KEGG   PATHWAY: hsa05030Help
Entry
hsa05030                    Pathway                                

Name
Cocaine addiction - Homo sapiens (human)
Description
Drug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences.There is strong evidence that the dopaminergic system that projects from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc), and to other forebrain sites, is the major substrate of reward and reinforcement for both natural rewards and addictive drugs. Cocaine binds strongly to the dopamine-reuptake transporter, preventing the reuptake of dopamine into the nerve terminal. Because of this blocking effect, dopamine remains at high concentrations in the synapse and continues to affect adjacent neurons, producing the characteristic cocaine "high." Activated D1 receptor activates the PKA signaling pathway, and this pathway plays a critical role in mediating the behavioral responses to cocaine administration. Cocaine-induced neuroadaptations, including dopamine depletion, may underlie craving and hedonic dysregulation.
Class
Human Diseases; Substance dependence
BRITE hierarchy
Pathway map
hsa05030  Cocaine addiction
hsa05030

Ortholog table
Drug
D00110  Cocaine (USP)
D02182  Cocaine hydrochloride (JP17/USP)
D05663  Pyrovalerone hydrochloride (USAN)
Other DBs
BSID: 546258
GO: 0042220
Organism
Homo sapiens (human) [GN:hsa]
Gene
7054  TH; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
1644  DDC; dopa decarboxylase [KO:K01593] [EC:4.1.1.105 4.1.1.28]
6570  SLC18A1; solute carrier family 18 member A1 [KO:K08155]
6571  SLC18A2; solute carrier family 18 member A2 [KO:K08155]
4129  MAOB; monoamine oxidase B [KO:K00274] [EC:1.4.3.4]
4128  MAOA; monoamine oxidase A [KO:K00274] [EC:1.4.3.4]
6531  SLC6A3; solute carrier family 6 member 3 [KO:K05036]
1812  DRD1; dopamine receptor D1 [KO:K04144]
2778  GNAS; GNAS complex locus [KO:K04632]
2912  GRM2; glutamate metabotropic receptor 2 [KO:K04605]
2913  GRM3; glutamate metabotropic receptor 3 [KO:K04605]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
1813  DRD2; dopamine receptor D2 [KO:K04145]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
26086  GPSM1; G protein signaling modulator 1 [KO:K15839]
8787  RGS9; regulator of G protein signaling 9 [KO:K13765]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
468  ATF4; activating transcription factor 4 [KO:K04374]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
5173  PDYN; prodynorphin [KO:K15840]
627  BDNF; brain derived neurotrophic factor [KO:K04355]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
2354  FOSB; FosB proto-oncogene, AP-1 transcription factor subunit [KO:K09029]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
1020  CDK5; cyclin dependent kinase 5 [KO:K02090] [EC:2.7.11.22]
8851  CDK5R1; cyclin dependent kinase 5 regulatory subunit 1 [KO:K11716]
2902  GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
2903  GRIN2A; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
2904  GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
2905  GRIN2C; glutamate ionotropic receptor NMDA type subunit 2C [KO:K05211]
2906  GRIN2D; glutamate ionotropic receptor NMDA type subunit 2D [KO:K05212]
116443  GRIN3A; glutamate ionotropic receptor NMDA type subunit 3A [KO:K05213]
116444  GRIN3B; glutamate ionotropic receptor NMDA type subunit 3B [KO:K05214]
1742  DLG4; discs large MAGUK scaffold protein 4 [KO:K11828]
84152  PPP1R1B; protein phosphatase 1 regulatory inhibitor subunit 1B [KO:K15494]
2891  GRIA2; glutamate ionotropic receptor AMPA type subunit 2 [KO:K05198]
Compound
C00025  L-Glutamate
C00027  Hydrogen peroxide
C00082  L-Tyrosine
C00355  3,4-Dihydroxy-L-phenylalanine
C00575  3',5'-Cyclic AMP
C01161  3,4-Dihydroxyphenylacetate
C03758  Dopamine
D00110  Cocaine (USP)
Reference
  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
  Authors
Cunha-Oliveira T, Rego AC, Oliveira CR
  Title
Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs.
  Journal
Brain Res Rev 58:192-208 (2008)
DOI:10.1016/j.brainresrev.2008.03.002
Reference
  Authors
Chen JC, Chen PC, Chiang YC
  Title
Molecular mechanisms of psychostimulant addiction.
  Journal
Chang Gung Med J 32:148-54 (2009)
Reference
  Authors
Nestler EJ
  Title
Is there a common molecular pathway for addiction?
  Journal
Nat Neurosci 8:1445-9 (2005)
DOI:10.1038/nn1578
Reference
  Authors
Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, Lanier SM, Kalivas PW
  Title
Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.
  Journal
Neuron 42:269-81 (2004)
DOI:10.1016/S0896-6273(04)00159-X
Reference
  Authors
Rahman Z, Schwarz J, Gold SJ, Zachariou V, Wein MN, Choi KH, Kovoor A, Chen CK, DiLeone RJ, Schwarz SC, Selley DE, Sim-Selley LJ, Barrot M, Luedtke RR, Self D, Neve RL, Lester HA, Simon MI, Nestler EJ
  Title
RGS9 modulates dopamine signaling in the basal ganglia.
  Journal
Neuron 38:941-52 (2003)
DOI:10.1016/S0896-6273(03)00321-0
Reference
  Authors
Horger BA, Iyasere CA, Berhow MT, Messer CJ, Nestler EJ, Taylor JR
  Title
Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.
  Journal
J Neurosci 19:4110-22 (1999)
DOI:10.1523/JNEUROSCI.19-10-04110.1999
Reference
  Authors
Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S
  Title
Dopamine transport function is elevated in cocaine users.
  Journal
J Neurochem 81:292-300 (2002)
DOI:10.1046/j.1471-4159.2002.00820.x
Reference
  Authors
McClung CA, Nestler EJ
  Title
Regulation of gene expression and cocaine reward by CREB and DeltaFosB.
  Journal
Nat Neurosci 6:1208-15 (2003)
DOI:10.1038/nn1143
Reference
  Authors
McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ
  Title
DeltaFosB: a molecular switch for long-term adaptation in the brain.
  Journal
Brain Res Mol Brain Res 132:146-54 (2004)
DOI:10.1016/j.molbrainres.2004.05.014
Reference
  Authors
Ang E, Chen J, Zagouras P, Magna H, Holland J, Schaeffer E, Nestler EJ
  Title
Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration.
  Journal
J Neurochem 79:221-4 (2001)
DOI:10.1046/j.1471-4159.2001.00563.x
Reference
  Authors
Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P
  Title
Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5.
  Journal
Nature 410:376-80 (2001)
DOI:10.1038/35066591
Reference
  Authors
Chao J, Nestler EJ
  Title
Molecular neurobiology of drug addiction.
  Journal
Annu Rev Med 55:113-32 (2004)
DOI:10.1146/annurev.med.55.091902.103730
KO pathway
ko05030   

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