Effect of substance P on acetylcholine and dopamine release in the rat striatum: a microdialysis study

In vivo microdialysis in urethane anaesthetised rats was used to investigate the effects of substance P (SP) on acetylcholine (ACh) and dopamine (DA) release in the rat striatum. Results showed that SP elicited a dose-dependent increase in ACh release between 1 and 50 pmol/l. The rise in ACh release occurred both during SP administration and for up to 60 min after it. Dose-response curves either based on the initial rise in ACh release, or the total duration of increased release, showed a bell shape with 100 fmol/l and 5 nmol/l doses failing to significantly alter release and a 500 pM dose being less effective than 50 pmol/l. In contrast to this, SP did not significantly alter DA release at doses ranging between 100 fmol/l and 5 nmol/l. There was evidence for a strong desensitisation effect of SP administration since after initial treatment with SP subsequent doses of the peptide, even at very high doses, failed to provoke further changes in ACh still showed the expected increase in release in response to a potassium challenge. Physalaemin and neurokinin A increased ACh release with a similar potency to SP at a 50 pmol/l dose whereas neurokinin B and neuropeptide gamma, while increasing ACh release at a 50 pmol/l dose, were less potent than SP. The effect of SP on ACh release is probably mediated via NK-1 receptors since ACh release in response to SP was reduced in a dose dependent manner by the NK-1 receptor antagonists CP-96,345 and RP-67580.