Entry Name Nicotine addiction - Pteropus vampyrus (large flying fox)
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 Pteropus vampyrus (large flying fox) [GN:
pvp ]
Gene 105289631 GABRR3; gamma-aminobutyric acid receptor subunit rho-3 [KO:K05190 ]
105289890 GABRG2; gamma-aminobutyric acid receptor subunit gamma-2 isoform X1 [KO:K05186 ]
105289891 GABRA1; gamma-aminobutyric acid receptor subunit alpha-1 isoform X1 [KO:K05175 ]
105289892 GABRA6; gamma-aminobutyric acid receptor subunit alpha-6 [KO:K05175 ]
105289947 GABRB2; gamma-aminobutyric acid receptor subunit beta-2 [KO:K05181 ]
105293734 SLC17A6; vesicular glutamate transporter 2 isoform X1 [KO:K12302 ]
105293897 GABRG1; gamma-aminobutyric acid receptor subunit gamma-1 [KO:K05186 ]
105293898 GABRB1; gamma-aminobutyric acid receptor subunit beta-1 isoform X1 [KO:K05181 ]
105293915 GABRA2; gamma-aminobutyric acid receptor subunit alpha-2 isoform X1 [KO:K05175 ]
105293917 GABRA4; gamma-aminobutyric acid receptor subunit alpha-4 [KO:K05175 ]
105296449 CHRNB2; neuronal acetylcholine receptor subunit beta-2 [KO:K04813 ]
105296978 GABRR2; gamma-aminobutyric acid receptor subunit rho-2 isoform X1 [KO:K05190 ]
105296979 GABRR1; gamma-aminobutyric acid receptor subunit rho-1 isoform X1 [KO:K05190 ]
105298564 GRIN1; glutamate receptor ionotropic, NMDA 1 isoform X1 [KO:K05208 ]
105298593 CACNA1B; voltage-dependent N-type calcium channel subunit alpha-1B [KO:K04849 ]
105300583 CHRNA6; neuronal acetylcholine receptor subunit alpha-6 isoform X1 [KO:K04808 ]
105301459 CHRNA4; neuronal acetylcholine receptor subunit alpha-4 [KO:K04806 ]
105303608 GABRD; gamma-aminobutyric acid receptor subunit delta [KO:K05184 ]
105305784 GABRA5; gamma-aminobutyric acid receptor subunit alpha-5 [KO:K05175 ]
105307194 CACNA1A; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344 ]
105308189 GABRE; gamma-aminobutyric acid receptor subunit epsilon [KO:K05185 ]
105308191 GABRA3; gamma-aminobutyric acid receptor subunit alpha-3 [KO:K05175 ]
105308196 GABRQ; gamma-aminobutyric acid receptor subunit theta [KO:K05192 ]
105310456 SLC17A8; vesicular glutamate transporter 3 isoform X2 [KO:K12302 ]
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
