MITOCHONDRIAL TOXINS IN MODELS OF NEURODEGENERATIVE DISEASES .2. ELEVATED ZIF268 TRANSCRIPTION AND INDEPENDENT TEMPORAL REGULATION OF STRIATAL D1 AND D2 RECEPTOR MESSENGER-RNAS 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 thro ugh mitochondrial DNA mutations. The N-methyl-4-phenyl-1,2,3,6-tetrahy dropydine (MPTP) model of experimental PD is believed to arise from lo ss of complex I activity in dopamine (DA) neurons after accumulation o f MPP+, a potent complex I inhibitor and the two electron monoamine ox idase B oxidation product of MPTP. Acute MPP+ infusion into striatum, possibly mimicking the in vivo situation after MPTP treatment, increas es release of DA and production of hydroxyl radical ((OH)-O-.). We tre ated C57BL/6 mice with MPTP and followed the expression of the immedia te-early gene zif268 in striatum as a marker of DA synaptic activity, determined the pharmacology of its activation during MPTP toxicity, an d assayed the time course of MPTP effects on striatal DA transporter ( DAT), and D1 and D2 DA receptor-binding sites and their mRNAs, MPTP (2 4 mg/kg b.i.d. for 4 doses) increased striatal zif268 expression, with peak effects observed 24 h after starting MPTP, Increased striatal zi f268 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-thir d of nigral DA neurons. We observed with [H-3]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 s howed a slight recovery at 2 weeks. Striatal D1 and D2 receptor-bindin g sites (measured with [H-3]SCH23390 and [H-3]spiperone binding, respe ctively) and mRNA levels for D1 and D2 receptors (determined with quan titative in situ hybridization) were altered after MPTP treatment in t emporally independent manners. MPTP toxicity to the nigrostriatal syst em likely induces substantial striatal DA release in vive and stimulat es transcription of at least one major IEG, zif268, in striatal neuron s. Increased striatal zif268 expression after MPTP appears to derive m ainly from DA released onto D1 receptors, not by a NO-dependent proces s which has been described in striatal neurons in vitro. The rapid los s of striatal DA terminals after MPTP treatment alters D1 and D2 recep tor sites independently of changes in their mRNA levels. Increased D1 and D2 gene transcription in this model may depend on re-innervation b y DA terminals of striatal neurons and likely is not related to the in creased zif268 transcription observed after MPTP. (C) 1997 Elsevier Sc ience B.V.