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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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