval system