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in the rat [
127
]. It has also been suggested that RFRP-3 plays a key role in stress-
induced suppression of gonadotropin secretion, since an increase in hypothalamic
RFRP
mRNA expression was associated with reduced LH secretion in response to
immobilization stress in the rat [
128
]. In addition, hypothalamic RFRP-3 neurons
express CRF-R1 and GR [
128
], and CRF per se increased
GPR147
mRNA expres-
sion, concomitant with reduced
GNRH1
mRNA levels in the GnRH-expressing N39
cells in vitro [
129
]. Moreover, RFRP-3 blocks kisspeptin-induced activation of
GnRH neurons [
119
]. It is conceivable that functional interactions between the
excitatory kisspeptin and inhibitory GnIH signaling pathways fi ne-tune the response
of the GnRH neural system to stressors, thus minimizing reproductive dysfunction.
GABAergic transmission underlies a signifi cant proportion of inhibitory stimuli
in the brain, including those at GnRH neurons [
130
,
131
]. Activity of GABA neu-
rons in the mPOA is stimulated by central CRF administration [
41
,
64
], as well as
by a range of stress paradigms [
45
,
132
-
134
]. We have recently shown mPOA
GABA receptors (GABA
A
R and GABA
B
R) to be differentially involved in mediat-
ing the suppressive effects of immunological and psychological stress on LH secre-
tion, respectively [
135
]. Furthermore, both GABA
A
R and GABA
B
R antagonists
block the inhibition of the LH pulse by CRF [
135
]. Therefore, the CRF neurons
projecting to the mPOA seem to mediate the GABA receptor-dependent effects of
stress on the GnRH neural system. Since AVPV kisspeptin neurons are predomi-
nantly GABAergic [
136
] and GABA
A
R antagonism potently induces kisspeptin
secretion in the stalk-median eminence of prepubertal monkeys [
137
], the balance
between stimulatory kisspeptin and inhibitory GABA inputs appears to govern
marked changes in the pattern of GnRH neurosecretion. Indeed, the pubertal
increase in GnRH release is preceded by a reduction in GABAergic inhibition, and
disinhibition of GnRH secretion through GABA
A
R antagonism induces precocious
puberty in juvenile monkeys [
138
]. Thus, it is probable that stress-induced suppres-
sion of GnRH secretion is secondary to the inhibition of kisspeptin and/or GnRH
neurons by GABA.
Conclusion
The complexity of the neural networks and signaling mechanisms involved in the
translation of sensory stimuli into a stress response, complicated further by periph-
eral feedback mechanisms (CORT and ACTH), as well as evidence for the conver-
gence of multiple stimulatory and inhibitory neuronal populations, makes a
reductionist approach to the interpretation of the interactions between stress and
reproduction suboptimal. Direct neural pathways are not a prerequisite for stress
suppression of kisspeptin signaling. Synaptic transmission through interneurons
[
139
], and/or paracrine volume transmission of neuropeptidergic signals [
140
], may
also be involved in the regulation of GnRH neurosecretion by signaling systems
associated with the stress response. Hypotheses arising through anatomical obser-
vations must be consolidated by functional data; however, intracellular events
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