Mitochondrial toxins in models of neurodegenerative diseases. II: Elevated zif268 transcription and independent temporal regulation of striatal D1 and D2 receptor mRNAs and D1 and D2 receptor-binding sites in C57BL/6 mice during MPTP treatment.
Sporadic Parkinson's disease (PD) may arise from a defect in complex I of the mitochondrial electron transport chain (ETC), transmitted through mitochondrial DNA mutations. The N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental PD is believed to arise from loss of complex I activity in dopamine (DA) neurons after accumulation of MPP+, a potent complex I inhibitor and the two electron monoamine oxidase B oxidation product of MPTP. Acute MPP+ infusion into striatum, possibly mimicking the in vivo situation after MPTP treatment, increases release of DA and production of hydroxyl radical (-OH). We treated C57BL/6 mice with MPTP and followed the expression of the immediate-early gene zif268 in striatum as a marker of DA synaptic activity, determined the pharmacology of its activation during MPTP toxicity, and assayed the time course of MPTP effects on striatal DA transporter (DAT), and D1 and D2 DA receptor-binding sites and their mRNAs. MPTP (24 mg/kg b.i.d. for 4 doses) increased striatal zif268 expression, with peak effects observed 24 h after starting MPTP. Increased striatal zif268 was dependent mainly on DA D1 and to a lesser extent on non-NMDA glutamate receptors and was not altered by inhibition of nitric oxide synthase (NOS). Our MPTP schedule resulted in a loss of about one-third of nigral DA neurons. We observed with [3H]mazindol autoradiography that loss of striatal DAT sites after starting MPTP was heterogenous and greatest in centromedial striatum, reached a maximum at 48 h and showed a slight recovery at 2 weeks. Striatal D1 and D2 receptor-binding sites (measured with [3H]SCH23390 and [3H]spiperone binding, respectively) and mRNA levels for D1 and D2 receptors (determined with quantitative in situ hybridization) were altered after MPTP treatment in temporally independent manners. MPTP toxicity to the nigrostriatal system likely induces substantial striatal DA release in vivo and stimulates transcription of at least one major IEG, zif268, in striatal neurons. Increased striatal zif268 expression after MPTP appears to derive mainly from DA released onto D1 receptors, not by a NO-dependent process which has been described in striatal neurons in vitro. The rapid loss of striatal DA terminals after MPTP treatment alters D1 and D2 receptor sites independently of changes in their mRNA levels. Increased D1 and D2 gene transcription in this model may depend on re-innervation by DA terminals of striatal neurons and likely is not related to the increased zif268 transcription observed after MPTP.
Smith
T S
TS
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Trimmer
P A
PA
Khan
S M
SM
Tinklepaugh
D L
DL
Bennett
J P
JP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D015259:Dopamine Agents; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine