KEGG   PATHWAY: mmu05034Help
Entry
mmu05034                    Pathway                                
Name
Alcoholism - Mus musculus (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
BRITE hierarchy
Pathway map
Alcoholism
mmu05034

All organismsOrtholog table
Other DBs
BSID: 
GO: 
Organism
Mus musculus (mouse) [GN:mmu]
Gene
21823  
Th; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
13195  
Ddc; dopa decarboxylase [KO:K01593] [EC:4.1.1.28]
110877  
Slc18a1; solute carrier family 18 (vesicular monoamine), member 1 [KO:K08155]
214084  
Slc18a2; solute carrier family 18 (vesicular monoamine), member 2 [KO:K08155]
17161  
Maoa; monoamine oxidase A [KO:K00274] [EC:1.4.3.4]
109731  
Maob; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
13162  
Slc6a3; solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 [KO:K05036]
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]
242443  
Grin3a; glutamate receptor ionotropic, NMDA3A [KO:K05213]
170483  
Grin3b; glutamate receptor, ionotropic, NMDA3B [KO:K05214]
15182  
Hdac2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
433759  
Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
15183  
Hdac3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
208727  
Hdac4; histone deacetylase 4 [KO:K11406] [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]
170787  
Hdac10; histone deacetylase 10 [KO:K11407] [EC:3.5.1.98]
56233  
Hdac7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
70315  
Hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
79221  
Hdac9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
232232  
Hdac11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
15270  
H2afx; H2A histone family, member X [KO:K11251]
319176  
Hist2h2ac; histone cluster 2, H2ac [KO:K11251]
547160  
Gm14484; predicted gene 14484 [KO:K11251]
Gm14478; predicted gene 14478 [KO:K11251]
319163  
Hist1h2aa; histone cluster 1, H2aa [KO:K11251]
319165  
Hist1h2ad; histone cluster 1, H2ad [KO:K11251]
319166  
Hist1h2ae; histone cluster 1, H2ae [KO:K11251]
319167  
Hist1h2ag; histone cluster 1, H2ag [KO:K11251]
319168  
Hist1h2ah; histone cluster 1, H2ah [KO:K11251]
319169  
Hist1h2ak; histone cluster 1, H2ak [KO:K11251]
319170  
Hist1h2an; histone cluster 1, H2an [KO:K11251]
319171  
Hist1h2ap; histone cluster 1, H2ap [KO:K11251]
319172  
Hist1h2ab; histone cluster 1, H2ab [KO:K11251]
319173  
Hist1h2af; histone cluster 1, H2af [KO:K11251]
319191  
Hist1h2ai; histone cluster 1, H2ai [KO:K11251]
319192  
Hist2h2aa2; histone cluster 2, H2aa2 [KO:K11251]
665433  
Hist1h2ao; histone cluster 1, H2ao [KO:K11251]
319164  
Hist1h2ac; histone cluster 1, H2ac [KO:K11251]
26914  
H2afy; H2A histone family, member Y [KO:K11251]
404634  
H2afy2; H2A histone family, member Y2 [KO:K11251]
232440  
H2afj; H2A histone family, member J [KO:K11251]
Gm14482; predicted gene 14482 [KO:K11251]
Gm14477; predicted gene 14477 [KO:K11251]
621893  
Hist2h2ab; histone cluster 2, H2ab [KO:K11251]
77605  
H2afv; H2A histone family, member V [KO:K11251]
Gm14483; predicted gene 14483 [KO:K11251]
333452  
Gm5132; predicted gene 5132 [KO:K11251]
385328  
Gm5382; predicted gene 5382 [KO:K11251]
68231  
H2afb1; H2A histone family, member B1 [KO:K11251]
Gm14475; predicted gene 14475 [KO:K11251]
624153  
H2afb2-ps; H2A histone family, member B2, pseudogene [KO:K11251]
236663  
Gm4906; predicted gene 4906 [KO:K11251]
76383  
1700012L04Rik; RIKEN cDNA 1700012L04 gene [KO:K11251]
Gm16501; predicted gene 16501 [KO:K11251]
Gm14476; predicted gene 14476 [KO:K11251]
51788  
H2afz; H2A histone family, member Z [KO:K11251]
319162  
Hist3h2a; histone cluster 3, H2a [KO:K11251]
15267  
Hist2h2aa1; histone cluster 2, H2aa1 [KO:K11251]
547210  
Gm6026; predicted gene 6026 [KO:K11251]
624957  
H2afb3-ps; H2A histone family, member B3, pseudogene [KO:K11251]
547154  
Gm14501; predicted gene 14501 [KO:K11251]
Gm14474; predicted gene 14474 [KO:K11251]
Gm14920; predicted pseudogene 14920 [KO:K11251]
Gm14479; predicted gene 14479 [KO:K11251]
319189  
Hist2h2bb; histone cluster 2, H2bb [KO:K11252]
69389  
H2bfm; H2B histone family, member M [KO:K11252]
319177  
Hist1h2ba; histone cluster 1, H2ba [KO:K11252]
69382  
1700024P04Rik; RIKEN cDNA 1700024P04 gene [KO:K11252]
319179  
Hist1h2be; histone cluster 1, H2be [KO:K11252]
319186  
Hist1h2bm; histone cluster 1, H2bm [KO:K11252]
68024  
Hist1h2bc; histone cluster 1, H2bc [KO:K11252]
78303  
Hist3h2ba; histone cluster 3, H2ba [KO:K11252]
382522  
Hist3h2bb-ps; histone cluster 3, H2bb, pseudogene [KO:K11252]
319178  
Hist1h2bb; histone cluster 1, H2bb [KO:K11252]
319180  
Hist1h2bf; histone cluster 1, H2bf [KO:K11252]
319181  
Hist1h2bg; histone cluster 1, H2bg [KO:K11252]
319182  
Hist1h2bh; histone cluster 1, H2bh [KO:K11252]
319183  
Hist1h2bj; histone cluster 1, H2bj [KO:K11252]
319184  
Hist1h2bk; histone cluster 1, H2bk [KO:K11252]
319185  
Hist1h2bl; histone cluster 1, H2bl [KO:K11252]
319187  
Hist1h2bn; histone cluster 1, H2bn [KO:K11252]
319188  
Hist1h2bp; histone cluster 1, H2bp [KO:K11252]
319190  
Hist2h2be; histone cluster 2, H2be [KO:K11252]
665596  
Hist1h2bq; histone cluster 1, H2bq [KO:K11252]
665622  
Hist1h2br; histone cluster 1 H2br [KO:K11252]
15078  
H3f3a; H3 histone, family 3A [KO:K11253]
15081  
H3f3b; H3 histone, family 3B [KO:K11253]
625328  
H3f3c; H3 histone, family 3C [KO:K11253]
667250  
Gm12657; predicted gene 12657 [KO:K11253]
319152  
Hist1h3h; histone cluster 1, H3h [KO:K11253]
15077  
Hist2h3c1; histone cluster 2, H3c1 [KO:K11253]
260423  
Hist1h3f; histone cluster 1, H3f [KO:K11253]
319148  
Hist1h3c; histone cluster 1, H3c [KO:K11253]
319149  
Hist1h3d; histone cluster 1, H3d [KO:K11253]
319150  
Hist1h3b; histone cluster 1, H3b [KO:K11253]
319151  
Hist1h3e; histone cluster 1, H3e [KO:K11253]
319153  
Hist1h3i; histone cluster 1, H3i [KO:K11253]
319154  
Hist2h3b; histone cluster 2, H3b [KO:K11253]
360198  
Hist1h3a; histone cluster 1, H3a [KO:K11253]
97114  
Hist2h3c2; histone cluster 2, H3c2 [KO:K11253]
97908  
Hist1h3g; histone cluster 1, H3g [KO:K11253]
544973  
Gm10257; predicted gene 10257 [KO:K11253]
626150  
Gm12271; predicted gene 12271 [KO:K11253]
319155  
Hist1h4c; histone cluster 1, H4c [KO:K11254]
319156  
Hist1h4d; histone cluster 1, H4d [KO:K11254]
319157  
Hist1h4f; histone cluster 1, H4f [KO:K11254]
319158  
Hist1h4i; histone cluster 1, H4i [KO:K11254]
319159  
Hist1h4j; histone cluster 1, H4j [KO:K11254]
319160  
Hist1h4k; histone cluster 1, H4k [KO:K11254]
319161  
Hist1h4n; histone cluster 1, H4n [KO:K11254]
320332  
Hist4h4; histone cluster 4, H4 [KO:K11254]
326619  
Hist1h4a; histone cluster 1, H4a [KO:K11254]
326620  
Hist1h4b; histone cluster 1, H4b [KO:K11254]
69386  
Hist1h4h; histone cluster 1, H4h [KO:K11254]
97122  
Hist2h4; histone cluster 2, H4 [KO:K11254]
Hist1h4m; histone cluster 1, H4m [KO:K11254]
107435  
Hat1; histone aminotransferase 1 [KO:K11303] [EC:2.3.1.48]
13488  
Drd1a; dopamine receptor D1A [KO:K04144]
14683  
Gnas; GNAS (guanine nucleotide binding protein, alpha stimulating) complex locus [KO:K04632]
13489  
Drd2; dopamine receptor D2 [KO:K04145]
14677  
Gnai1; guanine nucleotide binding protein (G protein), alpha inhibiting 1 [KO:K04630]
14679  
Gnai3; guanine nucleotide binding protein (G protein), alpha inhibiting 3 [KO:K04630]
14678  
Gnai2; guanine nucleotide binding protein (G protein), alpha inhibiting 2 [KO:K04630]
14681  
Gnao1; guanine nucleotide binding protein, alpha O [KO:K04534]
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]
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; guanine nucleotide binding protein (G protein), gamma 5 [KO:K04542]
Gm15776; predicted gene 15776 [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]
14700  
Gng10; guanine nucleotide binding protein (G protein), gamma 10 [KO:K04545]
66066  
Gng11; guanine nucleotide binding protein (G protein), gamma 11 [KO:K04546]
14701  
Gng12; guanine nucleotide binding protein (G protein), gamma 12 [KO:K04347]
Gm5741; predicted gene 5741 [KO:K04347]
64337  
Gng13; guanine nucleotide binding protein (G protein), gamma 13 [KO:K04547]
14699  
Gngt1; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 [KO:K04548]
14710  
Gngt2; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 2 [KO:K04549]
11540  
Adora2a; adenosine A2a receptor [KO:K04266]
11541  
Adora2b; adenosine A2b receptor [KO:K04267]
224129  
Adcy5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
12912  
Creb1; cAMP responsive element binding protein 1 [KO:K05870]
11909  
Atf2; activating transcription factor 2 [KO:K04450]
11911  
Atf4; activating transcription factor 4 [KO:K04374]
12913  
Creb3; cAMP responsive element binding protein 3 [KO:K09048]
26427  
Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
208647  
Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
208677  
Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
78284  
Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
231991  
Creb5; cAMP responsive element binding protein 5 [KO:K09047]
12915  
Atf6b; activating transcription factor 6 beta [KO:K09049]
12918  
Crh; corticotropin releasing hormone [KO:K05256]
109648  
Npy; neuropeptide Y [KO:K05232]
12064  
Bdnf; brain derived neurotrophic factor [KO:K04355]
18212  
Ntrk2; neurotrophic tyrosine kinase, receptor, type 2 [KO:K04360] [EC:2.7.10.1]
20416  
Shc1; src homology 2 domain-containing transforming protein C1 [KO:K06279]
216148  
Shc2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
20418  
Shc3; src homology 2 domain-containing transforming protein C3 [KO:K17448]
271849  
Shc4; SHC (Src homology 2 domain containing) family, member 4 [KO:K17449]
14784  
Grb2; growth factor receptor bound protein 2 [KO:K04364]
20662  
Sos1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
20663  
Sos2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
15461  
Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  
Kras; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  
Nras; neuroblastoma ras oncogene [KO:K07828]
11836  
Araf; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
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]
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]
18610  
Pdyn; prodynorphin [KO:K15840]
12313  
Calm1; calmodulin 1 [KO:K02183]
80796  
Calm4; calmodulin 4 [KO:K02183]
12315  
Calm3; calmodulin 3 [KO:K02183]
12314  
Calm2; calmodulin 2 [KO:K02183]
70405  
Calml3; calmodulin-like 3 [KO:K02183]
494124  
Calm5; calmodulin 5 [KO:K02183]
55984  
Camkk1; calcium/calmodulin-dependent protein kinase kinase 1, alpha [KO:K07359] [EC:2.7.11.17]
207565  
Camkk2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:2.7.11.17]
12326  
Camk4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
14282  
Fosb; FBJ osteosarcoma oncogene B [KO:K09029]
19049  
Ppp1r1b; protein phosphatase 1, regulatory (inhibitor) subunit 1B [KO:K15494]
19045  
Ppp1ca; protein phosphatase 1, catalytic subunit, alpha isoform [KO:K06269] [EC:3.1.3.16]
19046  
Ppp1cb; protein phosphatase 1, catalytic subunit, beta isoform [KO:K06269] [EC:3.1.3.16]
19047  
Ppp1cc; protein phosphatase 1, catalytic subunit, gamma isoform [KO:K06269] [EC:3.1.3.16]
18767  
Pkia; protein kinase inhibitor, alpha [KO:K15985]
18747  
Prkaca; protein kinase, cAMP dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
63959  
Slc29a1; solute carrier family 29 (nucleoside transporters), member 1 [KO:K15014]
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
  Authors
Spanagel R
  Title
Alcoholism: a systems approach from molecular physiology to addictive behavior.
  Journal
Physiol Rev 89:649-705 (2009)
Reference
  Authors
Newton PM, Messing RO
  Title
Intracellular signaling pathways that regulate behavioral responses to ethanol.
  Journal
Pharmacol Ther 109:227-37 (2006)
Reference
  Authors
Mailliard WS, Diamond I
  Title
Recent advances in the neurobiology of alcoholism: the role of adenosine.
  Journal
Pharmacol Ther 101:39-46 (2004)
Reference
  Authors
Ron D, Jurd R
  Title
The "ups and downs" of signaling cascades in addiction.
  Journal
Sci STKE 2005:re14 (2005)
Reference
  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)
Reference
  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)
Reference
  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)
Reference
  Authors
Zhang TA, Maldve RE, Morrisett RA
  Title
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
  Journal
Biochem Pharmacol 72:919-27 (2006)
Reference
  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)
Reference
  Authors
Lovinger DM
  Title
NMDA receptors lose their inhibitions.
  Journal
Nat Neurosci 5:614-6 (2002)
Reference
  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)
Reference
  Authors
Berke JD, Hyman SE
  Title
Addiction, dopamine, and the molecular mechanisms of memory.
  Journal
Neuron 25:515-32 (2000)
Reference
  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
  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)
Reference
  Authors
Lee AM, Messing RO
  Title
Protein kinases and addiction.
  Journal
Ann N Y Acad Sci 1141:22-57 (2008)
Reference
  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)
Reference
  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)
Reference
  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)
Reference
  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)
Reference
  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)
KO pathway
 
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