KEGG   PATHWAY: rno05034Help
Entry
rno05034                    Pathway                                
Name
Alcoholism - Rattus norvegicus (rat)
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
rno05034

All organismsOrtholog table
Other DBs
BSID: 
GO: 
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
25085  
Th; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
24311  
Ddc; dopa decarboxylase (aromatic L-amino acid decarboxylase) [KO:K01593] [EC:4.1.1.28]
25549  
Slc18a2; solute carrier family 18 (vesicular monoamine), member 2 [KO:K08155]
25693  
Slc18a1; solute carrier family 18 (vesicular monoamine), member 1 [KO:K08155]
25750  
Maob; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
29253  
Maoa; monoamine oxidase A [KO:K00274] [EC:1.4.3.4]
24898  
Slc6a3; solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 [KO:K05036]
24408  
Grin1; glutamate receptor, ionotropic, N-methyl D-aspartate 1 [KO:K05208]
24409  
Grin2a; glutamate receptor, ionotropic, N-methyl D-aspartate 2A [KO:K05209]
24410  
Grin2b; glutamate receptor, ionotropic, N-methyl D-aspartate 2B [KO:K05210]
24411  
Grin2c; glutamate receptor, ionotropic, N-methyl D-aspartate 2C [KO:K05211]
24412  
Grin2d; glutamate receptor, ionotropic, N-methyl D-aspartate 2D [KO:K05212]
191573  
Grin3a; glutamate receptor, ionotropic, N-methyl-D-aspartate 3A [KO:K05213]
170796  
Grin3b; glutamate receptor, ionotropic, N-methyl-D-aspartate 3B [KO:K05214]
297893  
Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
84576  
Hdac1l; histone deacetylase 1-like [KO:K06067] [EC:3.5.1.98]
84577  
Hdac2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
84578  
Hdac3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
363287  
Hdac4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
84580  
Hdac5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
84581  
Hdac6; histone deacetylase 6 [KO:K11407] [EC:3.5.1.98]
362981  
Hdac10; histone deacetylase 10 [KO:K11407] [EC:3.5.1.98]
histone deacetylase 6-like; K11407 histone deacetylase 6/10 [EC:3.5.1.98] [KO:K11407] [EC:3.5.1.98]
84582  
Hdac7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
363481  
Hdac8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
histone deacetylase 8-like; K11405 histone deacetylase 8 [EC:3.5.1.98] [KO:K11405] [EC:3.5.1.98]
687001  
Hdac9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
297453  
Hdac11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
500987  
H2afx; H2A histone family, member X [KO:K11251]
499675  
Hist2h2ac; histone cluster 2, H2ac [KO:K11251]
64646  
Hist3h2a; histone cluster 3, H2a [KO:K11251]
24828  
Hist1h2aa; histone cluster 1, H2aa [KO:K11251]
306970  
Hist1h2an; histone cluster 1, H2an [KO:K11251]
498753  
Hist1h2af; histone cluster 1, H2af [KO:K11251]
502125  
Hist1h2ah; histone cluster 1, H2ah [KO:K11251]
502129  
Hist1h2ai; histone cluster 1, H2ai [KO:K11251]
680615  
Hist1h2ak; histone cluster 1, H2ak [KO:K11251]
684773  
similar to histone 2a; K11251 histone H2A [KO:K11251]
690102  
Hist2h2ab; histone cluster 2, H2ab [KO:K11251]
690131  
similar to H2A histone family; K11251 histone H2A [KO:K11251]
690795  
H2afj; H2A histone family, member J [KO:K11251]
306962  
Hist1h2ac; histone cluster 1, H2ac [KO:K11251]
29384  
H2afy; H2A histone family, member Y [KO:K11251]
361844  
H2afy2; H2A histone family, member Y2 [KO:K11251]
498894  
RGD1560813; similar to H2A histone family, member V isoform 1 [KO:K11251]
685069  
similar to H2A histone family; K11251 histone H2A [KO:K11251]
685909  
H2afv; similar to H2A histone family, member V isoform 1 [KO:K11251]
689408  
similar to H2A histone family; K11251 histone H2A [KO:K11251]
365877  
Hist2h2aa3; histone cluster 2, H2aa3 [KO:K11251]
58940  
H2afz; H2A histone family, member Z [KO:K11251]
680322  
similar to Histone H2A type 1; K11251 histone H2A [KO:K11251]
364723  
Hist1h2ao; histone cluster 1, H2ao [KO:K11251]
302783  
H2afb3; H2A histone family, member B3 [KO:K11251]
histone cluster 1; K11251 histone H2A [KO:K11251]
histone variant H2al2-like; K11251 histone H2A [KO:K11251]
histone H2A.J-like; K11251 histone H2A [KO:K11251]
histone H2A type 1-F-like; K11251 histone H2A [KO:K11251]
291157  
Hist1h2bo; histone cluster 1, H2bo [KO:K11252]
24829  
Hist1h2ba; histone cluster 1, H2ba [KO:K11252]
684444  
similar to HIStone family member (his-41); K11252 histone H2B [KO:K11252]
306945  
Hist1h2bh; histone cluster 1, H2bh [KO:K11252]
306969  
Hist1h2bf; histone cluster 1, H2bf [KO:K11252]
295274  
Hist2h2be; histone cluster 2, H2be [KO:K11252]
303175  
Hist3h2ba; histone cluster 3, H2ba [KO:K11252]
361247  
Hist1h2bd; histone cluster 1, H2bd [KO:K11252]
64647  
Hist1h2bl; histone cluster 1, H2bl [KO:K11252]
680403  
Hist1h2bcl1; histone cluster 1, H2bc-like 1 [KO:K11252]
684797  
similar to Histone H2B 291B; K11252 histone H2B [KO:K11252]
691488  
Hist3h2bb; histone cluster 3, H2bb [KO:K11252]
680312  
Hist1h2bk; histone cluster 1, H2bk [KO:K11252]
679105  
similar to histone 1; K11252 histone H2B [KO:K11252]
histone cluster 1; K11252 histone H2B [KO:K11252]
histone cluster 1; K11252 histone H2B [KO:K11252]
histone H2B type 1-C/E/G-like; K11252 histone H2B [KO:K11252]
histone H2B type 2-B-like; K11252 histone H2B [KO:K11252]
691496  
similar to histone 1; K11253 histone H3 [KO:K11253]
367254  
RGD1564447; similar to Zgc:56193 [KO:K11253]
686736  
similar to H3 histone; K11253 histone H3 [KO:K11253]
291159  
Hist1h2ail; histone cluster 1, H2ai-like [KO:K11253]
117056  
H3f3b; H3 histone, family 3B [KO:K11253]
310678  
Hist2h3c2; histone cluster 2, H3c2 [KO:K11253]
679994  
similar to histone 1; K11253 histone H3 [KO:K11253]
680498  
similar to CG31613-PA; K11253 histone H3 [KO:K11253]
682330  
similar to histone 1; K11253 histone H3 [KO:K11253]
684762  
similar to CG31613-PA; K11253 histone H3 [KO:K11253]
684819  
similar to H3 histone; K11253 histone H3 [KO:K11253]
684841  
similar to CG31613-PA; K11253 histone H3 [KO:K11253]
501977  
RGD1564953; similar to Histone H3.3 [KO:K11253]
500882  
RGD1564548; similar to H3 histone, family 3B [KO:K11253]
histone H3.3B-like; K11253 histone H3 [KO:K11253]
690126  
hypothetical protein LOC690126; K11253 histone H3 [KO:K11253]
295277  
Hist2h4; histone cluster 2, H4 [KO:K11254]
500351  
RGD1562378; histone H4 variant H4-v.1 [KO:K11254]
502913  
Hist2h4a; histone cluster 2, H4 [KO:K11254]
64627  
Hist1h4b; histone cluster 1, H4b [KO:K11254]
679983  
similar to germinal histone H4 gene; K11254 histone H4 [KO:K11254]
680097  
similar to germinal histone H4 gene; K11254 histone H4 [KO:K11254]
680430  
similar to germinal histone H4 gene; K11254 histone H4 [KO:K11254]
291152  
Hist1h4m; histone cluster 1, H4m [KO:K11254]
GF20391-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
histone H4-like; K11254 histone H4 [KO:K11254]
296501  
Hat1; histone acetyltransferase 1 [KO:K11303] [EC:2.3.1.48]
24316  
Drd1; dopamine receptor D1 [KO:K04144]
24896  
Gnas; GNAS complex locus [KO:K04632]
24318  
Drd2; dopamine receptor D2 [KO:K04145]
25686  
Gnai1; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 [KO:K04630]
25643  
Gnai3; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 [KO:K04630]
81664  
Gnai2; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2 [KO:K04630]
50664  
Gnao1; guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O [KO:K04534]
24400  
Gnb1; guanine nucleotide binding protein (G protein), beta polypeptide 1 [KO:K04536]
81667  
Gnb2; guanine nucleotide binding protein (G protein), beta polypeptide 2 [KO:K04537]
60449  
Gnb3; guanine nucleotide binding protein (G protein), beta polypeptide 3 [KO:K07825]
294962  
Gnb4; guanine nucleotide binding protein (G protein), beta polypeptide 4 [KO:K04538]
83579  
Gnb5; guanine nucleotide binding protein (G protein), beta 5 [KO:K04539]
80850  
Gng2; guanine nucleotide binding protein (G protein), gamma 2 [KO:K07826]
114117  
Gng3; guanine nucleotide binding protein (G protein), gamma 3 [KO:K04540]
114118  
Gng4; guanine nucleotide binding protein (G protein), gamma 4 subunit [KO:K04541]
79218  
Gng5; guanine nucleotide binding protein (G protein), gamma 5 [KO:K04542]
guanine nucleotide binding protein (G protein); K04542 guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
58979  
Gng7; guanine nucleotide binding protein (G protein), gamma 7 [KO:K04543]
245986  
Gng8; guanine nucleotide binding protein (G protein), gamma 8 [KO:K04544]
114119  
Gng10; guanine nucleotide binding protein (G protein), gamma 10 [KO:K04545]
64199  
Gng11; guanine nucleotide binding protein (G protein), gamma 11 [KO:K04546]
guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11-like; K04546 guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
114120  
Gng12; guanine nucleotide binding protein (G protein), gamma 12 [KO:K04347]
685513  
similar to Guanine nucleotide-binding protein G(I)/G(S)/G(O) gamma-12 subunit precursor; K04347 guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
685451  
Gng13; guanine nucleotide binding protein (G protein), gamma 13 [KO:K04547]
680149  
Gngt1; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 [KO:K04548]
690825  
Gngt2; guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 2 [KO:K04549]
25369  
Adora2a; adenosine A2a receptor [KO:K04266]
29316  
Adora2b; adenosine A2B receptor [KO:K04267]
64532  
Adcy5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
81646  
Creb1; cAMP responsive element binding protein 1 [KO:K05870]
81647  
Atf2; activating transcription factor 2 [KO:K04450]
79255  
Atf4; activating transcription factor 4 (tax-responsive enhancer element B67) [KO:K04374]
310616  
Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
362165  
Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
362339  
Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
314638  
Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
500131  
Creb5; cAMP responsive element binding protein 5 [KO:K09047]
406169  
Atf6b; activating transcription factor 6 beta [KO:K09049]
81648  
Crh; corticotropin releasing hormone [KO:K05256]
24604  
Npy; neuropeptide Y [KO:K05232]
pro-neuropeptide Y-like; K05232 neuropeptide Y [KO:K05232]
24225  
Bdnf; brain-derived neurotrophic factor [KO:K04355]
25054  
Ntrk2; neurotrophic tyrosine kinase, receptor, type 2 [KO:K04360] [EC:2.7.10.1]
114858  
Shc3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K06279]
314612  
Shc2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K06279]
85385  
Shc1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
679845  
Shc4; SHC (Src homology 2 domain containing) family, member 4 [KO:K06279]
81504  
Grb2; growth factor receptor bound protein 2 [KO:K04364]
85384  
Sos2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
313845  
Sos1; Son of sevenless homolog 1 (Drosophila) [KO:K03099]
293621  
Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
24525  
Kras; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
24605  
Nras; neuroblastoma ras oncogene [KO:K07828]
64363  
Araf; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:2.7.11.1]
114486  
Braf; v-raf murine sarcoma viral oncogene homolog B1 [KO:K04365] [EC:2.7.11.1]
24703  
Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]
170851  
Map2k1; mitogen activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
116590  
Mapk1; mitogen activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  
Mapk3; mitogen activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
29190  
Pdyn; prodynorphin [KO:K15840]
50663  
Calm2; calmodulin 2 [KO:K02183]
24242  
Calm1; calmodulin 1 [KO:K02183]
24244  
Calm3; calmodulin 3 [KO:K02183]
364774  
Calml5; calmodulin-like 5 [KO:K02183]
307100  
Calml3; calmodulin-like 3 [KO:K02183]
60341  
Camkk1; calcium/calmodulin-dependent protein kinase kinase 1, alpha [KO:K07359] [EC:2.7.11.17]
83506  
Camkk2; calcium/calmodulin-dependent protein kinase kinase 2, beta [KO:K07359] [EC:2.7.11.17]
25050  
Camk4; calcium/calmodulin-dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
Fosb; FBJ osteosarcoma oncogene B [KO:K09029]
360616  
Ppp1r1b; protein phosphatase 1, regulatory (inhibitor) subunit 1B [KO:K15494]
24668  
Ppp1ca; protein phosphatase 1, catalytic subunit, alpha isozyme [KO:K06269] [EC:3.1.3.16]
24669  
Ppp1cc; protein phosphatase 1, catalytic subunit, gamma isozyme [KO:K06269] [EC:3.1.3.16]
25594  
Ppp1cb; protein phosphatase 1, catalytic subunit, beta isozyme [KO:K06269] [EC:3.1.3.16]
114906  
Pkia; protein kinase (cAMP-dependent, catalytic) inhibitor alpha [KO:K15985]
25636  
Prkaca; protein kinase, cAMP-dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
63997  
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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