Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: implication for their mechanism of action.
Monitoring gene expression has been intensively used to identify neurobiological and neuroanatomical substrates associated with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently associated with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calculate an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by anti-psychotic drugs are correlated with dopamine D2 receptor in the striatum and D2 and D3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine 2A/D2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addition to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacological effects.
Maheux
Jérôme
J
Neuroscience Unit, Centre de Recherche du Centre Hospitalier de l'Université Laval, Centre Hospitalier Universitaire du Québec, Québec, Canada.
Ethier
Isabelle
I
Rouillard
Claude
C
Lévesque
Daniel
D
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D003720:Densitometry; D004745:Enkephalins / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
D014150:Antipsychotic Agents; D004268:DNA-Binding Proteins; C493594:Drd3 protein, mouse; D004745:Enkephalins; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D018160:Receptors, Cytoplasmic and Nuclear; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017981:Receptors, Neurotransmitter; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors