Interaction Between Kisspeptin and Neurokinin B Neurons in Pubertal Female Rhesus Monkeys

Presentation Number: OR30-4
Date of Presentation: June 23rd, 2014

James P Garcia*1, Kathryn A Guerriero1, Kim L Keen2, Brian P Kenealy1, Joseph R Kurian1 and Ei Terasawa1
1University of Wisconsin-Madison, Madison, WI, 2Univ of Wisconsin, Madison, WI

Abstract

The KNDy network formed by kisspeptin, neurokinin B (NKB) and dynorphin neurons in the arcuate nucleus (ARC) has been implicated for the mechanism of GnRH pulse-generation in non-primate species. However, the role of KNDy neurons in the ARC in non-human primates is unclear. In this study, we investigated the interaction between kisspeptin and NKB neurons in pubertal female rhesus monkeys using microdialysis. We infused the kisspeptin agonist (KP-10) or antagonist (peptide 234) and the NKB agonist (senktide) or antagonist (SB222200) into the stalk-median eminence (S-ME), while dialysates were continuously collected at 20-min intervals. Agonists were infused for 20 min and antagonists were infused for 60 min (starting 40 min before and through agonist infusion). GnRH and kisspeptin levels in dialysates were measured by RIA. In Experiment 1, we found that senktide significantly stimulated both GnRH and kisspeptin release. This suggests that NKB stimulates GnRH release directly or indirectly though kisspeptin neurons, as KP-10 stimulates GnRH release in pubertal female monkeys (Guerriero et al., 2012, PMID:22166978). To assess whether NKB signals to GnRH neurons are mediated by kisspeptin neurons or kisspeptin signals are mediated by NKB neurons, we next examined the effects of peptide 234 on senktide-induced GnRH release (Experiment 2) and the effects of SB222200 on KP-10 induced GnRH release (Experiment 3). The results indicated that peptide 234 blocked senktide-induced GnRH release. Surprisingly, SB222200 also blocked KP-10 induced GnRH release. In experiments 2 and 3, we were not able to assess kisspeptin release, as both peptide 234 and KP-10 interfere with the kisspeptin RIA. These results suggest that there is a reciprocal relationship between kisspeptin and NKB signaling, both of which ultimately result in GnRH release. Although our finding that SB222200 blocked KP-10 effects on GnRH release contradicts an earlier report by Ramaswamy et al. (2011, PMID:21832818) in prepubertal male monkeys, there are considerable differences in approaches and methodologies. Considering a recent report in humans showing that there is a low degree of overlap between kisspeptin, NKB and dynorphin expressing neurons in the ARC (Hrabovszky et al., 2012, PMID:22903610), we speculate that there is considerable interaction between NKB, kisspeptin and GnRH neuroterminals in the S-ME. The role of dynorphin in this network remains to be investigated.

 

Nothing to Disclose: JPG, KAG, KLK, BPK, JRK, ET