title: Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain.
abstract: Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT(1A) and 5-HT(2A/2C), and α₁- and α₂-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT(2A/2C) agonist, MDL11939, a 5-HT(2A) antagonist, 8-OH-DPAT, a 5-HT(1A) agonist, prazosin, an α₁-adrenergic antagonist and idazoxan, an α₂-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT(2A/2C) agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α₂ antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α₁ antagonist) remained without effect. Taken together, these results show the ability of a 5-HT(1A) agonist or a 5-HT(2A) antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs.
authors.affiliation: Faculté de Pharmacie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Maheux
authors.forename: Laura
authors.initials: L
authors.lastname: Vuillier
authors.forename: Mylène
authors.initials: M
authors.lastname: Mahfouz
authors.forename: Claude
authors.initials: C
authors.lastname: Rouillard
authors.forename: Daniel
authors.initials: D
authors.lastname: Lévesque
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*
chemical_list: D018663:Adrenergic Agents; D004268:DNA-Binding Proteins; D018492:Dopamine Antagonists; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D018490:Serotonin Agents; D006220:Haloperidol