Striatonigral Tachykinin Biosynthesis I. Effect of the Dopamine Antagonist Haloperidol

The prominent substance P (SP) projection from the striatum to the substantia nigra is thought to play an important role in the regulation of basal ganglia function and the response to dopaminergic and other pharmacological agents. However, the physiological and pharmacological significance of this striatonigral tachykinin system has been difficult to assess, since no useful measures of SP turnover have been available. Previous studies have shown that the repeated administration of dopamine (DA) antagonist (antipsychotic) drugs decreases the concentration of SP in the substantia nigra [1–5], although the relationship between SP concentration and SP turnover remains obscure. It has recently been demonstrated [6,7] that two mRNAs derived from one preprotachykinin (PPT) gene by alternate RNA splicing encode for either SP alone (αPPT mRNA) or both SP and the newly discovered tachykinin [8,9] substance K (SK) (βPPT mRNA). Thus, the biosynthes is of these two tachykinins could be differentially regulated in response to DA antagonists or other stimuli. In the present experiments, striatonigral SP and SK immunoreactivities were characterized using specific radioimmunoassays (RIAs) coupled to high performance liquid chromatography (HPLC). The acute and chronic effects of the antipsychotic drug haloperidol on the levels of striatonigral PPT mRNA (as well as SP and SK peptide levels) in single rat brain striata were quantitated as a dynamic index of tachykinin turnover.