KEGG   PATHWAY: rno05034
rno05034                    Pathway                                

Alcoholism - Rattus norvegicus (rat)
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
Pathway map
rno05034  Alcoholism

Other DBs
GO: 0045471
Rattus norvegicus (rat) [GN:rno]
25085  Th; tyrosine 3-monooxygenase [KO:K00501] [EC:]
24311  Ddc; aromatic-L-amino-acid decarboxylase isoform a [KO:K01593] [EC:]
25549  Slc18a2; synaptic vesicular amine transporter [KO:K08155]
25693  Slc18a1; chromaffin granule amine transporter [KO:K08155]
25750  Maob; amine oxidase [flavin-containing] B [KO:K00274] [EC:]
29253  Maoa; amine oxidase [flavin-containing] A [KO:K00274] [EC:]
24898  Slc6a3; sodium-dependent dopamine transporter [KO:K05036]
24408  Grin1; glutamate receptor ionotropic, NMDA 1 isoform 1a precursor [KO:K05208]
24409  Grin2a; glutamate receptor ionotropic, NMDA 2A precursor [KO:K05209]
24410  Grin2b; glutamate receptor ionotropic, NMDA 2B precursor [KO:K05210]
24411  Grin2c; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
24412  Grin2d; glutamate receptor ionotropic, NMDA 2D precursor [KO:K05212]
191573  Grin3a; glutamate receptor ionotropic, NMDA 3A isoform 1 precursor [KO:K05213]
170796  Grin3b; glutamate receptor ionotropic, NMDA 3B precursor [KO:K05214]
297893  Hdac1; histone deacetylase 1 [KO:K06067] [EC:]
84576  Hdac1l; histone deacetylase 1-like [KO:K06067] [EC:]
84577  Hdac2; histone deacetylase 2 [KO:K06067] [EC:]
84578  Hdac3; histone deacetylase 3 [KO:K11404] [EC:]
363287  Hdac4; histone deacetylase 4 [KO:K11406] [EC:]
84580  Hdac5; histone deacetylase 5 [KO:K11406] [EC:]
108348065  histone deacetylase 6 [KO:K11407] [EC:]
84582  Hdac7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:]
363481  Hdac8; histone deacetylase 8 [KO:K11405] [EC:]
687001  Hdac9; histone deacetylase 9 [KO:K11409] [EC:]
362981  Hdac10; polyamine deacetylase HDAC10 [KO:K18671] [EC:]
297453  Hdac11; histone deacetylase 11 [KO:K11418] [EC:]
500987  H2ax; H2A.X variant histone [KO:K11251]
499675  H2ac20; histone H2A type 2-C [KO:K11251]
64646  Hist3h2a; histone H2A type 3 [KO:K11251]
24828  H2ac1; histone H2A type 4 [KO:K11251]
306970  Hist1h2an; histone cluster 1, H2an [KO:K11251]
498753  Hist1h2af; histone H2a [KO:K11251]
502125  Hist1h2ah; histone H2A type 1-E [KO:K11251]
502129  hist1h2ail2; histone H2A type 1-B [KO:K11251]
680615  Hist1h2ak; histone cluster 1, H2ak [KO:K11251]
690102  H2ac21; H2A clustered histone 21 [KO:K11251]
690131  Hist2h2aa2; histone H2A type 2-A [KO:K11251]
690795  H2aj; histone H2A.J [KO:K11251]
306962  Hist1h2ac; histone H2A type 1-B [KO:K11251]
29384  Macroh2a1; core histone macro-H2A.1 [KO:K11251]
361844  Macroh2a2; core histone macro-H2A.2 [KO:K11251]
498894  RGD1560813; histone H2A.V-like [KO:K11251]
685069  histone H2A.V-like [KO:K11251]
685909  H2az2; H2A.Z variant histone 2 [KO:K11251]
689408  histone H2A.V-like [KO:K11251]
365877  Hist2h2aa3; histone H2A type 1 [KO:K11251]
58940  H2az1; histone H2A.Z [KO:K11251]
680322  H2ac12; histone H2A type 1-H [KO:K11251]
302783  H2ab3; H2A.B variant histone 3 [KO:K11251]
100360754  Hist1h2ai; histone H2A type 1-B [KO:K11251]
100363171  histone H2A-Bbd type 1 [KO:K11251]
100910554  histone H2A type 1-B-like [KO:K11251]
103690190  histone H2A type 1-E [KO:K11251]
684773  histone H2A type 1-B [KO:K11251]
291157  Hist1h2bo; histone cluster 1 H2B family member o [KO:K11252]
24829  H2bc1; histone H2B type 1-A [KO:K11252]
684444  histone H2B subacrosomal variant [KO:K11252]
306945  Hist1h2bq; histone cluster 1 H2B family member Q [KO:K11252]
306969  Hist1h2bl; histone H2B type 1-C/E/F/G/I [KO:K11252]
295274  Hist2h2be; histone H2B type 2-E [KO:K11252]
303175  Hist3h2ba; histone cluster 3, H2ba [KO:K11252]
361247  Hist1h2bd; histone cluster 1 H2B family member D [KO:K11252]
64647  Hist1h2bg; histone H2B type 1 [KO:K11252]
680403  Hist1h2bc; histone H2B type 1-C/E/F/G/I [KO:K11252]
684797  histone H2B type 1-C/E/F/G/I [KO:K11252]
691488  H2bu1; H2B.U histone 1 [KO:K11252]
680312  H2bc12; histone H2B [KO:K11252]
100364835  histone H2B type 1-C/E/F/G/I [KO:K11252]
100365043  histone H2B type 1-C/E/F/G/I [KO:K11252]
100910200  histone H2B type 1-C/E/F/G/I [KO:K11252]
100912338  histone H2B type 2-F [KO:K11252]
102549061  histone H2B type 1-B [KO:K11252]
103690887  histone H2B-like [KO:K11252]
100359692  H2bc9; histone H2B type 1-C/E/F/G/I [KO:K11252]
691496  H3f4; H3.4 histone [KO:K11253]
367254  RGD1564447; histone H3.3A-like [KO:K11253]
291159  Hist1h2ail1; histone H3.1 [KO:K11253]
117056  H3f3b; histone H3.3 [KO:K11253]
310678  Hist2h3c2; histone cluster 2 H3 family member C2 [KO:K11253]
679994  H3c1; histone H3.1 [KO:K11253]
680498  Hist1h3b; histone H3.1 [KO:K11253]
684762  H3c13; histone H3 [KO:K11253]
500882  RGD1564548; histone H3.3A-like [KO:K11253]
100361558  H3f3a; histone H3.3A [KO:K11253]
102551184  uncharacterized protein LOC102551184 [KO:K11253]
102549173  LOW QUALITY PROTEIN: uncharacterized protein LOC102549173 [KO:K11253]
102548682  uncharacterized protein LOC102548682 [KO:K11253]
100360868  H3f3c; histone H3.3A [KO:K11253]
100360950  histone H3.1 [KO:K11253]
100359421  histone H3.3A-like [KO:K11253]
108349691  histone H3.3A-like [KO:K11253]
295277  Hist2h4; histone H4 [KO:K11254]
64627  Hist1h4b; histone H4 [KO:K11254]
291152  Hist1h4m; histone H4 [KO:K11254]
364723  Hist1h2ao; histone H2A type 1-E [KO:K11254]
296501  Hat1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:]
24316  Drd1; D(1A) dopamine receptor [KO:K04144]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
24318  Drd2; D(2) dopamine receptor [KO:K04145]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
50664  Gnao1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
24400  Gnb1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
81667  Gnb2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
60449  Gnb3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
294962  Gnb4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
83579  Gnb5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
80850  Gng2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
114117  Gng3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
114118  Gng4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
79218  Gng5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
108349548  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
58979  Gng7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
245986  Gng8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
114119  Gng10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
64199  Gng11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
114120  Gng12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
685513  Gng14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
685451  Gng13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
680149  Gngt1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
690825  Gngt2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
353307  Slc29a3; equilibrative nucleoside transporter 3 [KO:K15014]
63997  Slc29a1; equilibrative nucleoside transporter 1 [KO:K15014]
65194  Slc29a2; equilibrative nucleoside transporter 2 [KO:K15014]
25369  Adora2a; adenosine receptor A2a A2AR [KO:K04266]
29316  Adora2b; adenosine receptor A2b [KO:K04267]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
81648  Crh; corticoliberin precursor [KO:K05256]
24604  Npy; pro-neuropeptide Y preproprotein [KO:K05232]
24225  Bdnf; brain-derived neurotrophic factor isoform 3 preproprotein [KO:K04355]
25054  Ntrk2; BDNF/NT-3 growth factors receptor isoform 1 precursor [KO:K04360] [EC:]
85385  Shc1; SHC-transforming protein 1 isoform b [KO:K06279]
314612  Shc2; SHC-transforming protein 2 [KO:K17447]
114858  Shc3; SHC-transforming protein 3 [KO:K17448]
679845  Shc4; SHC-transforming protein 4 [KO:K17449]
81504  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
85384  Sos2; son of sevenless homolog 2 [KO:K03099]
313845  Sos1; son of sevenless homolog 1 [KO:K03099]
293621  Hras; GTPase HRas [KO:K02833]
367858  GTPase HRas [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
64363  Araf; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:]
114486  Braf; serine/threonine-protein kinase B-raf isoform X6 [KO:K04365] [EC:]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
29190  Pdyn; proenkephalin-B preproprotein [KO:K15840]
50663  Calm2; calmodulin-2 [KO:K02183]
24242  Calm1; calmodulin-1 [KO:K02183]
24244  Calm3; calmodulin-3 [KO:K02183]
364774  Calml5; calmodulin-like protein 5 [KO:K02183]
307100  Calml3; calmodulin-like protein 3 [KO:K02183]
691455  Calml4; calmodulin-like protein 4 [KO:K02183]
60341  Camkk1; calcium/calmodulin-dependent protein kinase kinase 1 [KO:K00908] [EC:]
83506  Camkk2; calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:]
25050  Camk4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:]
100360880  Fosb; protein fosB [KO:K09029]
360616  Ppp1r1b; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
24668  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:]
24669  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269] [EC:]
25594  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:]
100363225  disks large homolog 5-like isoform X1 [KO:K06269] [EC:]
114906  Pkia; cAMP-dependent protein kinase inhibitor alpha [KO:K15985]
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)
rno04010  MAPK signaling pathway
rno04728  Dopaminergic synapse
KO pathway

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