KEGG PATHWAY: ko05034

PATHWAY: ko05034

Entry

ko05034 Pathway

Name

Alcoholism

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

ko05034

Alcoholism

Other DBs

BSID:

587116

GO:

0045471

Orthology

K00501	tyrosine 3-monooxygenase [EC:1.14.16.2]
K01593	aromatic-L-amino-acid decarboxylase [EC:4.1.1.28]
K08155	MFS transporter, DHA1 family, solute carrier family 18 (vesicular amine transporter), member 1/2
K00274	monoamine oxidase [EC:1.4.3.4]
K05036	solute carrier family 6 (neurotransmitter transporter, dopamine) member 3
K05208	glutamate receptor ionotropic, NMDA 1
K05209	glutamate receptor ionotropic, NMDA 2A
K05210	glutamate receptor ionotropic, NMDA 2B
K05211	glutamate receptor ionotropic, NMDA 2C
K05212	glutamate receptor ionotropic, NMDA 2D
K05213	glutamate receptor ionotropic, NMDA 3A
K05214	glutamate receptor ionotropic, NMDA 3B
K06067	histone deacetylase 1/2 [EC:3.5.1.98]
K11404	histone deacetylase 3 [EC:3.5.1.98]
K11406	histone deacetylase 4/5 [EC:3.5.1.98]
K11407	histone deacetylase 6/10 [EC:3.5.1.98]
K11408	histone deacetylase 7 [EC:3.5.1.98]
K11405	histone deacetylase 8 [EC:3.5.1.98]
K11409	histone deacetylase 9 [EC:3.5.1.98]
K11418	histone deacetylase 11 [EC:3.5.1.98]
K11251	histone H2A
K11252	histone H2B
K11253	histone H3
K11254	histone H4
K11303	histone acetyltransferase 1 [EC:2.3.1.48]
K04144	dopamine receptor D1
K04632	guanine nucleotide-binding protein G(s) subunit alpha
K04145	dopamine receptor D2
K04630	guanine nucleotide-binding protein G(i) subunit alpha
K04534	guanine nucleotide-binding protein G(o) subunit alpha
K04536	guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537	guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K07825	guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K04538	guanine nucleotide-binding protein subunit beta-4
K04539	guanine nucleotide-binding protein subunit beta-5
K07826	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K04540	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04347	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04547	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548	guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549	guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K04266	adenosine receptor A2a
K04267	adenosine receptor A2b
K08045	adenylate cyclase 5 [EC:4.6.1.1]
K05870	cyclic AMP-responsive element-binding protein 1
K04450	cyclic AMP-dependent transcription factor ATF-2
K04374	cyclic AMP-dependent transcription factor ATF-4
K09048	cyclic AMP-responsive element-binding protein 3
K09047	cyclic AMP-responsive element-binding protein 5
K09049	cyclic AMP-dependent transcription factor ATF-6 beta
K05256	corticotropin-releasing hormone
K05232	neuropeptide Y
K04355	brain-derived neurotrophic factor
K04360	neurotrophic tyrosine kinase receptor type 2 [EC:2.7.10.1]
K06279	src homology 2 domain-containing transforming protein C
K04364	growth factor receptor-binding protein 2
K03099	son of sevenless
K02833	GTPase HRas
K07827	GTPase KRas
K07828	GTPase NRas
K08845	A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365	B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366	RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368	mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04371	extracellular signal-regulated kinase 1/2 [EC:2.7.11.24]
K15840	prodynorphin
K02183	calmodulin
K07359	calcium/calmodulin-dependent protein kinase kinase [EC:2.7.11.17]
K05869	calcium/calmodulin-dependent protein kinase IV [EC:2.7.11.17]
K09029	protein FosB
K15494	protein phosphatase 1 regulatory subunit 1B
K06269	protein phosphatase 1, catalytic subunit [EC:3.1.3.16]
K15985	cAMP-dependent protein kinase inhibitor alpha

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)

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)

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)

Reference

PMID:16278489

Authors

Ron D, Jurd R

Title

The "ups and downs" of signaling cascades in addiction.

Journal

Sci STKE 2005:re14 (2005)

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)

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)

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)

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)

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)

Reference

PMID:12085089

Authors

Lovinger DM

Title

NMDA receptors lose their inhibitions.

Journal

Nat Neurosci 5:614-6 (2002)

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)

Reference

PMID:10774721

Authors

Berke JD, Hyman SE

Title

Addiction, dopamine, and the molecular mechanisms of memory.

Journal

Neuron 25:515-32 (2000)

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)

Reference

PMID:18991950

Authors

Lee AM, Messing RO

Title

Protein kinases and addiction.

Journal

Ann N Y Acad Sci 1141:22-57 (2008)

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)

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)

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)

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)

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)

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Ontology (2)   
   KEGG BRITE (1)   
   GO (1)   
Pathway (2)   
   KEGG PATHWAY (1)   
   BioSystems (1)   
Chemical substance (10)   
   KEGG COMPOUND (10)   
Chemical reaction (12)   
   KEGG ENZYME (12)   
Gene (79)   
   KEGG ORTHOLOGY (79)   
Literature (20)   
   PubMed (20)   
All databases (125)   

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