KEGG   PATHWAY: lcat05034
Entry
lcat05034                   Pathway                                
Name
Alcoholism - Lemur catta (Ring-tailed lemur)
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
lcat05034  Alcoholism
lcat05034

Disease
H01611  Alcohol dependence
Other DBs
GO: 0045471
Organism
Lemur catta (Ring-tailed lemur) [GN:lcat]
Gene
123620635  CAMKK1; calcium/calmodulin-dependent protein kinase kinase 1 isoform X1 [KO:K00908] [EC:2.7.11.17]
123620748  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
123620832  PPP1R1B; protein phosphatase 1 regulatory subunit 1B [KO:K15494]
123621017  HDAC5; histone deacetylase 5 isoform X1 [KO:K11406] [EC:3.5.1.98]
123622308  [KO:K04632]
123622310  [KO:K04632]
123622389  SHC4; SHC-transforming protein 4 [KO:K17449]
123622515  PDYN; proenkephalin-B [KO:K15840]
123622795  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
123623035  CALML3; calmodulin-like protein 3 [KO:K02183]
123623036  CALML5; calmodulin-like protein 5 [KO:K02183]
123623141  DRD1; D(1A) dopamine receptor [KO:K04144]
123623249  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
123623873  GRIN2D; glutamate receptor ionotropic, NMDA 2D [KO:K05212]
123623917  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
123623919  CALM3; calmodulin-3 [KO:K02183]
123623954  FOSB; protein fosB [KO:K09029]
123625313  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
123625701  ADORA2A; LOW QUALITY PROTEIN: adenosine receptor A2a [KO:K04266]
123626056  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
123626079  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
123626228  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
123626346  SLC18A1; chromaffin granule amine transporter isoform X1 [KO:K08155]
123627362  [KO:K11251]
123627531  [KO:K11253]
123627584  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
123628152  [KO:K11251]
123628275  [KO:K11252]
123628370  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
123628637  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
123628802  [KO:K11251]
123628899  HDAC8; histone deacetylase 8 isoform X1 [KO:K11405] [EC:3.5.1.98]
123630240  [KO:K06067] [EC:3.5.1.98]
123630284  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
123630472  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
123630736  [KO:K11253]
123631427  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
123631625  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
123631640  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
123631755  CALML4; calmodulin-like protein 4 [KO:K02183]
123631772  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
123631933  SLC29A1; equilibrative nucleoside transporter 1 isoform X1 [KO:K15014]
123632067  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
123632367  GRIN2A; glutamate receptor ionotropic, NMDA 2A isoform X1 [KO:K05209]
123632440  GRIN3B; glutamate receptor ionotropic, NMDA 3B [KO:K05214]
123632778  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
123633182  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
123633190  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
123633488  [KO:K11251]
123633885  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
123633894  [KO:K11252]
123633895  [KO:K11251]
123633896  [KO:K11254]
123633898  [KO:K11252]
123633899  [KO:K11252]
123633900  [KO:K11253]
123633901  [KO:K11251]
123633903  [KO:K11252]
123633904  [KO:K11251]
123633905  [KO:K11251]
123634008  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
123634038  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
123634666  [KO:K06067] [EC:3.5.1.98]
123634771  [KO:K11253]
123634905  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
123635002  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
123635081  NRAS; GTPase NRas [KO:K07828]
123635476  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
123635536  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
123635833  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
123636000  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
123636681  [KO:K02183]
123636756  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
123636823  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
123636893  CALM2; calmodulin-2 [KO:K02183]
123637148  GNG14; LOW QUALITY PROTEIN: putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
123637477  [KO:K00274] [EC:1.4.3.4]
123637748  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
123637794  [KO:K11251]
123637903  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
123638125  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
123638143  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
123638378  [KO:K11253]
123638379  [KO:K11253]
123638380  [KO:K11251]
123638381  [KO:K11251]
123638382  [KO:K11251]
123638383  [KO:K11251]
123638385  [KO:K11251]
123638386  [KO:K11251]
123638387  [KO:K11251]
123638390  [KO:K11251]
123638391  [KO:K11251]
123638392  [KO:K11251]
123638393  [KO:K11252]
123638394  [KO:K11252]
123638396  [KO:K11252]
123638397  [KO:K11252]
123638398  [KO:K11252]
123638399  [KO:K11252]
123638400  [KO:K11252]
123638401  [KO:K11252]
123638402  [KO:K11252]
123638403  [KO:K11252]
123638404  [KO:K11252]
123638407  [KO:K11254]
123638408  [KO:K11254]
123638409  [KO:K11254]
123638410  [KO:K11254]
123638411  [KO:K11254]
123638416  [KO:K11253]
123638790  [KO:K11253]
123638793  [KO:K11252]
123638796  [KO:K11253]
123638923  [KO:K11252]
123638924  [KO:K11251]
123638926  [KO:K11252]
123639921  KRAS; GTPase KRas [KO:K07827]
123639972  [KO:K11251]
123639973  [KO:K11254]
123639979  GRIN2B; glutamate receptor ionotropic, NMDA 2B [KO:K05210]
123640104  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
123640339  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
123640469  HDAC7; histone deacetylase 7 isoform X1 [KO:K11408] [EC:3.5.1.98]
123640769  HDAC10; polyamine deacetylase HDAC10 isoform X1 [KO:K18671] [EC:3.5.1.98]
123641343  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
123641491  [KO:K11251]
123641670  DRD2; D(2) dopamine receptor isoform X1 [KO:K04145]
123641872  [KO:K11251]
123641901  SLC29A2; equilibrative nucleoside transporter 2 isoform X1 [KO:K15014]
123642542  BDNF; LOW QUALITY PROTEIN: brain-derived neurotrophic factor [KO:K04355]
123642645  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
123642855  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
123642916  TH; tyrosine 3-monooxygenase isoform X1 [KO:K00501] [EC:1.14.16.2]
123642937  HRAS; GTPase HRas isoform X1 [KO:K02833]
123643215  HDAC4; histone deacetylase 4 isoform X1 [KO:K11406] [EC:3.5.1.98]
123643282  [KO:K00274] [EC:1.4.3.4]
123643408  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
123643792  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
123644073  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
123644481  CRH; corticoliberin [KO:K05256]
123644560  PKIA; cAMP-dependent protein kinase inhibitor alpha [KO:K15985]
123645581  GRIN1; glutamate receptor ionotropic, NMDA 1 [KO:K05208]
123645611  CALM1; calmodulin-1 [KO:K02183]
123645739  GRIN3A; glutamate receptor ionotropic, NMDA 3A [KO:K05213]
123645777  NTRK2; BDNF/NT-3 growth factors receptor isoform X1 [KO:K04360] [EC:2.7.10.1]
123645857  SHC3; SHC-transforming protein 3 [KO:K17448]
123646158  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
123646542  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 isoform X1 [KO:K04545]
123646849  [KO:K11252]
123647116  NPY; pro-neuropeptide Y [KO:K05232]
123647150  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
123647151  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
123647351  DDC; aromatic-L-amino-acid decarboxylase [KO:K01593] [EC:4.1.1.28 4.1.1.105]
123647376  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
123647620  [KO:K11251]
123647623  HDAC9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
123647634  [KO:K09047]
123647642  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
123647675  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
123648018  SLC6A3; sodium-dependent dopamine transporter [KO:K05036]
123648135  [KO:K11253]
123648496  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X1 [KO:K05869] [EC:2.7.11.17]
123648542  [KO:K04542]
123648852  [KO:K00274] [EC:1.4.3.4]
123648873  [KO:K11252]
123649114  [KO:K11251]
123649115  [KO:K11252]
123649468  SOS2; son of sevenless homolog 2 [KO:K03099]
123649475  [KO:K11253]
123649896  [KO:K11253]
123650080  [KO:K11253]
123650389  SLC29A3; equilibrative nucleoside transporter 3 isoform X1 [KO:K15014]
123650440  [KO:K11251]
123650462  SLC18A2; synaptic vesicular amine transporter [KO:K08155]
123650568  ADORA2B; adenosine receptor A2b [KO:K04267]
123650764  GRIN2C; glutamate receptor ionotropic, NMDA 2C [KO:K05211]
123650792  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
123650806  [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
lcat04010  MAPK signaling pathway
lcat04728  Dopaminergic synapse
KO pathway
ko05034   

DBGET integrated database retrieval system