Endocrinology Vol. 140, No. 3 1279-1284
Copyright © 1999 by The Endocrine Society
Regulation of Growth Hormone Secretion by 
-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors in Infantile, Prepubertal, and Adult Male Rats1
L. C. González2,
L. Pinilla2,
M. Tena-Sempere and
E. Aguilar
Department of Physiology, Faculty of Medicine, Cordoba University,
14004 Cordoba, Spain
Address all correspondence and requests for reprints to: Dr. E. Aguilar, Department of Physiology, Faculty of Medicine, Cordoba University, 14004 Cordoba, Spain. E-mail: fi1agbee{at}lucano.uco.es
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Abstract
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Excitatory amino acids, such as glutamate, constitute a
major transmitter system in the control of hypothalamic-pituitary
function. Different subtypes of glutamate receptors, such as
N-methyl-D-aspartic acid and kainate
receptors, have been involved in the control of GH secretion. Other
excitatory amino acid receptor subtypes, as
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA),
amino-4-phosphobutyric acid, and metabotropic receptors, have been
identified, yet their role in the control of neuroendocrine function
remains to be completely characterized. The purpose of this study was
to assess the potential involvement of AMPA receptors in the control of
GH secretion. In a first set of experiments, neonatal (5 and 10 days)
and prepubertal (23 days) male rats were injected with AMPA (1, 2.5, or
5 mg/kg) or the antagonist of AMPA receptors,
1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulfonamide
(NBQX; 0.25 or 0.50 mg/kg). Serum GH concentrations significantly
increased 15 min after ip administration of AMPA in both neonatal and
prepubertal male rats. In addition, serum GH concentrations decreased
after NBQX treatment. The stimulatory effect of AMPA was abolished by
pretreatment with the blocker of nitric oxide synthase,
nitrow-arginine-methyl ester (40 mg/kg), and was partially
counteracted by the simultaneous administration of GH-releasing hormone
(500 µg/kg). Moreover, AMPA was unable to elicit in
vitro GH secretion by hemipituitaries from prepubertal males,
pointing out that the hypothalamus is probably the site of action for
the reported stimulatory action of AMPA on GH release. In a second set
of experiments, the effects of AMPA and NBQX were tested in adult male
rats. As in prepubertal animals, AMPA significantly increased GH
secretion in adult males, whereas NBQX (20 or 40 nmol), administered
through intracerebroventricular injection, induced a significant
decrease in the amplitude of GH pulses. In conclusion, our data
indicate that AMPA receptors have a physiological stimulatory role in
the control of GH secretion in male rats throughout the life span. This
effect depends on appropriate nitric oxide synthesis during the
prepubertal age. In addition, AMPA receptors appear to modulate
pulsatile GH secretion in adulthood.
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Introduction
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GH RELEASE is mainly controlled by the
interaction between the hypothalamic signals GH-releasing hormone
(GHRH) and somatostatin. In turn, GHRH and somatostatin secretion is
regulated by a complex network that involves multiple neurotransmitters
(for a review, see Ref. 1). Excitatory amino acids (EAAs) are the major
activating transmitters in the brain (2). The actions of EAAs are
mediated by different postsynaptic receptors, which include
N-methyl-D-aspartate (NMDA) receptors, kainate
(KA) receptors, (±)--amino-3-hydroxy-5-methyl-4-isoxazol propionic
acid (AMPA) receptors, amino-4-phosphobutyric acid receptors, and
metabotropic receptors (3).
Recently, agonists and antagonists of AMPA receptors have been
developed, making it possible to evaluate their role in the control of
neuroendocrine function. In this sense, it has been proven that
activation of AMPA receptors stimulates GnRH release from rat
hypothalamic fragments and immortalized GnRH neurons (4, 5, 6). In
addition, evidence for a physiological role of AMPA receptors in the
steroid-induced LH surge has been presented (7).
EAAs are involved in the control of GH secretion, and stimulation of GH
secretion after activation of NMDA and KA receptors has been reported
(8, 9, 10, 11, 12). However, to date, no study has addressed the role, if any, of
AMPA receptors in the control of GH secretion. To cover this issue, we
analyzed the effects on GH secretion of an agonist (AMPA) and an
antagonist
[1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)-quinoxaline-7-sulfonamide
(NBQX)] of AMPA receptors. The results presented herein demonstrate
that activation of AMPA receptors stimulates GH release in neonatal,
prepubertal, and adult male rats through a mechanism that requires, at
least in the prepubertal age, the generation of nitric oxide (NO).
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Materials and Methods
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Animals and drugs
Wistar male rats bred in our laboratory were used. The day the
litters were born was considered day 1 of life. At this time litter
size was adjusted to eight rats per dam. The animals were maintained
under controlled conditions of light (12 h of light, 12 h of
darkness; lights on at 0700 h) and temperature (22 C). The rats
were weaned at 21 days of age and housed in groups of four or five rats
per cage, with free access to pelleted food (Pacsa Sanders, Seville,
Spain) and tap water. AMPA and NBQX were purchased from Research Biochemicals International (Natick, MA). GH-releasing hormone
[GHRH-(1–29)] was donated by Serono (Madrid, Spain).
N-Nitrow-arginine-methyl ester (NAME), an
inhibitor of NO synthase (NOS), was obtained from Sigma Chemical Co. (Barcelona, Spain). AMPA and NBQX were dissolved initially
in a few drops of dimethylsulfoxide and thereafter in saline up to the
working concentration.
Experimental designs
The initial set of experiments was performed in infantile
and prepubertal rats. At this age GH pulsatility is not yet fully
established (13), and the secretory response to a given stimulus is not
hampered by the episodic nature of GH release. In Exp 1, 23-day-old
male rats were decapitated 15, 30, and 60 min after ip injection of
AMPA (2.5 or 5 mg/kg) or vehicle and 60 and 120 min after ip injection
of NBQX (0.25 and 0.50 mg/kg) or vehicle. Special caution was taken to
avoid any stressing influence on the experimental animals
(e.g. all rats were handled daily for a week before the
experiment and were killed by the same person, and the different drugs
were injected at random). Trunk blood was collected into polystyrene
tubes, and pituitaries were dissected and frozen immediately after
extraction. In Exp 2, we aimed to detect the age at which activation of
AMPA receptors is first able to elicit GH release. To this end, 5- and
10-day-old males were decapitated 15 min after the administration of 1
or 2.5 mg/kg AMPA. In Exp 3, to evaluate potential direct actions of
AMPA at the pituitary level in the control of GH secretion, anterior
hemipituitaries were obtained from 23-day-old male rats and placed in
glass scintillation vials (one per vial) in a Dubnoff shaker at 38 C in
an atmosphere of 95% O2-5% CO2. Each vial
contained 1 ml DMEM. After preincubation for 60 min, the medium was
replaced by fresh medium containing AMPA
(10-8–10-6 M) or GHRH
(10-6 M). Samples of medium were obtained
after 60 and 120 min of incubation. In Exp 4, to assess whether the
effects of GHRH and AMPA were additive, 23-day-old males were
decapitated 15 min after administration of AMPA (2.5 mg/kg), GHRH (500
µg/kg), AMPA plus GHRH, or vehicle. Finally, we previously described
that the stimulatory action of NMDA and KA on GH secretion requires the
presence of NO (10, 11). To evaluate the role of NO in the stimulatory
effect of AMPA, in Exp 5 we studied the effects of AMPA in male rats
pretreated with NAME (40 mg/kg at -60 min).
In a second set of experiments, the role of AMPA receptors in the
control of GH secretion in adult male rats was assessed. In Exp 6,
adult males were decapitated 15 min after ip injection of vehicle or
AMPA (2.5 mg/kg). In addition, in Exp 7, the effects of AMPA and NBQX
were analyzed in freely moving, adult male rats implanted with
intracerebroventricular and intracardiac cannulas under sodium
pentobarbital (50 mg/kg) anesthesia. After surgery, the animals were
placed directly in isolation test chambers for 5 days, with free access
to pelleted food and tap water. To evaluate the effects of AMPA on GH
release, blood samples (0.30 ml) were withdrawn every 15 min for 1
h. After this period, AMPA (2.5 mg/kg) or vehicle was injected ip, and
blood samples were obtained 10, 20, 30, and 40 min thereafter.
Additionally, freely moving, male rats were sampled at 15-min intervals
for periods of 6 h (1000–1600 h), as previously described (14).
At 1030 h, the animals received either vehicle or NBQX (20 or 40
nmol in 10 µl) by the intracerebroventricular route. During the
sampling period, the volume of blood withdrawn was replaced hourly by a
suspension of blood cells in sterile saline.
All experiments were approved by the Cordoba University ethical
committee for animal experimentation and were conducted in accordance
with the European Union normative for care and use of experimental
animals.
GH measurements
GH concentrations were measured by a specific RIA using rat GH
RP-2 as the standard. All samples were measured in duplicate. The
intra- and interassay variations were 7% and 11%, respectively, and
the sensitivity of the assay was 5 pg/tube.
Statistics
Assessment of pulsatile GH secretion was carried out with the
ULTRA program (Van Cauter, E., Department of Medicine, University
of Chicago, Chicago, IL), as described previously (14). Data are
expressed as the mean ± SEM. Differences between
groups were determined by one- or two-way ANOVA, followed by Tukey’s
test.
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Results
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Effects of AMPA and NBQX on serum GH levels and pituitary GH
content in 23-day-old male rats
The serum GH concentration significantly increased in male rats 15
and 30 min after the administration of 2.5 and 5 mg/kg AMPA and
returned to basal levels 60 min after drug injection (Fig. 1
, upper panel). In addition,
serum GH levels in males decreased 60 and 120 min after the
administration of 0.5 mg/kg NBQX, and 60 min after the administration
of 0.25 mg/kg NBQX (Fig. 1, lower panel).
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Figure 1. Serum GH concentrations in 23-day-old male rats
after the administration of AMPA or NBQX. In the upper
panel, serum GH levels 15, 30, and 60 min after ip
administration of vehicle or AMPA (2.5 or 5 mg/kg). In the lower
panel, serum GH concentrations 60 and 120 min after ip
administration of vehicle or NBQX (0.25 or 0.5 mg/kg). Values are given
as the mean ± SEM (10 animals/group). **,
P  0.01 vs. vehicle-injected group
(by ANOVA followed by Tukey’s test).
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The pituitary GH content was significantly increased in male rats 60
min after the administration of 5 mg/kg AMPA (Fig. 2, upper panel). The pituitary
GH content in males treated with NBQX showed a biphasic response, with
an initial increase observed at 60 min followed by a decrease at 120
min after drug administration (Fig. 2, lower panel).
Effects of AMPA on serum GH levels in infantile rats
The stimulatory effect of AMPA on GH secretion was also detected
in 5- and 10-day-old males. The magnitude of the GH response was
similar for both doses tested (1 and 2.5 mg/kg; Table 1).
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Table 1. Serum GH concentrations (nanograms per ml) in 5- and
10 day-old males, decapitated 15 min after AMPA administration
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Effects of AMPA on GH secretion by hemipituitaries in vitro
Incubation of hemipituitaries in the presence of AMPA failed to
evoke significant GH responses, and only a small increase was observed
120 min after exposure to the lowest concentration (10-8
M) tested (Fig. 3).
Effects of combined administration of AMPA and GHRH on GH
secretion
Serum GH concentrations slightly increased after GHRH
administration. In contrast, AMPA induced a clear-cut increase in GH
release. The stimulatory effect of AMPA was partially counteracted by
the simultaneous administration of GHRH (Table 2).
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Table 2. Serum concentrations (nanograms per ml) in
23-day-old male rats 15 min after injection of GHRH (500 µg/kg), AMPA
(2.5 mg/kg), or AMPA plus GHRH
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Role of NO in the stimulatory effect of AMPA on GH
secretion
The effectiveness of AMPA to elicit GH release was abolished in
the presence of the inhibitor of NOS synthase, NAME, which per
se had no effect on GH secretion (Table 3).
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Table 3. Effects of pretreatment with NAME on the stimulatory
effect of AMPA on GH secretion in 23-day-old male rats
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Effects of AMPA on GH secretion in adult male rats
Males decapitated 15 min after ip administration of AMPA showed a
sharp increase in serum GH concentrations (563 ± 73
vs. 3.8 ± 0.6 ng/ml in the vehicle-injected group).
The stimulatory effect of AMPA was also observed in chronically
catheterized, freely moving, male rats (Fig. 4), although it was significantly
attenuated compared with the results obtained in decapitated males
(maximum GH response, 15 ± 4 ng/ml 10 min after AMPA
injection).
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Figure 4. Serum GH concentrations in adult male rats after
ip administration of AMPA (2.5 mg/kg) or vehicle. Values are given as
the mean ± SEM (10 animals/group). *,
P 0.05 vs. preinjection levels
(by ANOVA followed by Tukey’s test).
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Effects of NBQX on GH secretion in adult male rats
Animals treated with vehicle or NBQX exhibited GH secretory pulses
with a frequency of approximately one or two pulses per 6 h (Fig. 5). Administration of a single injection
of 20 nmol NBQX significantly increased the GH nadir, whereas
administration of 40 nmol induced an increase in the GH nadir and a
significant decrease in the pulse amplitude (Fig. 6).
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Figure 5. Representative plasma profiles in individual male
rats after intracerebroventricular injection of vehicle (left
panels) or NBQX (20 nmol, middle panels; 40
nmol, right panels). All drugs were administered at
1030 h. Asterisks indicate GH pulses.
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Discussion
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The present set of experiments was undertaken to assess whether
AMPA receptors play a physiological role in the control of GH release
in the male rat. The results presented herein demonstrate that
activation of AMPA receptors stimulates GH secretion in prepubertal
male rats. In addition, activation of AMPA receptors, as demonstrated
previously for NMDA and KA receptors (9, 12), was effective in neonatal
rats, as significant increases in GH secretion were observed by day 5
of life. Moreover, the decrease in serum GH concentrations after NBQX
administration in prepubertal animals strongly suggests that AMPA
receptors are involved in the physiological control of GH secretion at
this age.
Besides its stimulatory action on GH release, the pituitary GH content
increased 60 min after the administration of AMPA in prepubertal males,
a fact that suggests that activation of AMPA receptors increases both
the synthesis and the secretion of GH. The pituitary content of GH
increased at 60 min and decreased 120 min after NBQX administration.
This biphasic response may be due to the initial reduction in the
release of the hormone, followed by the decline in the synthesis
of GH 120 min after AMPA receptor antagonization.
The mechanism(s) by which AMPA elicits GH release were evaluated. In
principle, such a stimulatory action may arise through 1) a direct
effect at the pituitary level, 2) an increase in GHRH release, and/or
3) an inhibition of the secretion of somatostatin. Despite the presence
of AMPA receptors in the pituitary gland (15, 16, 17, 18), a direct pituitary
effect of AMPA seems unlikely, as only very weak responses were
observed in vitro. Similarly, a potential increase in GHRH
release after AMPA administration does not fully explain its effects on
GH release, as GHRH administration induced, at the age tested, only a
small increase in serum GH levels. On the basis of present data, the
most likely mechanism for the effect of AMPA on GH secretion is an
inhibition of somatostatin release. Experiments are currently in
progress in our laboratory to confirm this hypothesis.
The stimulatory effect of AMPA on GH release was partially counteracted
by the simultaneous administration of GHRH. Different mechanisms may
account for such an intriguing phenomenon. First, compelling evidence
indicates that interactions between GHRH and the somatostatinergic
system exist (for a review, see Ref. 1), and it is possible that
GHRH-induced somatostatin release may partially antagonize the effects
of AMPA on GH release. In addition, it is well known that GH carries
out a negative feedback on its own secretion, acting at the
hypothalamic level (19, 20, 21). Considering that administration of
exogenous GHRH induces a very rapid increase in serum GH concentrations
(22, 23), it is also possible that the elevated GH levels after the
administration of 500 µg/kg GHRH may activate negative feedback
mechanisms, e.g. an increase in the somatostatinergic tone
(20, 21), that, in turn, partially counteracted the effects of AMPA on
GH release. Interestingly, examples of the partial counteraction
between two elicitors of GH release have been presented previously
(24).
Previous data from our group indicated that proper NO supply is
essential for the complete expression of the stimulatory action of
different elicitors of GH secretion, such as GHRH, GH-releasing
peptide-6, NMDA, and KA (10, 11). The present results extend our
previous observations and demonstrate that the action of AMPA requires
the adequate generation of NO. Considering that the different elicitors
mentioned above present different mechanisms of action, but all of them
require NO synthesis to induce GH release, it is tempting to
hypothesize that NO acts at the pituitary level, allowing a complete GH
secretory response after pleiotropic stimulation.
Our results indicate that the role of AMPA receptors in the control of
GH secretion is maintained in adulthood, as the administration of AMPA
was able to elicit GH responses in conscious, freely moving, adult
rats. This is in striking contrast to the inactivation of NMDA and KA
pathways in response to increased testosterone secretion after puberty
(25, 26), and previous data from our laboratory showing that the
ability of KA to stimulate GH release disappears in adulthood (12).
Further, the role of AMPAergic pathways in the physiological control of
pulsatile GH secretion in adult male rats is supported by data showing
that NBQX increased the GH nadir and decreased the amplitude of GH
pulses at this age. We do not have a clear explanation for this
unexpected finding. Assuming that nadir GH concentrations are due to
the action of somatostatin, it is possible that NBQX inhibited, to a
certain degree, the somatostatin release. On the contrary, the effects
on pulse amplitude might reflect a reduced secretion of GHRH in the
presence of NBQX. Obviously, further experiments are needed to clarify
these hypotheses.
In conclusion, our presents results demonstrate that activation of AMPA
receptors stimulates GH release in male rats throughout the life span.
This action is carried through a mechanism that requires, at least at
the prepubertal age, generation of NO. The inhibition of somatostatin
release appears to be the most likely mechanism involved in the
stimulatory effect of AMPA on GH secretion.
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Acknowledgments
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The NIH supplied the RIA materials for GH determinations. We are
indebted to Rocio Campón for her excellent technical
assistance.
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Footnotes
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1 This work was supported by grants from DGICYT (Spain). 
2 L.C.G. and L.P. contributed equally to this work and must be
considered as joint first authors.
Received June 1, 1998.
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Top
Abstract
Introduction
