Neurokinin-1 and neurokinin-3 receptors in primate substantia nigra

Striatonigral axons co-release GABA and substance P (SP) at their target sites, but little is known about the action of SP at nigral level. Therefore, we studied immunohistochemically the cellular and subcellular localization of SP and its high affinity receptors neurokinin-1 (NK-1R) and neurokinin-3 (NK-3R) at nigral level in squirrel monkeys. Immunofluorescent studies revealed that, although SP+ fibers arborised more densely in the pars reticulata (SNr) than in the pars compacta (SNc), the two nigral divisions harbored numerous neurons expressing NK-1R and NK-3R. Confocal microscopic analyses showed that numerous SNr neurons and virtually all SNc dopaminergic neurons contained both NK-1R and NK-3R. At the electron microscope level, NK-1R and NK-3R were mainly associated with intracellular sites or located at extrasynaptic position on plasma membrane. A small proportion of SP+ boutons also showed NK-3R immunoreactivity. The distribution of NK-1R and NK-3R in SNr and SNc suggests that SP exerts its effect through postsynaptic receptors, as well as via presynaptic autoreceptors and heteroreceptors. These findings indicate that the excitatory peptide SP can modulate the inhibitory action of GABA at nigral level and suggest that the co-release of these two neuroactive substances should be taken into account when considering the functional organization of the basal ganglia.