KEGG   PATHWAY: mmu05034Help
mmu05034                    Pathway                                

Alcoholism - Mus musculus (mouse)
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.
Human Diseases; Substance dependence
BRITE hierarchy
Pathway map
mmu05034  Alcoholism

Ortholog table
Other DBs
BSID: 585577
GO: 0045471
Mus musculus (mouse) [GN:mmu]
21823  Th; tyrosine hydroxylase [KO:K00501] [EC:]
13195  Ddc; dopa decarboxylase [KO:K01593] [EC:]
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:]
109731  Maob; monoamine oxidase B [KO:K00274] [EC:]
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:]
433759  Hdac1; histone deacetylase 1 [KO:K06067] [EC:]
15183  Hdac3; histone deacetylase 3 [KO:K11404] [EC:]
208727  Hdac4; histone deacetylase 4 [KO:K11406] [EC:]
15184  Hdac5; histone deacetylase 5 [KO:K11406] [EC:]
15185  Hdac6; histone deacetylase 6 [KO:K11407] [EC:]
56233  Hdac7; histone deacetylase 7 [KO:K11408] [EC:]
70315  Hdac8; histone deacetylase 8 [KO:K11405] [EC:]
79221  Hdac9; histone deacetylase 9 [KO:K11409] [EC:]
170787  Hdac10; histone deacetylase 10 [KO:K18671] [EC:]
232232  Hdac11; histone deacetylase 11 [KO:K11418] [EC:]
15270  H2afx; H2A histone family, member X [KO:K11251]
319176  Hist2h2ac; histone cluster 2, H2ac [KO:K11251]
547160  H2al1e; H2A histone family member L1E [KO:K11251]
100042944  H2al1h; H2A histone family member L1H [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]
100042943  H2al1g; H2A histone family member L1G [KO:K11251]
100042929  H2al1c; H2A histone family member L1C [KO:K11251]
621893  Hist2h2ab; histone cluster 2, H2ab [KO:K11251]
77605  H2afv; H2A histone family, member V [KO:K11251]
100042922  H2al1a; H2A histone family member L1A [KO:K11251]
333452  H2al1o; H2A histone family member L1O [KO:K11251]
385328  H2al1n; H2A histone family member L1N [KO:K11251]
68231  H2afb1; H2A histone family, member B1 [KO:K11251]
100042946  H2al1i; H2A histone family member L1I [KO:K11251]
624153  H2afb2; H2A histone family, member B2 [KO:K11251]
236663  H2al1j; H2A histone family member L1J [KO:K11251]
76383  H2al1m; H2A histone family member L1M [KO:K11251]
100042840  H2al2b; H2A histone family member L2B [KO:K11251]
100042931  H2al1d; H2A histone family member L1D [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  H2al2c; H2A histone family member L2C [KO:K11251]
624957  H2afb3; H2A histone family, member B3 [KO:K11251]
547154  H2al1k; H2A histone family member L1K [KO:K11251]
100042927  H2al1b; H2A histone family member L1B [KO:K11251]
100039319  Gm14920; predicted pseudogene 14920 [KO:K11251]
100042939  H2al1f; H2A histone family member L1F [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]
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]
382523  Gm12260; predicted gene 12260 [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]
100041230  Hist1h4m; histone cluster 1, H4m [KO:K11254]
107435  Hat1; histone aminotransferase 1 [KO:K11303] [EC:]
13488  Drd1; dopamine receptor D1 [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]
100043507  Gng5-ps; G protein subunit gamma 5, pseudogene [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]
100503710  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:]
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:]
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; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
20663  Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
11836  Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:]
109880  Braf; Braf transforming gene [KO:K04365] [EC:]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
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]
75600  Calml4; calmodulin-like 4 [KO:K02183]
55984  Camkk1; calcium/calmodulin-dependent protein kinase kinase 1, alpha [KO:K00908] [EC:]
207565  Camkk2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:]
12326  Camk4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:]
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:]
19046  Ppp1cb; protein phosphatase 1, catalytic subunit, beta isoform [KO:K06269] [EC:]
19047  Ppp1cc; protein phosphatase 1, catalytic subunit, gamma isoform [KO:K06269] [EC:]
434233  Gm5601; predicted pseudogene 5601 [KO:K06269] [EC:]
18767  Pkia; protein kinase inhibitor, alpha [KO:K15985]
18747  Prkaca; protein kinase, cAMP dependent, catalytic, alpha [KO:K04345] [EC:]
63959  Slc29a1; solute carrier family 29 (nucleoside transporters), member 1 [KO:K15014]
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
Spanagel R
Alcoholism: a systems approach from molecular physiology to addictive behavior.
Physiol Rev 89:649-705 (2009)
Newton PM, Messing RO
Intracellular signaling pathways that regulate behavioral responses to ethanol.
Pharmacol Ther 109:227-37 (2006)
Mailliard WS, Diamond I
Recent advances in the neurobiology of alcoholism: the role of adenosine.
Pharmacol Ther 101:39-46 (2004)
Ron D, Jurd R
The "ups and downs" of signaling cascades in addiction.
Sci STKE 2005:re14 (2005)
Diana M, Brodie M, Muntoni A, Puddu MC, Pillolla G, Steffensen S, Spiga S, Little HJ
Enduring effects of chronic ethanol in the CNS: basis for alcoholism.
Alcohol Clin Exp Res 27:354-61 (2003)
Moonat S, Starkman BG, Sakharkar A, Pandey SC
Neuroscience of alcoholism: molecular and cellular mechanisms.
Cell Mol Life Sci 67:73-88 (2010)
Pandey SC
The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction.
Pharmacol Ther 104:47-58 (2004)
Zhang TA, Maldve RE, Morrisett RA
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
Biochem Pharmacol 72:919-27 (2006)
Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA
DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens.
Nat Neurosci 5:641-8 (2002)
Lovinger DM
NMDA receptors lose their inhibitions.
Nat Neurosci 5:614-6 (2002)
Hyman SE, Malenka RC, Nestler EJ
Neural mechanisms of addiction: the role of reward-related learning and memory.
Annu Rev Neurosci 29:565-98 (2006)
Berke JD, Hyman SE
Addiction, dopamine, and the molecular mechanisms of memory.
Neuron 25:515-32 (2000)
Clapp P, Bhave SV, Hoffman PL
How Adaptation of the Brain to Alcohol Leads to Dependence: A Pharmacological Perspective.
Alcohol Res Health 31:310-339 (2008)
Jeanes ZM, Buske TR, Morrisett RA
In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell.
J Pharmacol Exp Ther 336:155-64 (2011)
Lee AM, Messing RO
Protein kinases and addiction.
Ann N Y Acad Sci 1141:22-57 (2008)
Repunte-Canonigo V, Lutjens R, van der Stap LD, Sanna PP
Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.
Brain Res 1138:48-56 (2007)
Logrip ML, Janak PH, Ron D
Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.
FASEB J 22:2393-404 (2008)
Shukla SD, Velazquez J, French SW, Lu SC, Ticku MK, Zakhari S
Emerging role of epigenetics in the actions of alcohol.
Alcohol Clin Exp Res 32:1525-34 (2008)
Pascual M, Boix J, Felipo V, Guerri C
Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.
J Neurochem 108:920-31 (2009)
Li J, Cheng Y, Bian W, Liu X, Zhang C, Ye JH
Region-specific induction of FosB/DeltaFosB by voluntary alcohol intake: effects of naltrexone.
Alcohol Clin Exp Res 34:1742-50 (2010)
KO pathway

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