Permissive role of neurokinin NK 3 receptors in NK 1 receptor‐mediated activation of the locus coeruleus revealed by SR 142801

The present experiments investigated the role of neurokinin‐1 (NK 1 ) and neurokinin‐3 (NK 3 ) 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 NK 1 receptor agonists [SAR 9 ,Met(O 2 ) 11 ]‐SP (10 μM) and septide (1 μM) as well as the selective NK 3 receptor agonist senktide (1 μM), 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 NK 1 and NK 3 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 NK 1 and NK 3 receptors located in the LC area modulates the activity of the LC‐NE system, and that the excitatory effects of NK 1 receptor agonists require NKB/NK 3 receptor activation in the LC. Synapse 43:62–69, 2002. © 2001 Wiley‐Liss, Inc.