Loss-of-function or inactivating mutations in the genes coding for kisspeptin 
and its receptor (KISS1R) or neurokinin B (NKB) and the NKB receptor (NK3R) in 
humans result in a delay in or the absence of puberty. However, precise 
mechanisms of kisspeptin and NKB signaling in the regulation of the pubertal 
increase in gonadotropin-releasing hormone (GnRH) release in primates are 
unknown. In this study, we conducted a series of experiments infusing agonists 
and antagonists of kisspeptin and NKB into the stalk-median eminence, where 
GnRH, kisspeptin, and NKB neuroterminal fibers are concentrated, and measuring 
GnRH release in prepubertal and pubertal female rhesus monkeys. Results indicate 
that (1) similar to those previously reported for GnRH stimulation by the KISS1R 
agonist (i.e., human kisspeptin-10), the NK3R agonist senktide stimulated GnRH 
release in a dose-responsive manner in both prepubertal and pubertal monkeys; 
(2) the senktide-induced GnRH release was blocked in the presence of the KISS1R 
antagonist peptide 234 in pubertal but not prepubertal monkeys; and (3) the 
kisspeptin-induced GnRH release was blocked in the presence of the NK3R 
antagonist SB222200 in the pubertal but not prepubertal monkeys. These results 
are interpreted to mean that although, in prepubertal female monkeys, kisspeptin 
and NKB signaling to GnRH release is independent, in pubertal female monkeys, a 
reciprocal signaling mechanism between kisspeptin and NKB neurons is 
established. We speculate that this cooperative mechanism by the kisspeptin and 
NKB network underlies the pubertal increase in GnRH release in female monkeys.