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Wisconsin Regional Primate Research Center (L.E.C., E.K., Y.S., F.M., E.T.), and Department of Pediatrics (E.T.), University of Wisconsin, Madison, Wisconsin 53715-1299
Address all correspondence and requests for reprints to: Ei Terasawa, Ph.D., Wisconsin Regional Primate Research Center, 1223 Capitol Court, Madison, Wisconsin 53715-1299. E-mail: terasawa{at}primate.wisc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A line of evidence indicates that the decrease in inhibition from
-amino butyric acid (GABA) neurons is responsible for the pubertal
increase in LHRH release at the onset of puberty (9): 1) GABA release
in the S-ME in prepubertal monkeys was much higher than that in
pubertal monkeys (10, 11); 2) the direct infusion of bicuculline, a
GABAA receptor antagonist, into the S-ME of
prepubertal monkeys induced a dramatic increase in LHRH release,
whereas it induced only a small increase in LHRH in pubertal monkeys
(10); 3) GABA infusion suppressed LHRH release in pubertal but not in
prepubertal monkeys (9); 4) the pulsatile infusion of bicuculline
resulted in precocious menarche and first ovulation (12); and 5)
infusion of antisense oligodeoxynucleotides for glutamic acid
decarboxylase (GAD67 and GAD65) messenger RNAs (mRNAs) into the S-ME of
prepubertal monkeys induced a dramatic increase in LHRH release (13, 14), presumably attributable to the reduction of synthesis and release
of GABA. GAD67 and GAD65, derived from two different genes, are the
catalytic enzymes for GABA synthesis from glutamate. Interestingly,
during the course of these earlier studies, we found that the reduction
in tonic GABA inhibition led to the prompt increase in release of the
excitatory neurotransmitter glutamate in the S-ME (11).
It has been reported that: 1) the stimulatory amino acid analog N-methyl-D,L-aspartate (NMA) elicited LH release in the prepubertal male monkey (15) and advanced the onset of puberty in the female rat and male monkey (16, 17, 18, 19); and 2) specific N-methyl D-aspartic acid (NMDA) receptor blockers suppressed pulsatile LH secretion in the rat (20) and delayed the timing of puberty and prevented prepubertal estradiol-induced LH surges in the rat (17, 21). Although both glutamate and NMDA perifusion to rat hypothalamic explants stimulated LHRH release in vitro (22, 23, 24), to date, it has not been shown that systemic injection of NMDA or direct infusion of NMDA into the S-ME results in LHRH release in vivo. Therefore, the present study examines the stimulatory effect of NMA on LHRH release and the hypothesis that stimulation of excitatory amino acid receptors contributes to the progress of puberty. The hypothalamic push-pull perfusion technique was used to directly observe the in vivo response of the LHRH neurosecretory system to NMA administration in fully conscious female monkeys, and the magnitude and dynamics of the response were compared at the prepubertal and pubertal stages of development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Push-pull perfusion
Before push-pull perfusion experiments, monkeys were
stereotaxically implanted with a stainless steel cranial pedestal (200
mm od) under halothane anesthesia, as described previously (26, 27, 28).
This pedestal was aligned dorsoventrally with the infundibular recess
of the third ventricle using an x-ray ventriculogram obtained after
ventricular injection of a radioopaque dye (iohexol). The pedestal was
then fixed to the skull with surgical bolts and dental acrylic. Monkeys
were allowed at least 4 weeks to recover and were gradually adapted to
a primate chair, the experimental environment, and the presence of the
researchers.
Three days before each push-pull perfusion experiment, the monkey was
anesthetized with 10 mg/kg BW ketamine hydrochloride (Bristol
Laboratories, Syracuse, NY) and placed in a stereotaxic apparatus
(Model 1504, David Kopf, Tujunga, CA). A hydraulic microdrive unit
(model MO95-B, Narishige, Tokyo, Japan), allowing precise
three-dimensional adjustment, was used to insert an outer cannula (20
gauge, 0.80 mm od) with an inner stylet (27 gauge, 0.42 mm od) into the
S-ME. As described previously (25, 26, 27), accurate placement of the
cannula was confirmed using x-rays that were compared with the
ventriculogram obtained earlier. The location of the outer cannula tip,
relative to the ventral tip of the third ventricle, was similar for
each of the groups in the two experiments of this study (Fig. 1
). After cannula placement, monkeys were
placed in a primate chair for 3 days. The procedure does not induce
stress, judged from cortisol levels and behaviors (26, 27), given that
monkeys were well adapted to primate chairs before this study.
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Experimental design
Exp 1. Effects of systemic administration of NMA
(Sigma, St. Louis, MO) on LHRH release were examined in
monkeys at the prepubertal stage (15.7 ± 0.9 months of age;
n = 10, with 7 monkeys, 3 of 7 being tested twice at different
ages within this stage), the early pubertal stage (26.3 ± 0.8
months of age; n = 9, with 7 monkeys, 2 of 9 being tested twice at
different ages within this stage), and the midpubertal stage (41.5
± 1.9 months of age; n = 10, with 8 monkeys, 2 of 8 being tested
twice at different ages within this stage). NMA (10 mg/kg BW) was
administered as an iv bolus via a catheter, which had been
placed in the femoral or saphenous vein on the day that the outer
cannula was inserted. The NMA dose was chosen based on earlier studies
in rats and monkeys (15, 16, 30), in which 15 mg/kg BW was used.
Perfusates were collected for three 10-min intervals before the
injection of NMA to provide a baseline period, and then for 6 10-min
intervals to observe changes in LHRH release. Control experiments with
saline injection were done in the same manner at the prepubertal
(16.9 ± 0.8 months of age, n = 8), the early pubertal
(25.9 ± 0.9 months of age; n = 9, with 7 monkeys, 2 of 7
being tested two times at different ages within this stage), and the
midpubertal stage (41.4 ± 1.9 months of age, n = 10). When
an individual was used more than once within an age group, the
experiments were separated by 2.0–3.0 months. One individual received
NMA at the prepubertal stage (17.3 months of age) and again at the
early pubertal stage (24.0 months of age). Four individuals received
NMA at both the early- and midpubertal stages, with the experiments
separated by 2.5–14.0 months. Different sites within the S-ME were
employed whenever an individual was used for more than one
perfusion.
Exp 2. To determine the effects of direct infusion of NMDA into the S-ME on LHRH release before and after the onset of puberty, push-pull perfusion was conducted in prepubertal (17.8 ± 0.2 months of age, n = 14) and pubertal (32.7 ± 1.1 months of age, n = 15) monkeys. After 2 h of control infusion, NMA dissolved in aCSF at 0.01, 1, or 100 µM was infused into the S-ME through the push cannula for 10 min, while perfusates were continuously collected through the pull cannula for LHRH determination. Vehicle was infused in the same manner as the control. These doses were chosen based on the studies by others (22, 23, 24). The challenges were performed at 90-min intervals for a period of 12 h in each experiment. This interval was chosen to obtain stable baseline data before the next NMA challenge after one, which would result in an LHRH response over 40 min. The order of infusion at different doses or vehicle was varied randomly in each experiment to avoid possible effects of priming or depletion of LHRH stores by the NMA challenge.
LHRH determination
LHRH concentration in perfusates was determined by RIA (31)
using antiserum R1245, kindly supplied by Dr. Terry Nett
(Colorado State University, Fort Collins, CO). Synthetic LHRH
(Peninsula Laboratories, Inc., Belmont, CA) was used as
the radiolabeled antigen and as the reference standard. Assay
sensitivity was 0.1 pg/tube at 95% binding. The intra- and interassay
coefficients of variation were 7.0% and 8.8%, respectively.
Data analysis
The raw LHRH concentrations per 10-min fraction (pg/ml) were
used for statistical analysis. In Exp 1, the significance of
differences before and after NMA injection, and between age groups was
determined by ANOVA for repeated measures, followed by post
hoc analysis with Student’s-Newman-Keuls’ test. The pre-NMA
baseline was defined as the mean of the first three samples. The
latency to the onset of the NMA-induced LHRH release was defined as the
interval from injection until the first LHRH value greater than 2
SD of the baseline above the preinjection value,
and the peak latency was defined as the interval between the time of
injection to the LHRH peak. Minimum latency was 5 min, because the
first perfusate sample after the NMA injection contained the first 5
min of perfusate already in the tubing before the injection. The
duration of the LHRH response was defined as the interval between the
first and the last significant LHRH increases (larger than 2
SD of the baseline). The amplitude of the peak
was expressed as picograms per milliliter and as a percent of the
baseline. In Exp 2, the effects of NMA infusion on LHRH release were
determined by using ANOVA for repeated measures followed by post
hoc Student’s-Newman-Keuls’ multiple-range tests. Mean levels of
LHRH during the 20-min period before each infusion were compared with
the mean LHRH levels in samples from the following 10-min samples. For
graphic expression, normalized values of LHRH, for which each data
point was expressed as a percentage of the mean of the first three (Exp
1) or two (Exp 2) baseline values for a given individual, were used.
P < 0.05 was considered significant for all tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In all individuals, regardless of age,
the onset of the increased LHRH release was apparent in the first or
second fraction collected after the injection; and all of the peak
values occurred in the first, second, or third fractions after
injection. Baseline LHRH levels in the midpubertal group were higher
than in both prepubertal and early pubertal groups (P
< 0.05, Table 1). Although there was a
tendency for the NMA-induced LHRH response to be larger in the early-
and midpubertal monkeys (Figs. 2 and 3), only
the duration of the NMDA-induced LHRH release in the midpubertal group
was longer than in the prepubertal group (P < 0.02,
Table 1). The latency to LHRH increase, the peak latency, and the peak
amplitude were not significantly different among groups. In particular,
lack of a significant difference between the peak amplitudes of
prepubertal and pubertal monkeys was attributable to the large
variation between individuals.
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). An ANOVA further
indicated that NMA injection resulted in significant effects on LHRH
release, compared with preinjection levels (within groups, all
P < 0.01). Post hoc analysis indicated that
either the first or second fraction collected after the NMA injection
was the peak, and LHRH levels of these fractions were significantly
higher (P < 0.05) than in all other fractions except
the one after the peak and were significantly higher (P
< 0.01) than in the three baseline fractions or the last two
fractions in the experiment. In the second fraction of the
midpubertal group after the NMA injection, LHRH was also
significantly elevated, relative to all fractions except the one
before it and the one after it (P < 0.05). A
significant difference between age groups was observed only in the
second fraction after NMA (P < 0.02). This difference
is attributable to the high mean levels of LHRH in the midpubertal
group. In fact, mean LHRH in the midpubertal group was the highest at
this second time point, rather than at the first time point (as seen in
the pre- and early pubertal groups).
In contrast to the effects of NMA on LHRH release, saline injection did
not result in any consistent effects on LHRH levels in individuals
(Fig. 2), or on group LHRH means over time or between age groups (Fig. 3).
Exp 2
In prepubertal monkeys, NMA infusion into the S-ME at all
doses, except for 100 µM, did not induce consistently
robust responses (Fig. 4). At 100
µM, NMA stimulated LHRH release (Fig. 4): in two of the
five prepubertal monkeys NMA resulted in a large LHRH response, whereas
in the remaining three prepubertal monkeys, moderate LHRH responses
were observed. In contrast, in pubertal monkeys, NMA infusion at
0.1–100 µM resulted in increases in LHRH release (Fig. 5). In all cases, the peak was observed in
the first or second sample after the initiation of NMA infusion, and
the LHRH increase lasted for 20–40 min. There was, however, no obvious
dose response to NMA. In addition, to test whether an extremely
high dose of NMA results in a higher response, we examined the effects
of NMA at 1 and 10 mM in two pubertal monkeys. LHRH
responses to these higher doses of NMA were similar to those observed
with lower doses (data not shown).
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Post hoc analysis further indicated that, in prepubertal
monkeys, the mean LHRH level, 10 and 20 min after the NMA (100
µM) infusion, was significantly higher
(P < 0.05) than that of the preinfusion basal level
(Fig. 6A). In contrast, in pubertal monkeys, similar infusion of
NMA at all doses (0.01, 1 and 100 µM)
significantly (for all P < 0.05) stimulated LHRH
release (Fig. 6B). Post hoc analysis indicated the
significant increases in LHRH release occurred during the first
10-min period after the initiation of NMA infusion at 0.01
µM, the first 20 min after NMA at 1
µM, and a 40-min period after NMA at 100
µM (P < 0.01 to
P < 0.05, Fig. 6B). Vehicle did not induce any
significant changes in either age group. A significant difference in
age groups was observed with NMA at 0.01 and 1
µM (P < 0.05) but not at 100
µM.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The individual LHRH profiles in Exp 1 suggest that the amplitude of the LHRH responses to NMA in older monkeys was larger than in younger monkeys, but the difference did not reach a significant level. Moreover, a higher proportion of individuals in the pre- and early pubertal groups had peak LHRH values in the first fraction after the NMA injection; whereas in the midpubertal group, more had LHRH peaks in the second fraction after the NMA. Indeed, the NMA-induced LHRH increases in older monkeys were larger than in younger monkeys because the sustained levels of NMA-induced LHRH release (duration) lasted significantly longer. Because NMA was administered on a mg/kg BW basis, a delayed response would be attributable to differences in the pharmacodynamics between those in the injection site (femoral vein) and those in the target site (S-ME), among the age groups. Nonetheless, the data suggest that the LHRH neurosecretory system is less responsive in younger monkeys than in older monkeys, similar to results reported in the rat (23, 32). This conclusion is further supported by the results of Exp 2, in which NMA at lower doses was more effective in pubertal monkeys than in prepubertal monkeys. The question of whether the developmental changes in LHRH responsiveness to NMA in female monkeys is ovarian steroid-dependent, -independent, or both, remains to be investigated.
In the present study, systemic injection of NMA at 10 mg/kg resulted in more robust effects on LHRH release than direct application of NMA with any doses at 0.01–100 µM into the S-ME. In pubertal monkeys, NMA injection induced an average increase of 400% over the baseline LHRH levels, whereas direct application of NMA at most doses resulted in increases of only up to 200% . Similarly, in prepubertal monkeys, NMA injection induced a 360% increase over the baseline, whereas direct infusion of NMA at 100 µM caused increases only up to 200% , except for a few cases in which a higher increase was observed, and doses at 0.1 and 1 µM failed to induce any consistent changes. In addition, when we tested the effects of NMA at 10 mM infusion in pubertal monkeys, the LHRH responses were essentially similar to those of NMA at lower doses. The systemic dose of NMA at 10 mg/kg would be equivalent to approximately 500 µM, assuming that NMA transported into the brain through the blood-brain-barrier is equal to that transported to the whole body. These results are interpreted to mean that direct infusion of NMA into the S-ME (where LHRH neuroterminals are concentrated but only a small number of LHRH perikarya are present) is not as effective as systemic NMA administration, by which NMA is delivered widely into the brain (where not only a large number of LHRH perikarya, but also interneurons, are exposed to NMA). Therefore, input to the LHRH soma (either directly on LHRH neurons or indirectly via interneurons), rather than input to LHRH neuroterminals, seems to be more important for the activation of NMDA receptors, resulting in LHRH release.
It has been shown that NMDA receptors are widely distributed in
the hypothalamus (see 33), but only 8–17% of the NMDA-preferring
subunits NMDAR1 and NMDAR2A
are colocalized within LHRH perikarya of the rat preoptic area and
hypothalamus (34), and almost no colocalization of the
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring
subunits Glu R1, Glu R2,
Glu R3, and Glu R4 with
LHRH neurons is observed. In contrast, approximately one third of LHRH
perikarya contain the kianate receptor subunit
(KA2), and LHRH fibers in the ME expressed
KA2 (34). Therefore, NMDA receptor-mediated
activation of the LHRH neuronal system seems to occur indirectly
through interneurons, rather than directly to LHRH neurons themselves.
Moreover, preliminary data indicate that infusion of glutamate itself,
as well as non-NMDA receptor agonists such as
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kianate, at
0.01–1 µM into the S-ME, was even less effective in
stimulating LHRH release than NMDA reported here (Kasuya and Terasawa,
unpublished observation), even though it has been reported that
systemic injection of kianate stimulates robust LH release (30). In
fact, the consistency and effectiveness of infused glutamate and its
receptor agonists in the S-ME are not even close to those of NPY
(35, 36, 37). These results indicate that glutamate in the S-ME and
glutamatergic input to the LHRH neurons (and to the LHRH
neuroterminals, in particular) may not play a simple stimulatory role
in enhancing LHRH release. Alternatively, it is possible that the
effect of direct infusion of NMA in the S-ME on LHRH release is small,
because LHRH neurons are under a tonic inhibitory influence by other
neurons, such as GABA neurons (10, 11, 13) and NPY neurons (38).
Additional experiments are necessary to substantiate these
hypotheses.
Even though the LHRH neurosecretory system in prepubertal monkeys is less sensitive to NMA stimulation, the prepubertal monkey is clearly able to respond to this single bolus treatment. This finding is consistent with an earlier study in the prepubertal male monkey in which NMA was shown to trigger increases in LH concentrations (15), and also with an earlier study in our laboratory that evaluated the age-specific responsiveness of the LHRH neurosecretory system to electrical stimulation in the medial basal hypothalamus (8). In this latter study, electrical stimulation of the medial basal hypothalamus caused LHRH release for 20–40 min, with a short latency and an amplitude similar to that seen with NMA. However, with electrical stimulation, there was no difference in responsiveness among the pre-, early, and midpubertal stages of development. Perhaps the absence of age-related effects of electrical stimulation on LHRH release is attributable to the fact that electrical stimulation may depolarize LHRH neurons and neuroterminals directly. In contrast, NMA may stimulate the LHRH neuronal system through interneurons, interacting with other excitatory and inhibitory neurons. Connectivity between LHRH neurons and interneurons may undergo developmental changes.
Glutamate, the most dominant excitatory neurotransmitter in the hypothalamus (39), plays a significant role in the preovulatory LHRH surge (32). Activation of NMDA receptors stimulated LHRH release in prepubertal and pubertal animals (22, 40, 41) and resulted in precocious puberty in monkeys and rats (15, 16, 17, 18, 19), whereas administration of NMDA blockers delayed the timing of puberty in rats (21). Measurement of developmental changes in glutamate release in the female monkey indicated that glutamate concentrations in the S-ME were very low in prepubertal monkeys, strikingly increased in early pubertal monkeys, and then declined in midpubertal monkeys, although the glutamate levels in midpubertal monkeys were still much higher than those in prepubertal monkeys (11). Moreover, in prepubertal monkeys treated with antisense GAD, GABA release declined during the first 3 h after the initiation of the antisense treatment, whereas glutamate release was significantly elevated several hours after the initiation of the antisense infusion (11). The results of the present study further suggest that the sensitivity of the LHRH neurosecretory system to NMDA receptor activation is higher in pubertal monkeys than in prepubertal monkeys. Therefore, an increase in glutamate in the S-ME and changes in sensitivity to NMDA are both parts of the mechanism for the pubertal increase in pulsatile LHRH release at the early stage of puberty, after the decrease in GABA release in the S-ME occurs at the onset of puberty.
It has been documented that excess exposure to glutamate can result in neurotoxicity caused by an over influx of Ca2+ into the cell, predominantly through NMDA receptors (42). Because relatively high doses of NMDA have been used in the literature, we examined the effects of 1 and 10 mM NMA infusion into the S-ME on LHRH release in 2 pubertal monkeys and found that the results with higher doses of NMA did not differ from those of the lower doses. Subsequently, we kept track of any pathological signs of lesions in the brains of these monkeys, and we found that one of the two exhibited extreme obesity followed by delayed puberty with anovulation. Monkeys treated with NMA at 100 M or less or treated with iv injection of NMA did not exhibit any signs of abnormality.
The results of the present and previous studies (8) clearly indicate that the LHRH neurosecretory system is mature before the onset of puberty. A decrease in tonic inhibition of the LHRH neurosecretory system by GABA neurons triggers the cascade of events associated with puberty in female rhesus monkeys (9, 10, 12). An increase in glutamate release occurs shortly after the reduction in GABA inhibition; and increases in the activity of other excitatory neurons, such as NE and NPY neurons (37, 43), may follow. Further studies, to elucidate the mechanism involved in the decrease in tonic inhibition followed by the increase in excitatory mechanism, will clarify the timing of the mechanism controlling the onset of puberty.
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Acknowledgments |
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Footnotes |
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2 Present address: Contraceptive Research and Development Program,
Eastern Virginia Medical School, 1611 North Kent Street, Arlington,
Virginia 22209.
3 Present address: Department of Neurosurgery, Osaka University,
School of Medicine, 2–2 Yamadaoka, Suita, Osaka, Japan.
4 Present address: Parker College of Chiropractic, 2500 Walnut Hill
Lane, Dallas, Texas 75229.
Received June 21, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-aminobutyric acid (GABA) and glutamate in control of puberty in
female rhesus monkeys: effects of an antisense oligodeoxynucleotide for
GAD67 mRNA and MK801 on luteinizing hormone-releasing hormone release.
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