Compensatory activation of substance P biosynthesis by L-dihydroxyphenylalanine in striatonigral neurons of neonatal dopaminergic denervated rats.
Previous studies have shown that L-dihydroxyphenylalanine (L-DOPA) administration to adult rats that had been subjected to dopamingergic denervation with 6-hydroxydopamine during early postnatal period, led to a marked decrease in the levels of striatonigral substance P (SP). The present study examined the hypothesis of whether there is a compensatory activation of SP biosynthesis in order to replenish the L-DOPA-induced SP depletion. Three-day old Sprague-Dawley rat pups were lesioned with 6-hydroxydopamine and were challenged with L-DOPA at about 60 days of age. The animals were sacrificed 75 min, 6 hr or 24 hr after the L-DOPA administration. The levels of SP (in the striatum and substantia nigra) were determined by radioimmunoassay. The abundance of SP-encoding preprotachykinin (PPT) messenger RNA (mRNA) in the striatum was determined by Northern blot analysis and the abundance of individual PPT-mRNAs (alpha, beta and gamma) was determined by nuclease protection assays. Concentrations of dopamine and its acid metabolite, dihydroxyphenyl acetic acid were determined by high-pressure liquid chromatography with electrochemical detection. At the 75 min time point, L-DOPA produced a greater decrease in SP levels in the striatum and the substantia nigra, than that observed with lesion alone. The SP levels recovered to lesioned-control levels by 6 hr and remained at this level at the 24-hr time point. This recovery was accompanied by a marked increase in striatal SP-encoding PPT-mRNA abundance at 6 hr; mRNA levels were below lesioned-control value at 24 hr. There were no differential changes in the individual SP-encoding PPT-mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Gary.
S P
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Sivam
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Krause
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis / Q000502:physiology*; D005260:Female; D007274:Injections, Intraperitoneal; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D010648:Phenylacetates / Q000378:metabolism*; D011498:Protein Precursors / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013373:Substance P / Q000096:biosynthesis*; D015320:Tachykinins / Q000032:analysis
D010648:Phenylacetates; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D015102:3,4-Dihydroxyphenylacetic Acid; D013373:Substance P; D007980:Levodopa; D004298:Dopamine