KEGG   PATHWAY: ko05033Help
Entry
ko05033                     Pathway                                

Name
Nicotine addiction
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
Nicotine addiction
ko05033

All organismsOrtholog table
Other DBs
BSID: 
GO: 
Orthology
K15015  
solute carrier family 32 (vesicular inhibitory amino acid transporter)
K04808  
nicotinic acetylcholine receptor alpha-6
K04344  
voltage-dependent calcium channel P/Q type alpha-1A
K04849  
voltage-dependent calcium channel N type alpha-1B
K04806  
nicotinic acetylcholine receptor alpha-4
K04813  
nicotinic acetylcholine receptor beta-2
K05175  
gamma-aminobutyric acid receptor subunit alpha
K05181  
gamma-aminobutyric acid receptor subunit beta
K05186  
gmma-aminobutyric acid receptor subunit gamma
K05184  
gamma-aminobutyric acid receptor subunit delta
K05185  
gamma-aminobutyric acid receptor subunit epsilon
K05192  
gamma-aminobutyric acid receptor subunit theta
K05189  
gamma-aminobutyric acid receptor subunit pi
K05190  
gamma-aminobutyric acid receptor subunit rho
K12302  
MFS transporter, ACS family, solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6/7/8
K04809  
nicotinic acetylcholine receptor alpha-7
K05208  
glutamate receptor ionotropic, NMDA 1
K05209  
glutamate receptor ionotropic, NMDA 2A
K05210  
glutamate receptor ionotropic, NMDA 2B
K05211  
glutamate receptor ionotropic, NMDA 2C
K05212  
glutamate receptor ionotropic, NMDA 2D
K05213  
glutamate receptor ionotropic, NMDA 3A
K05214  
glutamate receptor ionotropic, NMDA 3B
K05197  
glutamate receptor 1
K05198  
glutamate receptor 2
K05199  
glutamate receptor 3
K05200  
glutamate receptor 4
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)
Reference
  Authors
Wonnacott S, Sidhpura N, Balfour DJ
  Title
Nicotine: from molecular mechanisms to behaviour.
  Journal
Curr Opin Pharmacol 5:53-9 (2005)
Reference
  Authors
Mao D, McGehee DS
  Title
Nicotine and behavioral sensitization.
  Journal
J Mol Neurosci 40:154-63 (2010)
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)
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)
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)
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)
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)
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)
Reference
  Authors
Changeux JP
  Title
Nicotine addiction and nicotinic receptors: lessons from genetically modified mice.
  Journal
Nat Rev Neurosci 11:389-401 (2010)
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)
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)
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)
Reference
  Authors
Ortells MO, Arias HR
  Title
Neuronal networks of nicotine addiction.
  Journal
Int J Biochem Cell Biol 42:1931-5 (2010)
Reference
  Authors
Dani JA, Harris RA
  Title
Nicotine addiction and comorbidity with alcohol abuse and mental illness.
  Journal
Nat Neurosci 8:1465-70 (2005)
Reference
  Authors
Markou A
  Title
Review. Neurobiology of nicotine dependence.
  Journal
Philos Trans R Soc Lond B Biol Sci 363:3159-68 (2008)
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)

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