Interactions Between Kisspeptins and Neurokinin B - Kisspeptin Signaling in Reproductive Biology - page 325

dimorphism in the response to senktide. Corander et al. fi rst documented the absence
of LH release after NKB administration in intact adult male mice [ 84 ]; however,
shortly after, in a study performed in adult male mice, we reported a positive
response to senktide administration, with a robust increase in LH release and also,
to a lesser extent, FSH [ 59 ]. Although speculative, this discrepancy might be due to
different effi cacy in the activation of NK3R after administration of senktide [ 59 ] vs.
NKB itself [ 84 ] or, purportedly, to the delivery method, i.e., limitation of NKB to
dissolve into solution in saline vehicles [ 84 ].
Recently, we have expanded our knowledge of the actions of senktide on LH
release in male and female rats along postnatal development. Intact female rats at
every assessed developmental stage (i.e., infantile, juvenile, prepubertal, pubertal,
and adult in diestrus) display conspicuous stimulation of LH secretion after senktide
treatment [ 22 , 67 ]. Male rats, however, progress from being responsive to senktide
prepubertally to becoming irresponsive from puberty onwards, dissociating them-
selves from adult female rats and male mice [ 67 ]. These data unveil a striking sexual
dimorphism in the rat as well as important differences in otherwise closely related
species, i.e., mice and rats. The precise mechanisms underlying these differences
require further investigation in order to clarify the role of NKB in the control of
gonadotropin secretion.
Kiss1 Neurons as Primary Targets of NKB Action
As described previously, KNDy neurons express NK3R [ 25 , 26 ], which supports
the possibility of autosynaptic loops within the network of NKB/kisspeptin fi bers
surrounding KNDy neurons in the ARC [ 25 , 30 , 33 ]. The following evidence sup-
ports the contention that NKB acts upstream of, or immediately on, Kiss1 neurons
in the ARC: (a) senktide and NKB strongly depolarize Kiss1 neurons in the mouse,
and this effect is prevented by the NKB antagonist SB222200 [ 59 ]; (b) central
administration of senktide to gonadectomized and estradiol-replaced (OVX+E 2 )
female rats induces c - fos mRNA expression in Kiss1 neurons [ 22 ]; (c) goats treated
centrally with NKB exhibit a clear increase in the frequency and amplitude of mul-
tiunit activity (MUA) volleys in the ARC, which are invariably mirrored by LH
pulses [ 76 ], yet the administration of kisspeptin modifi es LH pulses without modi-
fying MUA volleys [ 85 ].
Kiss1 neurons, however, express a number of other co-transmitters (e.g.,
dynorphin and glutamate). For this reason, any action of NKB upon GnRH release,
evoked by the activation of ARC Kiss1 neurons, could not be entirely attributed to
the release of kisspeptin. For instance, these kisspeptin neurons have been also
shown to innervate the tuberoinfundibular dopaminergic (TIDA) neurons in the
ARC [ 86 ]. Yet, compelling evidence indicates that kisspeptin release is, indeed, nec-
essary for the reproductive role of NKB given the following data: (a) mice bearing
nonfunctional kisspeptin receptors ( Kiss1r KO mice) are irresponsive to the central
administration of senktide in terms of LH release [ 82 ]; (b) juvenile monkeys showing