Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity.
Nurr1, an orphan nuclear receptor, is essential for the differentiation of the midbrain dopamine (DA) neurons; however, its function in adult midbrain DA neurons has not been determined. The present study compared regional brain levels of catecholamines and spontaneous and pharmacologically induced locomotor behaviors between mice heterozygous for the Nurr1-null allele (+/-) and wild type (+/+) littermates. The Nurr1 +/- mice had significantly lower levels of DA in whole brain, midbrain, prefrontal cortex and nucleus accumbens, although no significant differences were observed in the striatum, olfactory bulb or hippocampus. Nurr1 +/- mice displayed significantly greater locomotor activity in a novel open field and after saline injection with no significant difference in activity after treatment with amphetamine (2.5 or 5.0 mg/kg) or MK 801 (0.2 or 0.4 mg/kg). A similar elevation in locomotor activity was observed in Nurr1 +/- mice at 35 days old as was found in 70 days old adults. These data demonstrate that the loss of a single Nurr1 allele results in reduced DA levels in mesolimbic and mesocortical pathways and increased locomotor activity in response to mild stress. The involvement of Nurr1 in DA neurotransmission and the implications for schizophrenia are discussed.
Eells
J B
JB
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Dr., MSC 1766, Bethesda, MD 20892-1766, USA.
Lipska
B K
BK
Yeung
S K
SK
Misler
J A
JA
Nikodem
V M
VM
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D006579:Heterozygote; D008032:Limbic System / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000378:metabolism / Q000523:psychology*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D002395:Catecholamines; D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D000661:Amphetamine; D004298:Dopamine