Neurokinin receptors differentially mediate endogenous acetylcholine release evoked by tachykinins in the neostriatum

Abstract

The regulation of neostriatal cholinergic function by tachykinins (TKs) has been studied by measuring endogenous ACh released from rat neostriatal slices. Septide (SEP; a highly selective substance P analog), neurokinin A (NKA), and neurokinin B (NKB) elicited endogenous ACh release in a concentration-dependent manner. The rank order in potency was the following: NKB (EC50 ~ 0.5 nM) > NKA (EC50 ~ 7 nM) > SEP (EC50 ~ 12 nM). Spantide (SPA) was less effective (39% inhibition) than [D-Arg6, D-Trp7,9, N-Methyl- Phe8]-substance P fragment 6-11 (53% inhibition) at antagonizing ACh release evoked by SEP and NKA. Smaller doses of the antagonists inhibited the effects of SEP compared to NKA, and the effects of NKB could only be antagonized by SPA. These findings suggest the involvement of the three neurokinin (NK) receptors in ACh release evoked by TKs with the following rank order: NK3 > NK2 > NK1. 6-Hydroxydopamine lesions of nigrostriatal neurons and tetrodotoxin (TTX) intoxication of striatal tissue revealed two different pattern of regulation of cholinergic function by TKs. On the one hand, SEP and NKA evoked ACh release, independently of the nigrostriatal dopaminergic system, by acting on NK1 and NK2 receptors that are probably localized on the somatodendritic field of cholinergic neurons receiving substance P terminals. On the other hand, dopaminergic terminals seem to regulate NKB neurons that modulate cholinergic neurons, because NKB-evoked ACh release decreased by 24% in the denervated striata. In addition, TTX partially blocked (50%) ACh release evoked by NKB, suggesting that NKB acts on NK3 receptors at both the nerve terminals and the somatodendritic field of cholinergic neurons. Therefore, NKB neurons could play a crucial role in regulating cholinergic terminals by partially mediating the dopaminergic influence on cholinergic neurons. This finding may provide some clues in the organization of the basal ganglia and in the understanding of basal ganglia disorders.