Entry Name Nicotine addiction - Peromyscus leucopus (white-footed mouse)
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 dependenceBRITE hierarchy
Pathway map Other DBs Organism Peromyscus leucopus (white-footed mouse) [GN:
pleu ]
Gene 114684093 Grin3b; LOW QUALITY PROTEIN: glutamate receptor ionotropic, NMDA 3B [KO:K05214 ]
114684157 Cacna1a; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344 ]
114687010 Gabra4; gamma-aminobutyric acid receptor subunit alpha-4 isoform X1 [KO:K05175 ]
114687164 Slc17a7; vesicular glutamate transporter 1 isoform X1 [KO:K12302 ]
114687296 Gabrb1; gamma-aminobutyric acid receptor subunit beta-1 [KO:K05181 ]
114687433 Gabra3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175 ]
114687634 Gabra2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175 ]
114687896 Gabrg1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186 ]
114688173 Gabrq; gamma-aminobutyric acid receptor subunit theta isoform X1 [KO:K05192 ]
114689530 Gabre; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185 ]
114689842 Gabrb2; gamma-aminobutyric acid receptor subunit beta-2 isoform X1 [KO:K05181 ]
114689843 Gabra6; gamma-aminobutyric acid receptor subunit alpha-6 isoform X1 [KO:K05175 ]
114689844 Gabra1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175 ]
114689845 Gabrg2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186 ]
114692733 Cacna1b; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849 ]
114692778 Grin1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208 ]
114695430 Gabrr1; gamma-aminobutyric acid receptor subunit rho-1 [KO:K05190 ]
114695452 Gabrr2; gamma-aminobutyric acid receptor subunit rho-2 [KO:K05190 ]
114695505 Chrna7; neuronal acetylcholine receptor subunit alpha-7 [KO:K04809 ]
114700027 Gabrr3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190 ]
114704184 Chrna4; LOW QUALITY PROTEIN: neuronal acetylcholine receptor subunit alpha-4 [KO:K04806 ]
114707044 Grin2c; glutamate receptor ionotropic, NMDA 2C isoform X2 [KO:K05211 ]
114707959 Chrnb2; LOW QUALITY PROTEIN: neuronal acetylcholine receptor subunit beta-2 [KO:K04813 ]
114708256 Gabrd; gamma-aminobutyric acid receptor subunit delta [KO:K05184 ]
114708487 Chrna6; LOW QUALITY PROTEIN: neuronal acetylcholine receptor subunit alpha-6 [KO:K04808 ]
114710495 Gabra5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175 ]
114710496 Gabrg3; gamma-aminobutyric acid receptor subunit gamma-3 [KO:K05186 ]
114710497 Gabrb3; gamma-aminobutyric acid receptor subunit beta-3 isoform X1 [KO:K05181 ]
Compound Reference Authors Mansvelder HD, McGehee DS
Title Cellular and synaptic mechanisms of nicotine addiction.
Journal Reference Authors Wonnacott S, Sidhpura N, Balfour DJ
Title Nicotine: from molecular mechanisms to behaviour.
Journal Reference Authors Mao D, McGehee DS
Title Nicotine and behavioral sensitization.
Journal Reference Authors Barik J, Wonnacott S
Title Molecular and cellular mechanisms of action of nicotine in the CNS.
Journal Reference Authors Yang KC, Jin GZ, Wu J
Title Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology.
Journal 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 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 Reference Authors Xi ZX, Spiller K, Gardner EL
Title Mechanism-based medication development for the treatment of nicotine dependence.
Journal Reference Authors Laviolette SR, van der Kooy D
Title The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour.
Journal Reference Authors Changeux JP
Title Nicotine addiction and nicotinic receptors: lessons from genetically modified mice.
Journal Reference Authors Dani JA, Bertrand D
Title Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.
Journal Reference Authors Mansvelder HD, Keath JR, McGehee DS
Title Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.
Journal Reference Authors O'Dell LE
Title A psychobiological framework of the substrates that mediate nicotine use during adolescence.
Journal Reference Authors Ortells MO, Arias HR
Title Neuronal networks of nicotine addiction.
Journal Reference Authors Dani JA, Harris RA
Title Nicotine addiction and comorbidity with alcohol abuse and mental illness.
Journal Reference Authors Markou A
Title Review. Neurobiology of nicotine dependence.
Journal Reference Authors Dajas-Bailador F, Wonnacott S
Title Nicotinic acetylcholine receptors and the regulation of neuronal signalling.
Journal Related KO pathway
