KEGG   PATHWAY: hsa05030
hsa05030                    Pathway                                
Cocaine addiction - Homo sapiens (human)
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.
Human Diseases; Substance dependence
Pathway map
hsa05030  Cocaine addiction

D00110  Cocaine (USP)
D02182  Cocaine hydrochloride (JP18/USP)
D05663  Pyrovalerone hydrochloride (USAN)
Other DBs
GO: 0042220
Homo sapiens (human) [GN:hsa]
7054  TH; tyrosine hydroxylase [KO:K00501] [EC:]
1644  DDC; dopa decarboxylase [KO:K01593] [EC:]
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:]
4128  MAOA; monoamine oxidase A [KO:K00274] [EC:]
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:K04606]
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:]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:]
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:]
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]
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)
Ron D, Jurd R
The "ups and downs" of signaling cascades in addiction.
Sci STKE 2005:re14 (2005)
Cunha-Oliveira T, Rego AC, Oliveira CR
Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs.
Brain Res Rev 58:192-208 (2008)
Chen JC, Chen PC, Chiang YC
Molecular mechanisms of psychostimulant addiction.
Chang Gung Med J 32:148-54 (2009)
Nestler EJ
Is there a common molecular pathway for addiction?
Nat Neurosci 8:1445-9 (2005)
Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, Lanier SM, Kalivas PW
Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.
Neuron 42:269-81 (2004)
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
RGS9 modulates dopamine signaling in the basal ganglia.
Neuron 38:941-52 (2003)
Horger BA, Iyasere CA, Berhow MT, Messer CJ, Nestler EJ, Taylor JR
Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.
J Neurosci 19:4110-22 (1999)
Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S
Dopamine transport function is elevated in cocaine users.
J Neurochem 81:292-300 (2002)
McClung CA, Nestler EJ
Regulation of gene expression and cocaine reward by CREB and DeltaFosB.
Nat Neurosci 6:1208-15 (2003)
McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ
DeltaFosB: a molecular switch for long-term adaptation in the brain.
Brain Res Mol Brain Res 132:146-54 (2004)
Ang E, Chen J, Zagouras P, Magna H, Holland J, Schaeffer E, Nestler EJ
Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration.
J Neurochem 79:221-4 (2001)
Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P
Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5.
Nature 410:376-80 (2001)
Chao J, Nestler EJ
Molecular neurobiology of drug addiction.
Annu Rev Med 55:113-32 (2004)
hsa04728  Dopaminergic synapse
KO pathway

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