Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover.
BACKGROUND
Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely associated with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and ant-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive.


METHODS
We compared various behavioral and biochemical parameters between Nur77 knockout -/- and wild-type +/+ mice in basal and haloperidol-challenged conditions.


RESULTS
We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are associated with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression.


CONCLUSIONS
Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochemical activity and dopamine turnover.
Gilbert
François
F
Neuroscience Unit, CRCHUL and Faculty of Medicine, Laval University, Ste-Foy, Quebec, Canada.
Morissette
Marc
M
St-Hilaire
Michel
M
Paquet
Brigitte
B
Rouillard
Claude
C
Di Paolo
Thérèse
T
Lévesque
Daniel
D
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001923:Brain Chemistry / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004563:Electrochemistry / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007980:Levodopa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D011987:Receptors, Steroid / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D002394:Catechol O-Methyltransferase; D004298:Dopamine