Entry Name Cocaine addiction
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 Other DBs Orthology K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K04144 DRD1; dopamine receptor D1
K04145 DRD2; dopamine receptor D2
K04355 BDNF; brain-derived neurotrophic factor
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04448 JUN; transcription factor AP-1
K04450 ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04605 GRM2; metabotropic glutamate receptor 2
K04606 GRM3; metabotropic glutamate receptor 3
K04630 GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04632 GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04735 RELA; transcription factor p65
K05036 SLC6A3, DAT; solute carrier family 6 (neurotransmitter transporter, dopamine) member 3
K05198 GRIA2; glutamate receptor 2
K05208 GRIN1; glutamate receptor ionotropic, NMDA 1
K05209 GRIN2A; glutamate receptor ionotropic, NMDA 2A
K05210 GRIN2B; glutamate receptor ionotropic, NMDA 2B
K05211 GRIN2C; glutamate receptor ionotropic, NMDA 2C
K05212 GRIN2D; glutamate receptor ionotropic, NMDA 2D
K05213 GRIN3A; glutamate receptor ionotropic, NMDA 3A
K05214 GRIN3B; glutamate receptor ionotropic, NMDA 3B
K05870 CREB1; cyclic AMP-responsive element-binding protein 1
K08155 SLC18A1_2, VMAT; MFS transporter, DHA1 family, solute carrier family 18 (vesicular amine transporter), member 1/2
K09047 CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048 CREB3; cyclic AMP-responsive element-binding protein 3
K09049 ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K11716 CDK5R1; cyclin-dependent kinase 5 activator 1
K11828 DLG4, PSD95; discs large protein 4
K13765 RGS9; regulator of G-protein signaling 9
K15494 PPP1R1B, DARPP32; protein phosphatase 1 regulatory subunit 1B
K15839 GPSM1, AGS3; G-protein signaling modulator 1
K15840 PDYN, PENKB; proenkephalin B (prodynorphin)
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.
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