ELECTROPHYSIOLOGICAL, BEHAVIORAL AND BIOCHEMICAL-EVIDENCE FOR ACTIVATION OF BRAIN NORADRENERGIC SYSTEMS FOLLOWING NEUROKININ NK3 RECEPTOR STIMULATION

The objective of the present in vitro and in vivo experiments was to e xamine the involvement of neurokinin NK3 receptors in the regulation o f the noradrenergic function in gerbils and guinea-pigs. Application o f senktide, a peptide NK3 receptor agonist, on guinea-pig locus coerul eus slices increased the firing rate of presumed noradrenergic neurons (EC(50)=26 nM) in a concentration-dependent manner. Given i.c.v., sen ktide (0.5-2 mu g) and (MePhe(7))neurokinin B (1-10 mu g); another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose- dependent manner (2 mu g of senktide producing a 50% reduction of loco motor activity and rearing). In vivo microdialysis experiments in uret hane-anaesthetized guinea-pigs showed that senktide (2-8 mu g i.c.v.) induced a dose-dependent increase in norepinephrine release in the med ial prefrontal cortex. The electrophysiological, behavioural and bioch emical changes elicited by senktide were concentration- or dose-depend ently reduced by SR 142801, the selective non-peptide NK3 receptor ant agonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injec ted i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrin e release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reve rsed the reduction of exploratory behaviour induced by senktide (1 mu g). By contrast, the 100-fold less active enantiomer, SR 142806, did n ot exert any antagonism in these models. Finally, the reduction of exp loratory behaviour in gerbils was found to be reversed by prazosin (0. 25-2.56 mu g/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by s timulation of neurokinin NK3 receptors. Copyright (C) 1996 IBRO. Publi shed by Elsevier Science Ltd.