ENTRY       hsa05033                    Pathway
NAME        Nicotine addiction - Homo sapiens (human)
DESCRIPTION Nicotine is one of the main psychoactive ingredients in tobacco that contributes to the harmful tobacco smoking habit. A common feature of addictive drugs, including nicotine, is that they increase dopamine (DA) release in the nucleus accumbens (NAc). The principal dopaminergic projections to NAc arise from neurons in the ventral tegmental area (VTA). In the VTA, alpha6- and alpha4beta2-containing nAChRs (alpha6*-AChRs and alpha4beta2*-AChRs, respectively) are located on GABAergic terminals and provide inhibitory inputs onto DAergic neuons, while alpha7*-nAChRs are located on glutamatergic terminals and activation of these receptors enhances glutamate release and increases excitability of DAergic neurons. Nicotine acts as an agonist to activate and desensitize these nicotinic acetylcholine receptors (nAChRs). After a short exposure to nicotine, alpha6*- and alpha4beta2*- nAChRs on GABAergic afferents are desensitized, decreasing GABA release and decreasing local inhibition of DA neurons. But the alpha7*-nAChRs on glutamatergic afferents remain active and enhance glutamate excitation of the DA neurons, leading to increased DA release in the NAc -and so facilitate the reinforcing effects of nicotine.
CLASS       Human Diseases; Substance dependence
PATHWAY_MAP hsa05033  Nicotine addiction
DRUG        D03365  Nicotine (USP)
            D05156  Nicotine bitartrate (USAN)
            D05157  Nicotine polacrilex (USP)
            D10613  Bradanicline (USAN/INN)
            D10693  Bradanicline hydrochloride (USAN)
DBLINKS     GO: 0035094
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        140679  SLC32A1; solute carrier family 32 member 1 [KO:K15015]
            8973  CHRNA6; cholinergic receptor nicotinic alpha 6 subunit [KO:K04808]
            773  CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
            774  CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
            1137  CHRNA4; cholinergic receptor nicotinic alpha 4 subunit [KO:K04806]
            1141  CHRNB2; cholinergic receptor nicotinic beta 2 subunit [KO:K04813]
            2554  GABRA1; gamma-aminobutyric acid type A receptor subunit alpha1 [KO:K05175]
            2555  GABRA2; gamma-aminobutyric acid type A receptor subunit alpha2 [KO:K05175]
            2556  GABRA3; gamma-aminobutyric acid type A receptor subunit alpha3 [KO:K05175]
            2557  GABRA4; gamma-aminobutyric acid type A receptor subunit alpha4 [KO:K05175]
            2558  GABRA5; gamma-aminobutyric acid type A receptor subunit alpha5 [KO:K05175]
            2559  GABRA6; gamma-aminobutyric acid type A receptor subunit alpha6 [KO:K05175]
            2560  GABRB1; gamma-aminobutyric acid type A receptor subunit beta1 [KO:K05181]
            2562  GABRB3; gamma-aminobutyric acid type A receptor subunit beta3 [KO:K05181]
            2561  GABRB2; gamma-aminobutyric acid type A receptor subunit beta2 [KO:K05181]
            2565  GABRG1; gamma-aminobutyric acid type A receptor subunit gamma1 [KO:K05186]
            2566  GABRG2; gamma-aminobutyric acid type A receptor subunit gamma2 [KO:K05186]
            2567  GABRG3; gamma-aminobutyric acid type A receptor subunit gamma3 [KO:K05186]
            2563  GABRD; gamma-aminobutyric acid type A receptor subunit delta [KO:K05184]
            2564  GABRE; gamma-aminobutyric acid type A receptor subunit epsilon [KO:K05185]
            55879  GABRQ; gamma-aminobutyric acid type A receptor subunit theta [KO:K05192]
            2568  GABRP; gamma-aminobutyric acid type A receptor subunit pi [KO:K05189]
            2569  GABRR1; gamma-aminobutyric acid type A receptor subunit rho1 [KO:K05190]
            2570  GABRR2; gamma-aminobutyric acid type A receptor subunit rho2 [KO:K05190]
            200959  GABRR3; gamma-aminobutyric acid type A receptor subunit rho3 [KO:K05190]
            57084  SLC17A6; solute carrier family 17 member 6 [KO:K12302]
            246213  SLC17A8; solute carrier family 17 member 8 [KO:K12302]
            57030  SLC17A7; solute carrier family 17 member 7 [KO:K12302]
            1139  CHRNA7; cholinergic receptor nicotinic alpha 7 subunit [KO:K04809]
            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]
COMPOUND    C00025  L-Glutamate
            C00076  Calcium cation
            C00334  4-Aminobutanoate
            C00698  Cl-
            C00745  Nicotine
            C01330  Sodium cation
            C01996  Acetylcholine
REFERENCE   PMID:12436424
  AUTHORS   Mansvelder HD, McGehee DS
  TITLE     Cellular and synaptic mechanisms of nicotine addiction.
  JOURNAL   J Neurobiol 53:606-17 (2002)
            DOI:10.1002/neu.10148
REFERENCE   PMID:15661626
  AUTHORS   Wonnacott S, Sidhpura N, Balfour DJ
  TITLE     Nicotine: from molecular mechanisms to behaviour.
  JOURNAL   Curr Opin Pharmacol 5:53-9 (2005)
            DOI:10.1016/j.coph.2004.12.002
REFERENCE   PMID:19669944
  AUTHORS   Mao D, McGehee DS
  TITLE     Nicotine and behavioral sensitization.
  JOURNAL   J Mol Neurosci 40:154-63 (2010)
            DOI:10.1007/s12031-009-9230-7
REFERENCE   PMID:19184650
  AUTHORS   Barik J, Wonnacott S
  TITLE     Molecular and cellular mechanisms of action of nicotine in the CNS.
  JOURNAL   Handb Exp Pharmacol 173-207 (2009)
            DOI:10.1007/978-3-540-69248-5_7
REFERENCE   PMID:19498417
  AUTHORS   Yang KC, Jin GZ, Wu J
  TITLE     Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology.
  JOURNAL   Acta Pharmacol Sin 30:740-51 (2009)
            DOI:10.1038/aps.2009.63
REFERENCE   PMID:14747518
  AUTHORS   Pidoplichko VI, Noguchi J, Areola OO, Liang Y, Peterson J, Zhang T, Dani JA
  TITLE     Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction.
  JOURNAL   Learn Mem 11:60-9 (2004)
            DOI:10.1101/lm.70004
REFERENCE   PMID:12716925
  AUTHORS   Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA
  TITLE     Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas.
  JOURNAL   J Neurosci 23:3176-85 (2003)
            DOI:10.1523/JNEUROSCI.23-08-03176.2003
REFERENCE   PMID:19434058
  AUTHORS   Xi ZX, Spiller K, Gardner EL
  TITLE     Mechanism-based medication development for the treatment of nicotine dependence.
  JOURNAL   Acta Pharmacol Sin 30:723-39 (2009)
            DOI:10.1038/aps.2009.46
REFERENCE   PMID:14708004
  AUTHORS   Laviolette SR, van der Kooy D
  TITLE     The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour.
  JOURNAL   Nat Rev Neurosci 5:55-65 (2004)
            DOI:10.1038/nrn1298
REFERENCE   PMID:20485364
  AUTHORS   Changeux JP
  TITLE     Nicotine addiction and nicotinic receptors: lessons from genetically modified mice.
  JOURNAL   Nat Rev Neurosci 11:389-401 (2010)
            DOI:10.1038/nrn2849
REFERENCE   PMID:17009926
  AUTHORS   Dani JA, Bertrand D
  TITLE     Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.
  JOURNAL   Annu Rev Pharmacol Toxicol 47:699-729 (2007)
            DOI:10.1146/annurev.pharmtox.47.120505.105214
REFERENCE   PMID:11906697
  AUTHORS   Mansvelder HD, Keath JR, McGehee DS
  TITLE     Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.
  JOURNAL   Neuron 33:905-19 (2002)
            DOI:10.1016/S0896-6273(02)00625-6
REFERENCE   PMID:18723034
  AUTHORS   O'Dell LE
  TITLE     A psychobiological framework of the substrates that mediate nicotine use during adolescence.
  JOURNAL   Neuropharmacology 56 Suppl 1:263-78 (2009)
            DOI:10.1016/j.neuropharm.2008.07.039
REFERENCE   PMID:20833261
  AUTHORS   Ortells MO, Arias HR
  TITLE     Neuronal networks of nicotine addiction.
  JOURNAL   Int J Biochem Cell Biol 42:1931-5 (2010)
            DOI:10.1016/j.biocel.2010.08.019
REFERENCE   PMID:16251989
  AUTHORS   Dani JA, Harris RA
  TITLE     Nicotine addiction and comorbidity with alcohol abuse and mental illness.
  JOURNAL   Nat Neurosci 8:1465-70 (2005)
            DOI:10.1038/nn1580
REFERENCE   PMID:18640919
  AUTHORS   Markou A
  TITLE     Review. Neurobiology of nicotine dependence.
  JOURNAL   Philos Trans R Soc Lond B Biol Sci 363:3159-68 (2008)
            DOI:10.1098/rstb.2008.0095
REFERENCE   PMID:15165747
  AUTHORS   Dajas-Bailador F, Wonnacott S
  TITLE     Nicotinic acetylcholine receptors and the regulation of neuronal signalling.
  JOURNAL   Trends Pharmacol Sci 25:317-24 (2004)
            DOI:10.1016/j.tips.2004.04.006
REL_PATHWAY hsa04724  Glutamatergic synapse
            hsa04727  GABAergic synapse
            hsa04728  Dopaminergic synapse
KO_PATHWAY  ko05033
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