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4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-

We examined the expression and presence of NK2 receptors in the septal area of rat brain, and investigated their functional role in the regulation of the septohippocampal cholinergic system. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we showed the presence of NK2 receptor mRNA expression in the septal area, and detected septal NK2 binding sites by using a fluorescent-tagged neurokinin A (NKA) derivative. In vivo microdialysis was employed to explore the functional role of NK2 receptors in the release of hippocampal acetylcholine evoked by tactile stimulation in freely moving rats. Two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, produced a marked and reproducible increase in hippocampal acetylcholine release. This effect was dose-dependently prevented by intraperitoneal administration of the two selective non-peptide tachykinin NK2 receptor antagonists SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3 and 1 mg/kg, i.p.), but not by the inactive enantiomer of SR48968 (SR48965, 1 mg/kg) nor by the two non-peptide NK1 receptor antagonists SR140333 (3 mg/kg, i.p.) and GR205171 (1 mg/kg, i.p.). Furthermore, the intraseptal application of SR144190 (10(-8) M) reduced the sensory response. Finally, intraseptal perfusion of neurokinin A (0.01-10 microM) in anaesthetized rats produced a concentration-dependent increase in hippocampal acetylcholine release. The response to neurokinin A (0.1 microM) was prevented by SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3-1 mg/kg, i.p.). In conclusion, this study provides direct evidence for the role of endogenous NKA/substance P, through the activation of NK2 receptors, in regulating the septohippocampal cholinergic function.

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The regulation of striatal cholinergic function by tachykinins was examined in urethane-anesthetized rats by using microdialysis . Substance P (0 .01-1 pM), [Sar',Met(02 ) 11 ]substance P (1-10 p, M), septide (0 .1-3 pM), neurokinin (NK) A (0.1-10 p,M), and senktide (0 .1-10 pM) produced concentration-dependent increases in striatal acetylcholine (ACh) release. Septide was the most potent agonist for inducing release of ACh, whereas the stimulating effect of senktide was less pronounced and more progressive in onset . The response to septide was prevented by intraperitoneal administration of the nonpeptide NK, antagonist SR 140333 (1-3 mg/kg) but not by the nonpeptide NK2 receptor antagonist SR 48968, indicating that the effect was mediated specifically by NK, receptors. ACh release caused by NKA was reduced by SR 48968 (1-3 mg/kg) and slightly affected by SR 140333, indicating a principal role for NK2 receptors in the peptide response . The similar efficacy of SR 140333 and SR 48968 in blocking substance P-induced ACh release suggested that the effect of this peptide involves the stimulation of both NK, and NK2 receptors . Finally, our results indicate that the increase in striatal ACh release induced by the D, agonist (+)-SKF-38393 (3 pM) may be mediated indirectly through local release of NKA or substance P acting at NK2 receptors.