Effects of intranigral substance p and neurokinin a on striatal dopamine release—i. Interactions with substance p antagonists

Abstract

The functional role of striatonigral neurokinins were studied by analysing the effects of intranigral injections of substance P and neurokinin A on the extracellular level of dopamine and dihydroxyphenylacetic acid in the striatum, as measured by in vivo microdialysis in rats. Two substance P antagonists, substance P d-Pro 2 d-Trp 7,9 and substance P d-Arg 1 d-Trp 7,9 Leu 11 were tested and analysed for their ability to block the neurokinin effects. Unilateral injections of substance P (0.00007–7.0 nmol injected in 0.2 μl) as well as neurokinin A (0.009–9.0 nmol) into the substantia nigra, pars reticulata of halothane anaesthetized rats produced long-lasting increases in ipsilateral striatal dopamine and dihydroxyphenylacetic acid levels. The dose-response relationship for substance P on dopamine was biphasic, with maximal effects occurring after the middle dose (0.007–0.07 nmol). The dose-response relationship for neurokinin A was monophasic. Intranigral injections of substance P d-Pro 2 d-Trp (0.07–0.7 nmol) or substance P d-Arg 1 d-Trp 7,9 Leu 11 (0.07–0.7 nmol) produced a decrease in striatal dopamine, but an increase in striatal dihydroxyphenylacetic acid. At a low dose (0.07 nmol) substance P d-Pro 2 d-Trp 7,9 enhanced the dopamine increase produced by intranigral substance P (0.07 nmol) or neurokinin A (0.09), while at a high dose (0.7 nmol) it blocked both substance P and neurokinin A effects. Both doses of substance P d-Arg 1 d-Trp 7,9 Leu 11 (0.07 and 0.7 nmol) blocked the substance P- but not the neurokinin A-induced increase in striatal dopamine. Immunohistochemical analysis revealed that high doses of substance P (7.0 nmol) and neurokinin A (0.9 and 9.0 nmol), as well as substance d-Arg 1 d-Trp 7,9 and substance P d-Arg 1 d-Trp 7,9 Leu 11 (0.07 and 0.7 nmol), induced a restricted loss of tyrosine hydroxylase in dendrites and cells, and neuropeptide K in terminals, at the site of injection. Further analysis shows that co-administration of substance P (0.07 nmol) or neurokinin A (0.09 nmol) did not modify the extent of the depletion of both immunoreactivities induced by substance P d-Arg 1 d-Trp 7,9 Leu 11 (0.7 nmol). The extent of the effect produced by substance P d-Arg 1 d-Trp 7,9 Leu 11 (0.7 nmol) was, however, smaller than the spread of intranigral injection of [ 125I]Bolton-Hunter-labelled substance P d-Arg 1 d-Trp 7,9 Leu 11, and it is suggested that the “neurotoxic” effects of the substance P antagonists are not primarily involved in their abilities to inhibit striatal dopamine release and block the stimulation of dopamine after intranigral substance P and neurokinin A. We propose that striatonigral substance P and neurokinin A produce a tonic excitatory modulation of nigrostriatal dopamine via neurokinin receptors which can be blocked by substance P d-Arg 1 d-Trp 7,9. However, substance P and neurokinin A are probably acting via different receptors since substance P d-Arg 1 d-Trp 7,9 Leu 11 blocked substance P but not neurokinin A stimulation of striatal dopamine release.