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the signals responsible for timing the application and removal of this central neuro-
biological brake. In this section, we discuss possible neuronal substrates responsible
for “central inhibition.”
Two laboratories have each proposed a different neuronal subtype. First,
Terasawa and her colleagues have proposed the hypothesis that tonic inhibition by
γ
-amino butyric acid (GABA) neurotransmission is responsible for this central
inhibition in female rhesus monkeys [
17
]. This hypothesis is based on the obser-
vations that (1) GABA levels are higher when GnRH release is low in prepubertal
monkeys, whereas GABA levels are lower after the onset of puberty when GnRH
release is elevated [
84
], (2) infusion of the GABA
A
receptor antagonist, bicucul-
line, into the S-ME stimulates GnRH release to a much greater extent in prepu-
bertal, than in pubertal, monkeys, whereas infusion of GABA is effective in
suppressing GnRH release in pubertal, but not prepubertal, monkeys, presumably
because of the reduction in tonic GABA inhibition at the onset of puberty [
84
],
and (3) a long-term infusion of bicuculline into the S-ME of juvenile female pri-
mates results in precocious puberty and fi rst ovulation [
85
]. Second, Plant and his
colleagues have proposed the hypothesis that neuropeptide Y (NPY) neurons are
responsible for the central inhibition of pulsatile GnRH release during juvenile
development in male monkeys. This hypothesis is based on the fi nding that mRNA
and peptide levels of NPY in the MBH are signifi cantly lower during the neonatal
period compared to those during the juvenile period, whereas mRNA and peptide
levels of NPY in the MBH decrease, while GnRH mRNA levels increase, across
puberty in male monkeys [
86
]. Presently, whether the sex-differences noted in the
“juvenile hiatus” in gonadotropin secretion are attributable to central inhibition
mediated by GABA neurons in females vs. NPY neurons in males is unclear.
Nonetheless, it is possible that the same population of neurons in the MBH is
responsible for gonadal steroid-independent central inhibition, as a large number
of GABA neurons in the rat ARC express NPY [
87
,
88
].
A recent study from Terasawa's group indicates that bicuculline infusion into
the S-ME of prepubertal female monkeys stimulates kisspeptin-54 release
(Fig.
12.4a
) [
89
], similar to the bicuculline-induced stimulation of GnRH release
observed in prepubertal monkeys [
84
]. Moreover, the bicuculline-induced GnRH
release was blocked by simultaneous infusion of the kisspeptin antagonist, pep-
tide 234 (Fig.
12.4b
) [
89
]. These latter results are consistent with the view that
inhibitory GABA neurotransmission is an important component in the upstream
suppression of the GnRH pulse generating mechanism during juvenile develop-
ment in primates. It is, however, unclear what reduces GABA inhibition prior to
puberty and whether additional (or alternative) neuronal substrates and somatic
cues [
90
-
93
] are involved in the upstream control of GnRH pulse generation.
Thus, the most important question of exactly what triggers the onset of puberty
in primates remains a mystery.
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