title: Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro.
abstract: Chronic blockade or activation of dopamine receptors is critical for the pharmacological treatment of diseases like schizophrenia, Parkinson's or attention deficit and hyperactivity disorder. However, the long-term impact of such treatments on dopamine neurons is unclear. Chronic blockade of the dopamine D2 receptor in vivo triggers an increase in the axonal arborization of dopamine neurons [European Journal of Neuroscience, 2002, 16, 787-794]. However, the specific involvement of presynaptic (autoreceptors) vs. postsynaptic D2 receptors as well as the molecular mechanisms involved have not been determined. Here, we examined the role of D2 autoreceptors in regulating the ability of mouse dopamine neurons to establish axon terminals. Chronic activation of this receptor with quinpirole, a specific agonist, decreased the number of axon terminals established by isolated dopamine neurons. This effect was accompanied by a decrease in dopamine release and was mediated through inhibition of protein kinase A. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin pathway of mRNA translation was blocked. Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. This study provides a better understanding of the impact of long-term pharmacological interventions acting through the D2 receptor.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Fasano
authors.forename: A
authors.initials: A
authors.lastname: Poirier
authors.forename: L
authors.initials: L
authors.lastname: DesGroseillers
authors.forename: L-E
authors.initials: LE
authors.lastname: Trudeau
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D017660:Autoreceptors; D002352:Carrier Proteins; D018491:Dopamine Agonists; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine