Electrophysiological, behavioural 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 examine the involvement of neurokinin NK3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC50 = 26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 micrograms) and (MePhe7)neurokinin B (1-10 micrograms), another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 micrograms of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 micrograms i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration- or dose-dependently reduce by SR 142801, the selective non-peptide NK3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 microgram). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-2.56 micrograms/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 stimulation of neurokinin NK3 receptors.
Jung
M
M
Sanofi Recherche, Neuropsychiatry Department, Montpellier, France.
Michaud
J C
JC
Steinberg
R
R
Barnouin
M C
MC
Hayar
A
A
Mons
G
G
Souilhac
J
J
Emonds-Alt
X
X
Soubrié
P
P
Le Fur
G
G
D000320:Adrenergic Fibers / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D006168:Guinea Pigs; D008125:Locus Coeruleus / Q000187:drug effects*; D017551:Microdialysis; D009479:Neuropeptides / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D018042:Receptors, Neurokinin-3 / Q000187:drug effects*; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology
D009479:Neuropeptides; D010446:Peptide Fragments; D010880:Piperidines; D018042:Receptors, Neurokinin-3; C054724:senktide; D013373:Substance P; C091554:SR 142801; D009638:Norepinephrine; D011224:Prazosin