Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons.
Nicotine, acting on nicotinic acetylcholine receptors (nAChRs) expressed at pre-synaptic dopaminergic terminals, has been shown to stimulate the release of dopamine in the neostriatum. However, the molecular consequences of pre-synaptic nAChR activation in post-synaptic neostriatal neurons are not clearly understood. Here, we investigated the effect of nAChR activation on dopaminergic signaling in medium spiny neurons by measuring phosphorylated DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (the PKA-site) in mouse neostriatal slices. Nicotine produced dose-dependent responses, with a low concentration (1 microm) causing a sustained decrease in DARPP-32 Thr34 phosphorylation and a high concentration (100 microm) causing a transient increase in DARPP-32 Thr34 phosphorylation. Depending on the concentration of nicotine, either dopamine D2 or D1 receptor signaling was predominantly activated. Nicotine at a low concentration (1 microm) activated dopamine D2 receptor signaling in striatopallidal/indirect pathway neurons, likely by activating alpha4beta2* nAChRs at dopaminergic terminals. Nicotine at a high concentration (100 microm) activated dopamine D1 receptor signaling in striatonigral/direct pathway neurons, likely by activating (i) alpha4beta2* nAChRs at dopaminergic terminals and (ii) alpha7 nAChRs at glutamatergic terminals, which, by stimulating the release of glutamate, activated NMDA/AMPA receptors at dopaminergic terminals. The differential effects of low and high nicotine concentrations on D2- and D1-dependent signaling pathways in striatal neurons may contribute to dose-dependent actions of this drug of abuse.
Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
Miho
M
Hamada
Hideho
H
Higashi
Angus C
AC
Nairn
Paul
P
Greengard
Akinori
A
Nishi
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002038:Bungarotoxins / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020891:Raclopride / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism
D001552:Benzazepines; D002038:Bungarotoxins; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010750:Phosphoproteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D004079:Dihydro-beta-Erythroidine; D013912:Threonine; D020891:Raclopride; D013779:Tetrodotoxin; D008464:Mecamylamine; D016291:Dizocilpine Maleate; D009538:Nicotine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016572:Cyclosporine