KEGG   PATHWAY: hsa05033Help
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
BRITE hierarchy
Pathway map
hsa05033  Nicotine addiction
hsa05033

Ortholog table
Drug
D03365  Nicotine (USP)
D05156  Nicotine bitartrate (USAN)
D05157  Nicotine polacrilex (USAN)
D10613  Bradanicline (USAN/INN)
D10693  Bradanicline hydrochloride (USAN)
Other DBs
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 alpha1 subunit [KO:K05175]
2555  GABRA2; gamma-aminobutyric acid type A receptor alpha2 subunit [KO:K05175]
2556  GABRA3; gamma-aminobutyric acid type A receptor alpha3 subunit [KO:K05175]
2557  GABRA4; gamma-aminobutyric acid type A receptor alpha4 subunit [KO:K05175]
2558  GABRA5; gamma-aminobutyric acid type A receptor alpha5 subunit [KO:K05175]
2559  GABRA6; gamma-aminobutyric acid type A receptor alpha6 subunit [KO:K05175]
2560  GABRB1; gamma-aminobutyric acid type A receptor beta1 subunit [KO:K05181]
2562  GABRB3; gamma-aminobutyric acid type A receptor beta3 subunit [KO:K05181]
2561  GABRB2; gamma-aminobutyric acid type A receptor beta2 subunit [KO:K05181]
2565  GABRG1; gamma-aminobutyric acid type A receptor gamma1 subunit [KO:K05186]
2566  GABRG2; gamma-aminobutyric acid type A receptor gamma2 subunit [KO:K05186]
2567  GABRG3; gamma-aminobutyric acid type A receptor gamma3 subunit [KO:K05186]
2563  GABRD; gamma-aminobutyric acid type A receptor delta subunit [KO:K05184]
2564  GABRE; gamma-aminobutyric acid type A receptor epsilon subunit [KO:K05185]
55879  GABRQ; gamma-aminobutyric acid type A receptor theta subunit [KO:K05192]
2568  GABRP; gamma-aminobutyric acid type A receptor pi subunit [KO:K05189]
2569  GABRR1; gamma-aminobutyric acid type A receptor rho1 subunit [KO:K05190]
2570  GABRR2; gamma-aminobutyric acid type A receptor rho2 subunit [KO:K05190]
200959  GABRR3; gamma-aminobutyric acid type A receptor rho3 subunit (gene/pseudogene) [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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
KO pathway
ko05033   

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