Compensatory activation of substance P biosynthesis by L-dihydroxyphenylalanine in striatonigral neurons of neonatal dopaminergic denervated rats

S. P. Sivam, J. E. Krause

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Previous studies have shown that L-dihydroxyphenylalanine (L-DOPA) administration to adult rats that had been subjected to dopaminergic 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 (α, β and γ) 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. The results indicate that the L-DOPA-induced depletion of SP levels in the lesioned rats is followed by enhanced de novo synthesis of SP-encoding mRNAs and subsequently the peptide. A compensatory activation of PPT transcriptional machinery may be involved in this process. The results provide further evidence for the regulatory control of dopamine to the development and function of striatonigral SP neurons.

Original languageEnglish (US)
Pages (from-to)433-439
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume254
Issue number2
StatePublished - Jan 1 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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