Entry 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 dependenceBRITE hierarchy
Pathway map Ortholog table Drug D02182 Cocaine hydrochloride (JP18/USP)
D05663 Pyrovalerone hydrochloride (USAN)
Other DBs Organism Homo sapiens (human) [GN:
hsa ]
Gene 6570 SLC18A1; solute carrier family 18 member A1 [KO:K08155 ]
6571 SLC18A2; solute carrier family 18 member A2 [KO:K08155 ]
6531 SLC6A3; solute carrier family 6 member 3 [KO:K05036 ]
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 ]
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 ]
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 ]
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 C00355 3,4-Dihydroxy-L-phenylalanine
C01161 3,4-Dihydroxyphenylacetate
Reference Authors Ron D, Jurd R
Title The "ups and downs" of signaling cascades in addiction.
Journal Reference Authors Cunha-Oliveira T, Rego AC, Oliveira CR
Title Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs.
Journal 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 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 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 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 Reference Authors Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S
Title Dopamine transport function is elevated in cocaine users.
Journal Reference Authors McClung CA, Nestler EJ
Title Regulation of gene expression and cocaine reward by CREB and DeltaFosB.
Journal 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 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 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 Reference Authors Chao J, Nestler EJ
Title Molecular neurobiology of drug addiction.
Journal Related KO pathway
