266 Senktide attenuates scopolamine-induced impairment of spontaneous alternation performance in mice

Abstract

To test the hypothesis that different neurokinin receptors might be involved in the generation of either phasic or tonic muscular activity, selective ligands for the 6 neurokinin-1-receptor, [Sar9, Met(O2)]-SP, the neurokinin-2-receptor, [Nle10]-NKA4–10, and the neurokinin-3 receptor, [βAsp4,MePhe7]-NKB4–10, were used to evaluate the excitatory effects of these agonists in the longitudinal rat ileal muscle in vitro. The excitatory effect was analyzed as total response (area under the curve) and as tonic or phasic (area under or within the peaks) activity. Substance P (SP, relative amount of phasic activity in comparison to total activity: 3 × 10−8 M 87%, 3×10−6 M 30%) and the neurokinin-2-receptor selective agonist [Nle10]-NKA4–10 (N-NKA: 3×10−8 M 67%, 3 × 10−6 M 59%) caused both tonic and phasic responses, with the percentage of phasic responses decreasing at higher concentrations. The neurokinin-1-receptor selective agonist [βAla4, Sar9, Met(O2)]-SP4–11 caused a predominantly tonic response with only a small phasic component (10−8 M 27.1% 10−6 M 13.8%). The selective neurokinin-3 receptor agonist [βAsp4, MePhe7]-NKB4–10 caused a predominantly phasic motor response (SM-SP: 3 × 10−8 M 98%, 3 × 10−6 M 87%). Tetrodotoxin (TTX 10−6 M), omega-conotoxin (CTX 10−7 M) and atropine (10−6 M) had no significant influence on the contractile responses to all four peptides, indicating a direct action on the smooth muscle cell. Nitrendipine (10−7 M) and Ca2+-free medium significantly reduced phasic and tonic activity in response to all peptides. This showed the important role of the influx of extracellular calcium on the contractile process.These data demonstrated that phasic and tonic activity could be induced via a postsynaptic mechanism with selective neurokinin analogues. The NK-3 selective ligand produced phasic activity, whereas the NK-1 selective ligand produced tonic activity. This suggests that different neurokinin receptor subtypes are present on the smooth muscle cell which can elicit these different contractile responses.