Entry
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
Ortholog table
Other DBs
Organism
Rattus norvegicus (rat) [GN:
rno ]
Gene
25549 Slc18a2; synaptic vesicular amine transporter [KO:K08155 ]
25693 Slc18a1; chromaffin granule amine transporter [KO:K08155 ]
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 ]
502129 hist1h2ail2; histone cluster 1, H2ai-like2 [KO:K11251 ]
306962 Hist1h2ac; histone cluster 1 H2A family member C [KO:K11251 ]
291157 Hist1h2bo; histone cluster 1 H2B family member O [KO:K11252 ]
306945 Hist1h2bq; histone cluster 1 H2B family member Q [KO:K11252 ]
306969 H2bc8; histone cluster 1 H2B family member l [KO:K11252 ]
295274 Hist2h2be; histone cluster 2 H2B family member E [KO:K11252 ]
361247 Hist1h2bd; histone cluster 1 H2B family member D [KO:K11252 ]
310678 Hist2h3c2; histone cluster 2 H3 family member C2 [KO:K11253 ]
24896 Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632 ]
24318 Drd2; D(2) dopamine receptor isoform 1 [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-3 [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 isoform B [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 ]
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 ]
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 isoform 1 [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 ]
24604 Npy; pro-neuropeptide Y preproprotein [KO:K05232 ]
24225 Bdnf; brain-derived neurotrophic factor isoform 3 preproprotein [KO:K04355 ]
85385 Shc1; SHC-transforming protein 1 isoform b [KO:K06279 ]
81504 Grb2; growth factor receptor-bound protein 2 [KO:K04364 ]
367858 Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833 ]
83506 Camkk2; calcium/calmodulin-dependent protein kinase kinase 2 isoform 1 [KO:K07359 ] [EC:2.7.11.17 ]
360616 Ppp1r1b; protein phosphatase 1 regulatory subunit 1B [KO:K15494 ]
24668 Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
24669 Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269 ] [EC:3.1.3.16 ]
25594 Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
114906 Pkia; cAMP-dependent protein kinase inhibitor alpha [KO:K15985 ]
Compound
C00355 3,4-Dihydroxy-L-phenylalanine
C01161 3,4-Dihydroxyphenylacetate
Reference
Authors
Spanagel R
Title
Alcoholism: a systems approach from molecular physiology to addictive behavior.
Journal
Reference
Authors
Newton PM, Messing RO
Title
Intracellular signaling pathways that regulate behavioral responses to ethanol.
Journal
Reference
Authors
Mailliard WS, Diamond I
Title
Recent advances in the neurobiology of alcoholism: the role of adenosine.
Journal
Reference
Authors
Ron D, Jurd R
Title
The "ups and downs" of signaling cascades in addiction.
Journal
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
Reference
Authors
Moonat S, Starkman BG, Sakharkar A, Pandey SC
Title
Neuroscience of alcoholism: molecular and cellular mechanisms.
Journal
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
Reference
Authors
Zhang TA, Maldve RE, Morrisett RA
Title
Coincident signaling in mesolimbic structures underlying alcohol reinforcement.
Journal
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
Reference
Authors
Lovinger DM
Title
NMDA receptors lose their inhibitions.
Journal
Reference
Authors
Hyman SE, Malenka RC, Nestler EJ
Title
Neural mechanisms of addiction: the role of reward-related learning and memory.
Journal
Reference
Authors
Berke JD, Hyman SE
Title
Addiction, dopamine, and the molecular mechanisms of memory.
Journal
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
Reference
Authors
Lee AM, Messing RO
Title
Protein kinases and addiction.
Journal
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
Reference
Authors
Logrip ML, Janak PH, Ron D
Title
Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.
Journal
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
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
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
Related pathway
KO pathway