title: Modulation of basal and stress-induced amygdaloid substance P release by the potent and selective NK1 receptor antagonist L-822429.
abstract: It has been shown that anxiety and stress responses are modulated by substance P (SP) released within the amygdala. However, there is an important gap in our knowledge concerning the mechanisms regulating extracellular SP in this brain region. To study a possible self-regulating role of SP, we used a selective neurokinin-1 (NK1) receptor antagonist to investigate whether blockade of NK1 receptors results in altered basal and/or stress-evoked SP release in the medial amygdala (MeA), a critical brain area for a functional involvement of SP transmission in enhanced anxiety responses induced by stressor exposure. In vitro binding and functional receptor assays revealed that L-822429 represents a potent and selective rat NK1 receptor antagonist. Intra-amygdaloid administration of L-822429 via inverse microdialysis enhanced basal, but attenuated swim stress-induced SP release, while the low-affinity enantiomer of L-822429 had no effect. Using light and electron microscopy, synaptic contacts between SP-containing fibres and dendrites expressing NK1 receptors was demonstrated in the medial amygdala. Our findings suggest self-regulatory capacity of SP-mediated neurotransmission that differs in the effect on basal and stress-induced release of SP. Under basal conditions endogenous SP can serve as a signal that tonically inhibits its own release via a NK1 receptor-mediated negative feedback action, while under stress conditions SP release is further facilitated by activation of NK1 receptors, likely leading to high local levels of SP and activation of receptors to which SP binds with lower affinity.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria. nicolas.singewald@uibk.ac.at
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Thurner
authors.forename: Kwei-Lan
authors.initials: KL
authors.lastname: Tsao
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
authors.forename: Hari Kishore
authors.initials: HK
authors.lastname: Sreepathi
authors.forename: Francesco
authors.initials: F
authors.lastname: Ferraguti
authors.forename: Georg M
authors.initials: GM
authors.lastname: Singewald
authors.forename: Karl
authors.initials: K
authors.lastname: Ebner
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D008024:Ligands; C532739:N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013373:Substance P