The new neurokinin 1‐sensitive receptor mediates the facilitation by endogenous tachykinins of the NMDA‐evoked release of acetylcholine after suppression of dopaminergic transmission in the matrix of the rat striatum

Using an in vitro microsuperfusion procedure, the NMDA‐evoked release of [3H]ACh was studied after suppression of dopamine (DA) transmission (α‐methyl‐p‐tyrosine) in striatal compartments of the rat. The effects of tachykinin neurokinin 1 (NK1) receptor antagonists and the ability of appropriate agonists to counteract the antagonist responses were investigated to determine whether tachykinin NK1 classic, septide‐sensitive and/or new NK1‐sensitive receptors mediate these regulations. The NK1 antagonists, SR140333, SSR240600, GR205171 but not GR82334 and RP67580 (0.1 and 1 µm) markedly reduced the NMDA (1 mm + d‐serine 10 µm)‐evoked release of [3H]ACh only in the matrix. These responses unchanged by coapplication with NMDA of NK2 or NK3 agonists, [Lys5,MeLeu9,Nle10]NKA(4–10) or senktide, respectively, were completely counteracted by the selective NK1 agonist, [Pro9]substance P but also by neurokinin A and neuropeptide K (1 nm each). According to the rank order of potency of agonists for counteracting the antagonist responses ([Pro9]substance P, 0.013 nm > neurokinin A, 0.15 nm ≫ substance P(6–11) 7.7 nm = septide 8.7 nm), the new NK1‐sensitive receptors mediate the facilitation by endogenous tachykinins of the NMDA‐evoked release of ACh in the matrix, after suppression of DA transmission. Solely the NK1 antagonists having a high affinity for these receptors could be used as indirect anti‐cholinergic agents.