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expressed by parvocellular neurons of the PVN, act synergistically to stimulate ACTH
secretion from the anterior pituitary, although different mechanisms are involved in
regulating AVP and CRF expression in response to acute and chronic stress exposure
[
102
]. AVP neurons of the suprachiasmatic nucleus (SCN) of the hypothalamus inner-
vate the kisspeptin neuron population in the AVPV, and estradiol has been shown to
increase the number of these monosynaptic connections [
103
]. Moreover, icv admin-
istration of kisspeptin increases plasma AVP levels in rats [
104
], although without
altering the fi ring rate of AVP/oxytocin neurons of the supraoptic nucleus of the hypo-
thalamus [
105
]. This could suggest that kisspeptin is involved in a feedback mecha-
nism bridging the stress response with reproductive function.
CGRP neurons project from the caudal aspect of the organum vasculosum of the
lamina terminalis (OVLT), via the AVPV, to the medial preoptic nucleus [
106
], and
form direct contacts with CRF neurons of the CeA [
107
,
108
]. Central administra-
tion of CGRP induces c-fos expression in the CeA [
109
], mPOA, and PVN [
110
].
Moreover, CGRP-treated rats demonstrate elevated circulating CORT levels [
110
,
111
] and GnRH pulse generator inhibition [
110
,
112
], effects that are dependent on
CRF-R1 signaling [
109
]. Administered intra-mPOA, CGRP dose dependently sup-
pressed LH pulse frequency [
112
], while intra-PVN administration of CGRP stimu-
lates ACTH and CORT release [
111
]. A GnRH cell line expresses CGRP receptors,
and CGRP dose dependently suppresses GnRH release in vitro [
113
]. These data
strongly implicate hypothalamic CGRP signaling in the inhibition of the GnRH
pulse generator in response to HPA axis activation.
The endogenous opioid peptide, Dyn, is coexpressed with kisspeptin and NKB
in ARC KNDy neurons that project to GnRH neurons [
114
,
115
]. Central adminis-
tration of a Dyn analog, selective for the kappa-subtype of the opioid receptor
(KOR), suppresses pulsatile LH secretion in female rats [
116
], and KOR antago-
nism blocks the CGRP- and NKB-mediated suppression of pulsatile LH secretion
[
116
,
117
]. Because endogenous opioid peptides play an important role in stress-
induced suppression of the reproductive axis, and since KNDy neurons express
KOR, Dyn might inhibit the GnRH pulse generator through autocrine inhibition of
the kisspeptin tone.
RF-amide-related peptide type-3 (RFRP-3), a member of the same RF-amine
superfamily as kisspeptin and a mammalian ortholog of avian gonadotropin-
inhibitory hormone (GnIH), is inhibitory to both GnRH neuron fi ring [
118
,
119
]
and LH secretion [
120
,
121
], while RFRP receptor antagonists are stimulatory to
LH secretion [
122
,
123
]. In addition to the widespread distribution of RFRP-3 neu-
ron fi bers in the hypothalamus, with abundant close appositions to GnRH cells
[
124
], these fi bers are also present in the hypothalamic PVN and limbic areas,
including the BNST and MeA [
120
,
125
]. Taken together, these data provide an
anatomical substrate for the hypothesis that stress-induced suppression of the HPG
axis is mediated, in part, by RFRP-3.
Indeed, there are numerous PVN CRF neurons with close RFRP-3 fi ber apposi-
tions [
126
] and there is abundant expression of
GPR147
mRNA, encoding the puta-
tive RFRP receptor, in the PVN [
127
]. Further, central administration of RFRP-3
evokes c-fos expression in the PVN, increases ACTH release, and induces anxiety
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