Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine.
Gene targeting experiments, in which both alleles of the Nurr1 gene were deleted, have shown that this molecule plays an essential role in the development of midbrain dopaminergic neurons, as shown by the loss of dopaminergic markers and the neurotransmitter dopamine (DA) in the ventral mesencephalon of Nurr1 null mutant mice. Nurr1-deficient mice die within a few hours of birth. Herein, we investigated whether adult mice (12-15-month-old), heterozygous for the Nurr1 mutation (Nurr1(+/-)), show alterations in locomotor function and in the nigrostriatal dopaminergic system after acute exposure to methamphetamine. We first evaluated spontaneous and amphetamine-induced (5mg/kg) locomotor response of >12-month-old wildtype (Nurr1(+/+)) and Nurr1(+/-) mice. Both, spontaneous and methamphetamine-induced locomotor behavior was significantly increased in the Nurr1(+/-) animals as compared to Nurr1(+/+) mice. Striatal DA and DA metabolite levels were measured in untreated animals and methamphetamine-treated animals. No significant differences in striatal dopamine levels or its metabolites DOPAC and HVA were found in the Nurr1(+/-) as compared to Nurr1(+/+) mice in untreated or methamphetamine-treated animals. These data show that deletion of a single allele of the Nurr1 gene alters the locomotor activity of 12-15-month-old Nurr1(+/-) animals. While total dopamine levels were not altered in the striatum of Nurr1(+/-) mice, future studies will be necessary to determine if processes involved with the dynamics of DA release/clearance within the nigrostriatal system may be altered in Nurr1(+/-) mutant mice.
Bäckman
Cristina
C
Cellular Neurobiology Branch, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21221, USA. cbackman@intra.nida.nih.gov
You
Zhi Bing
ZB
Perlmann
Thomas
T
Hoffer
Barry J
BJ
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D006579:Heterozygote; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; D015259:Dopamine Agents; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D008694:Methamphetamine; D004298:Dopamine