ENTRY       hsa05031                    Pathway
NAME        Amphetamine addiction - Homo sapiens (human)
DESCRIPTION Amphetamine is a psychostimulant drug that exerts persistent addictive effects. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. Acute administration of amphetamine induces phosphorylation of cAMP response element-binding protein (CREB) and expression of a number of immediate early genes (IEGs), such as c-fos. The IEGs is likely to initiate downstream molecular events, which may have important roles in the induction and maintenance of addictive states. Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
CLASS       Human Diseases; Substance dependence
PATHWAY_MAP hsa05031  Amphetamine addiction
DRUG        D02074  Amphetamine sulfate (USP)
            D02078  Dextroamphetamine sulfate (USP)
            D02242  Methamphetamine hydrochloride (JP18/USP)
            D03740  Dextroamphetamine (USAN)
            D07445  Amfetamine (INN)
            D08187  Metamfetamine (INN)
            D11622  Amphetamine aspartate monohydrate
            D11623  Dextroamphetamine saccharate
DBLINKS     GO: 0001975
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:4.1.1.28 4.1.1.105]
            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]
            775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
            776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
            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]
            2890  GRIA1; glutamate ionotropic receptor AMPA type subunit 1 [KO:K05197]
            2891  GRIA2; glutamate ionotropic receptor AMPA type subunit 2 [KO:K05198]
            2892  GRIA3; glutamate ionotropic receptor AMPA type subunit 3 [KO:K05199]
            2893  GRIA4; glutamate ionotropic receptor AMPA type subunit 4 [KO:K05200]
            1812  DRD1; dopamine receptor D1 [KO:K04144]
            5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
            5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
            5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
            6804  STX1A; syntaxin 1A [KO:K04560]
            815  CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
            817  CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
            816  CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
            818  CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
            810  CALML3; calmodulin like 3 [KO:K02183]
            805  CALM2; calmodulin 2 [KO:K02183]
            808  CALM3; calmodulin 3 [KO:K02183]
            801  CALM1; calmodulin 1 [KO:K02183]
            163688  CALML6; calmodulin like 6 [KO:K02183]
            51806  CALML5; calmodulin like 5 [KO:K02183]
            91860  CALML4; calmodulin like 4 [KO:K02183]
            814  CAMK4; calcium/calmodulin dependent protein kinase IV [KO:K05869] [EC:2.7.11.17]
            2778  GNAS; GNAS complex locus [KO:K04632]
            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]
            84152  PPP1R1B; protein phosphatase 1 regulatory inhibitor subunit 1B [KO:K15494]
            5499  PPP1CA; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
            5500  PPP1CB; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
            5501  PPP1CC; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
            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]
            23237  ARC; activity regulated cytoskeleton associated protein [KO:K15867]
            2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
            5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
            5532  PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
            5533  PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
            5534  PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
            5535  PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268]
            3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
            2354  FOSB; FosB proto-oncogene, AP-1 transcription factor subunit [KO:K09029]
            23411  SIRT1; sirtuin 1 [KO:K11411] [EC:2.3.1.286]
            3065  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
            3066  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
COMPOUND    C00025  L-Glutamate
            C00027  Hydrogen peroxide
            C00076  Calcium cation
            C00082  L-Tyrosine
            C00355  3,4-Dihydroxy-L-phenylalanine
            C00575  3',5'-Cyclic AMP
            C01161  3,4-Dihydroxyphenylacetate
            C01330  Sodium cation
            C03758  Dopamine
            D07445  Amfetamine (INN)
REFERENCE   PMID:16724157
  AUTHORS   Rajadhyaksha AM, Kosofsky BE
  TITLE     Psychostimulants, Protein phosphorylation and Gene expression: a growing role of L-type calcium channels.
  JOURNAL   Cellscience 2:127-144 (2005)
            DOI:10.1901/jaba.2005.2-127
REFERENCE   PMID:18440072
  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   PMID:16776597
  AUTHORS   Hyman SE, Malenka RC, Nestler EJ
  TITLE     Neural mechanisms of addiction: the role of reward-related learning and memory.
  JOURNAL   Annu Rev Neurosci 29:565-98 (2006)
            DOI:10.1146/annurev.neuro.29.051605.113009
REFERENCE   PMID:16151049
  AUTHORS   Rajadhyaksha AM, Kosofsky BE
  TITLE     Psychostimulants, L-type calcium channels, kinases, and phosphatases.
  JOURNAL   Neuroscientist 11:494-502 (2005)
            DOI:10.1177/1073858405278236
REFERENCE   PMID:14622123
  AUTHORS   Dudman JT, Eaton ME, Rajadhyaksha A, Macias W, Taher M, Barczak A, Kameyama K, Huganir R, Konradi C
  TITLE     Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.
  JOURNAL   J Neurochem 87:922-34 (2003)
            DOI:10.1046/j.1471-4159.2003.02067.x
REFERENCE   PMID:10414964
  AUTHORS   Rajadhyaksha A, Barczak A, Macias W, Leveque JC, Lewis SE, Konradi C
  TITLE     L-Type Ca(2+) channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons.
  JOURNAL   J Neurosci 19:6348-59 (1999)
            DOI:10.1523/JNEUROSCI.19-15-06348.1999
REFERENCE   PMID:8753884
  AUTHORS   Konradi C, Leveque JC, Hyman SE
  TITLE     Amphetamine and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium.
  JOURNAL   J Neurosci 16:4231-9 (1996)
            DOI:10.1523/JNEUROSCI.16-13-04231.1996
REFERENCE   PMID:10774721
  AUTHORS   Berke JD, Hyman SE
  TITLE     Addiction, dopamine, and the molecular mechanisms of memory.
  JOURNAL   Neuron 25:515-32 (2000)
            DOI:10.1016/S0896-6273(00)81056-9
REFERENCE   PMID:17728700
  AUTHORS   McClung CA, Nestler EJ
  TITLE     Neuroplasticity mediated by altered gene expression.
  JOURNAL   Neuropsychopharmacology 33:3-17 (2008)
            DOI:10.1038/sj.npp.1301544
REFERENCE   PMID:14746512
  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
REFERENCE   PMID:19199083
  AUTHORS   Robertson SD, Matthies HJ, Galli A
  TITLE     A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters.
  JOURNAL   Mol Neurobiol 39:73-80 (2009)
            DOI:10.1007/s12035-009-8053-4
REFERENCE   PMID:18617632
  AUTHORS   Binda F, Dipace C, Bowton E, Robertson SD, Lute BJ, Fog JU, Zhang M, Sen N, Colbran RJ, Gnegy ME, Gether U, Javitch JA, Erreger K, Galli A
  TITLE     Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux.
  JOURNAL   Mol Pharmacol 74:1101-8 (2008)
            DOI:10.1124/mol.108.048447
REFERENCE   PMID:21338876
  AUTHORS   Sulzer D
  TITLE     How addictive drugs disrupt presynaptic dopamine neurotransmission.
  JOURNAL   Neuron 69:628-49 (2011)
            DOI:10.1016/j.neuron.2011.02.010
REFERENCE   PMID:8630246
  AUTHORS   Hyman SE
  TITLE     Addiction to cocaine and amphetamine.
  JOURNAL   Neuron 16:901-4 (1996)
            DOI:10.1016/S0896-6273(00)80111-7
REFERENCE   PMID:18632938
  AUTHORS   Renthal W, Carle TL, Maze I, Covington HE 3rd, Truong HT, Alibhai I, Kumar A, Montgomery RL, Olson EN, Nestler EJ
  TITLE     Delta FosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure.
  JOURNAL   J Neurosci 28:7344-9 (2008)
            DOI:10.1523/JNEUROSCI.1043-08.2008
REFERENCE   PMID:21989194
  AUTHORS   Robison AJ, Nestler EJ
  TITLE     Transcriptional and epigenetic mechanisms of addiction.
  JOURNAL   Nat Rev Neurosci 12:623-37 (2011)
            DOI:10.1038/nrn3111
REFERENCE   PMID:14529709
  AUTHORS   Snyder GL, Galdi S, Fienberg AA, Allen P, Nairn AC, Greengard P
  TITLE     Regulation of AMPA receptor dephosphorylation by glutamate receptor agonists.
  JOURNAL   Neuropharmacology 45:703-13 (2003)
            DOI:10.1016/S0028-3908(03)00319-8
REFERENCE   PMID:19222557
  AUTHORS   Banerjee PS, Aston J, Khundakar AA, Zetterstrom TS
  TITLE     Differential regulation of psychostimulant-induced gene expression of brain derived neurotrophic factor and the immediate-early gene Arc in the juvenile and adult brain.
  JOURNAL   Eur J Neurosci 29:465-76 (2009)
            DOI:10.1111/j.1460-9568.2008.06601.x
REL_PATHWAY hsa04728  Dopaminergic synapse
KO_PATHWAY  ko05031
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