Permissive role of neurokinin NK3 receptors in NK1 receptor-mediated activation of the locus coeruleus revealed by SR 142801

The present experiments investigated the role of neurokinin-1 (NK1) and neurokinin-3 (NK3) receptors on the activity of the locus coeruleus (LC)-noradrenergic system by using a dual probe microdialysis technique in anesthetized guinea pigs. The local application in the LC of the selective NK1 receptor agonists [SAR(9),Met(O-2)(11)]-SP (10 muM) and septide (1 muM) as well as the selective NK3 receptor agonist senktide (1 LM), enhanced the extracellular norepinephrine (NE) levels in the prefrontal cortex. The enhancing effect of [SAR(9),Met(O-2)(11)]-SP was completely blocked by the peripheral administration of the selective non peptide NK1 and NK3 receptor antagonists, GR 205171 (1 mg/kg, i.p.) and SR 142801 (0.1 mg/kg, i.p.), respectively, whereas SR 142806 (0.1 mg/kg, i.p.) the inactive enantiomer of SR 142801 had no effect. Moreover, the [SAR(9),Met(O-2)(11)]-SP-induced increase in LC DOPAC concentrations, is only antagonized by GR 205171. In contrast, only SR 142801 (0.3 mg/kg, i.p.) could block stereoselectively the senktide-evoked increase in NE levels. Both [SAR(9),Met(O-2)(11)]-SP and senktide effects were blocked by local infusion into the LC of SR 142801 (10(-9) M). These results demonstrate that stimulation of NK1 and NK3 receptors located in the LC area modulates the activity of the LC-NE system, and that the excitatory effects of NK1 receptor agonists require NKB/NK3 receptor activation in the LC. (C) 2001 Wiley-Liss, Inc.