Biomedical subjects

E Terasawa

Publications and source records attributed to E Terasawa.

At least 19 recordsLinked to original sources

PubMed2004

Projections from estrogen receptor-alpha immunoreactive neurons in the periaqueductal gray to the lateral medulla oblongata in the rhesus monkey.

The periaqueductal gray (PAG) contains numerous estrogen receptor-alpha immunoreactive (ER-alpha IR) neurons that are distributed in a species-specific way. These neurons might modulate different types of behavior that are mediated by the PAG such as active and passive coping responses, analgesia, and reproductive behavior. In primates, it is not known whether ER-alpha IR PAG neurons represent local interneurons and/or neurons that project to brainstem areas that control these behaviors. In this double labeling study, we asked whether ER-alpha IR neurons in the PAG of the rhesus monkey project to the nucleus retroambiguus (NRA), an area in the ventrolateral caudal medulla oblongata that is involved in expiration, vocalization, and reproductive behavior. Tracer was injected into the caudal lateral medulla oblongata to retrogradely label PAG neurons, and ER-alpha was visualized immunohistochemically. Although ER-alpha IR neurons and NRA-projection neurons were present at similar levels of the PAG, their distributions hardly overlapped. ER-alpha IR PAG neurons that project to the lateral caudal medulla represented less than 2% of ER-alpha IR PAG neurons. These double-labeled neurons were mainly located in the ipsilateral caudal PAG. The cluster of neurons in the medial part of the lateral PAG that projects specifically to the NRA-region did not contain double-labeled cells. The results indicate that only a few ER-alpha IR PAG neurons project to the NRA-region. This might be related to the modest effects of estrogen on mating-related behavior in primates compared most other mammalian species. Remaining ER-alpha IR PAG neurons might act locally on other PAG neurons, or they might represent neurons that project to other areas. Furthermore, the finding that the distributions of ER-alpha IR neurons and neurons that project to premotor neurons in the NRA-region scarcely overlap illustrates that the PAG in primates is very highly organized into anatomically distinct regions compared with other species.

Animals↗

PubMed2002

Effect of dietary sulfur amino acids on the taurine content of rat tissues.

The effect of dietary sulfur amino acids on the taurine content of rat blood and tissues was investigated. Three types of diet were prepared for this study: a low-taurine diet (LTD), normal taurine diet (NTD; LTD + 0.5% Met), and high-taurine diet (HTD; LTD + 0.5% Met + 3% taurine). These diets had no differing effect on the growth of the rats. The concentration of taurine in the blood from the HTD- and NTD-fed rats was respectively 1200% and 200% more than that from LTD-. In such rat tissues as the liver, the taurine content was significantly affected by dietary sulfur amino acids, resulting in a higher content with HTD and lower content with LTD. However, little or no effect on taurine content was apparent in the heart or eye. The activity for taurine uptake by the small intestine was not affected by dietary sulfur amino acids. The expression level of taurine transporter mRNA was altered only in the kidney under these dietary conditions: a higher expression level with LTD and lower expression level with HTD.

Animals↗

PubMed2002

Synchronization of Ca(2+) oscillations among primate LHRH neurons and nonneuronal cells in vitro.

Periodic release of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus is essential for normal reproductive function. Pulsatile LHRH release appears to result from the synchronous activity of LHRH neurons. However, how the activity of these neurons is synchronized to release LHRH peptide in a pulsatile manner is unclear. Because there is little evidence of physical coupling among LHRH neurons in the hypothalamus, we hypothesized that the activity of LHRH neurons might be coordinated by indirect intercellular communication via intermediary (nonneural) cells rather than direct interneural coupling. In this study, we used an in vitro preparation of LHRH neurons derived from the olfactory placode of monkey embryos to assess whether nonneuronal cells, play a role in coordinating LHRH neuronal activity. We found that cultured LHRH neurons and nonneuronal cells both exhibit spontaneous oscillations in the concentration of intracellular Ca(2+) ([Ca(2+)](i)) at similar frequencies. Moreover, [Ca(2+)](i) oscillations in both types of cell were periodically synchronized. Synchronized [Ca(2+)](i) oscillations spread as intercellular Ca(2+) waves across fields of cells that included LHRH neurons and nonneuronal cells, although waves spread at a higher velocity among LHRH neurons. These results suggest that LHRH neurons and nonneuronal cells are functionally integrated and that nonneuronal cells could be involved in synchronizing the activity of the LHRH neurosecretory network.

Animals↗

PubMed2001

Presence of luteinizing hormone-releasing hormone fragments in the rhesus monkey forebrain.

Previously, we have shown that two types of luteinizing hormone-releasing hormone (LHRH) -like neurons, "early" and "late" cells, were discernible in the forebrain of rhesus monkey fetuses by using antiserum GF-6, which cross-reacts with several forms of LHRH. The "late" cells that arose from the olfactory placode of monkey fetuses at embryonic days (E) 32-E36, are bona fide LHRH neurons. The "early" cells were found in the forebrain at E32-E34 and settled in the extrahypothalamic area. The molecular form of LHRH in "early" cells differs from "late" cells, because "early" cells were not immunopositive with any specific antisera against known forms of LHRH. In this study, we investigated the molecular form of LHRH in the "early" cells in the nasal regions and brains of 13 monkey fetuses at E35 to E78. In situ hybridization studies suggested that both "early" and "late" LHRH cells expressed mammalian LHRH mRNA. Furthermore, "early" cells predominantly contain LHRH1-5-like peptide and its cleavage enzyme, metalloendopeptidase E.C.3.4.24.15 (EP24.15), which cleaves LHRH at the Tyr5-Gly6 position. This conclusion was based on immunocytochemical labeling with various antisera, including those against LHRH1-5, LHRH4-10, or EP24.15, and on preabsorption tests. Therefore, in primates, a group of neurons containing mammalian LHRH mRNA arises at an early embryonic stage before the migration of bona fide LHRH neurons, and is ultimately distributed in the extrahypothalamic region. These extrahypothalamic neurons contain LHRH fragments, rather than fully mature mammalian LHRH. The origin and function of these neurons remain to be determined.

Animals↗

PubMed2001

A novel mammalian receptor for the evolutionarily conserved type II GnRH.

Mammalian gonadotropin-releasing hormone (GnRH I: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) stimulates pituitary gonadotropin secretion, which in turn stimulates the gonads. Whereas a hypothalamic form of GnRH of variable structure (designated type I) had been shown to regulate reproduction through a cognate type I receptor, it has recently become evident that most vertebrates have one or two other forms of GnRH. One of these, designated type II GnRH (GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2), is conserved from fish to man and is widely distributed in the brain, suggesting important neuromodulatory functions such as regulating K+ channels and stimulating sexual arousal. We now report the cloning of a type II GnRH receptor from marmoset cDNA. The receptor has only 41% identity with the type I receptor and, unlike the type I receptor, has a carboxyl-terminal tail. The receptor is highly selective for GnRH II. As with the type I receptor, it couples to G(alpha)q/11 and also activates extracellular signal-regulated kinase (ERK1/2) but differs in activating p38 mitogen activated protein (MAP) kinase. The type II receptor is more widely distributed than the type I receptor and is expressed throughout the brain, including areas associated with sexual arousal, and in diverse non-neural and reproductive tissues, suggesting a variety of functions. Surprisingly, the type II receptor is expressed in the majority of gonadotropes. The presence of two GnRH receptors in gonadotropes, together with the differences in their signaling, suggests different roles in gonadotrope functioning.

Amino Acid Sequence↗

PubMed2001

Luteinizing hormone-releasing hormone (LHRH) neurons: mechanism of pulsatile LHRH release.

Many types of neurons and glia exhibit oscillatory changes in membrane potentials and cytoplasmic Ca2+ concentrations. In neurons and neuroendocrine cells an elevation of intracellular Ca2+ concentration is associated with neurosecretion. Since both oscillatory membrane potentials and intracellular Ca2+ oscillations have been described in primary LHRH neurons and in GT1 cells, it is evident that an endogenous pulse-generator/oscillator is present in the LHRH neuron in vitro. The hourly rhythms of LHRH neurosecretion appear to be the synchronization of a population of LHRH neurons. How a network of LHRH neurons synchronizes their activity, i.e., whether by the result of synaptic mechanisms or electrical coupling through gap junctions or through a diffusible substance(s), remains to be clarified. Even though LHRH neurons themselves possess an endogenous pulse-generating mechanism, they may be controlled by other neuronal and nonneuronal elements in vivo. NE, NPY, glutamate, and GABA are neurotransmitters possibly controlling pulsatile LHRH release, and NO, cAMP, and ATP may be diffusible substances involved in pulsatile LHRH release without synaptic input. Although synaptic inputs to the perikarya of LHRH neurons could control the activity of LHRH neurons, a line of evidence suggests that direct neuronal and nonneuronal inputs, especially those from astrocytes to LHRH neuroterminals, appear to be more important for pusatile LHRH release.

Animals↗

PubMed2001

Monosynaptic projections from the nucleus retroambiguus region to laryngeal motoneurons in the rhesus monkey.

Vocalization and straining-related activities require the activation of laryngeal muscles. The control of laryngeal muscles during these activities is thought to be mediated by a pathway from the periaqueductal gray via premotor neurons in the nucleus retroambiguus to laryngeal motoneurons in the nucleus ambiguus. However, direct contacts between the nucleus retroambiguus and laryngeal motoneurons have never been demonstrated anatomically. Moreover, data in primates about the nucleus retroambiguus-nucleus ambiguus pathway are lacking. Therefore, the present study examines the projection from the nucleus retroambiguus region to laryngeal motoneurons in the rhesus monkey at the light and electron microscopic levels. Injections with wheat germ agglutinin-horseradish peroxidase were made into the nucleus retroambiguus in five rhesus monkeys to anterogradely label fibers in the nucleus ambiguus. In two of these animals, the cricothyroid muscle was injected with cholera toxin subunit b to identify the motoneurons that supply it. The results show that the nucleus retroambiguus region most densely projects to the compact formation of the nucleus ambiguus, whereas cricothyroid motoneurons, which surround the compact formation, receive a moderate projection. The projections are bilateral, with a contralateral predominance. Ultrastructurally, anterogradely labeled terminal profiles from the nucleus retroambiguus contact cholera toxin subunit b-labeled dendrites of cricothyroid motoneurons. The terminal profiles contain primarily spherical vesicles and form asymmetrical contacts with cricothyroid motoneurons. This study demonstrates that the nucleus retroambiguus region projects to the nucleus ambiguus in the primate. Some of these projections include monosynaptic connections to laryngeal motoneurons. This pathway is important for the control of the vocal folds during vocalization and straining-related activities.

Animals↗

PubMed2001

Neural mechanisms underlying the pubertal increase in LHRH release in the rhesus monkey.

Puberty is triggered by an increase in pulsatile release of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus. Although the LHRH neurosecretory system is mature well before the onset of puberty, a central inhibitory mechanism restrains LHRH release in juvenile primates. Recent studies suggest that this central inhibition is primarily because of GABAergic neurotransmission. A reduction of GABAergic restraint appears to be essential for the initiation of puberty, but the mechanism that underlies the disinhibition process remains to be elucidated. Future research into the regulation of central inhibition should provide more effective treatments for the prevention of disease associated with abnormal pubertal development.

Aging↗

PubMed2001

Neural circuits regulating pulsatile luteinizing hormone release in the female guinea-pig: opioid, adrenergic and serotonergic interactions.

We studied three neurotransmitters involved in the regulation of pulsatile luteinizing hormone (LH) release: opioid peptides, serotonin and norepinephrine, using the ovariectomized guinea-pig. This is an attractive animal model due to the regularity of its LH pulses, enabling any disruptions to be clearly ascertained. In all experiments, a specific agonist or antagonist was administered, either alone or serially to enable detection of interactions, and effects on mean LH concentrations, pulse amplitude and interpulse interval were determined by PULSAR analysis. In the ovariectomized guinea-pig, catecholamines are stimulatory (acting through the alpha1 and alpha2 but not beta receptors, unlike other species), opioids inhibitory and serotonin permissively stimulatory to pulsatile LH release. Stimulatory effects of the opiate antagonist were not blocked by pretreatment with an alpha1- or alpha2-adrenergic antagonist. Similarly, pretreatment with the opiate antagonist did not prevent the suppression of LH release by alpha1 and alpha2 antagonists. This suggests that, in the guinea-pig, effects of opiates and catecholamines on LH release are exerted by independent pathways to luteinizing hormone releasing hormone (LHRH) neurones. For the opiate-serotonin interactions, pretreatment with the serotonergic antagonist did not block the stimulatory effect of the opiate antagonist on LH release. However, pretreatment with the opiate agonist could not be overcome by the serotonergic agonist. This suggests that the effects of the serotonin system on LHRH release may be indirectly mediated by opioid neurones. Taken together, these studies demonstrate that the three neurotransmitter systems studied are critically involved in normal pulsatile LH release in the female guinea-pig, and demonstrate novel functional relationships between the opioid and the adrenergic and serotonergic systems.

Animals↗

PubMed2001

Neurobiological mechanisms of the onset of puberty in primates.

An increase in pulsatile release of LHRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in LHRH release is still unclear. In primates the LHRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state in the juvenile/prepubertal period. Neither gonadal steroid hormones nor the absence of facilitatory neuronal inputs to LHRH neurons is responsible for the low levels of LHRH release before the onset of puberty in primates. Recent studies suggest that during the prepubertal period an inhibitory neuronal system suppresses LHRH release and that during the subsequent maturation of the hypothalamus this prepubertal inhibition is removed, allowing the adult pattern of pulsatile LHRH release. In fact, y-aminobutyric acid (GABA) appears to be an inhibitory neurotransmitter responsible for restricting LHRH release before the onset of puberty in female rhesus monkeys. In addition, it appears that the reduction in tonic GABA inhibition allows an increase in the release of glutamate as well as other neurotransmitters, which contributes to the increase in pubertal LHRH release. In this review, developmental changes in several neurotransmitter systems controlling pulsatile LHRH release are extensively reviewed.

Animals↗

PubMed2000

Monosynaptic projections from the nucleus retroambiguus to motoneurons supplying the abdominal wall, axial, hindlimb, and pelvic floor muscles in the female rhesus monkey.

The nucleus retroambiguus (NRA) consists of premotor neurons in the caudal medulla. It is involved in expiration, vomiting, vocalization, and probably reproductive behavior by means of projections to distinct motoneuronal cell groups. Because no information is available about the NRA and its efferent pathways in primates, the present study examines NRA projections to the lumbosacral spinal cord in female rhesus monkeys. To identify the NRA, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into the lumbosacral cord in three monkeys. To study the distribution of NRA axons in the lumbosacral cord, WGA-HRP injections were made into the NRA in seven monkeys. To identify motoneuronal cell groups receiving input from the NRA, the same seven monkeys also received cholera toxin subunit b (CTb) injections into different hindlimb, axial, and pelvic floor muscles. The results show that NRA neurons projecting to the lumbosacral cord are mainly located between 1 to 4 mm caudal to the obex. They send numerous axons to external oblique and pelvic floor motoneurons, whereas projections to iliopsoas and axial motoneurons are less numerous. The projections are bilateral, but show a clear contralateral predominance in the iliopsoas, axial, and pelvic floor motoneuronal cell groups. At the ultrastructural level, NRA-terminal profiles make asymmetrical contacts with labeled and unlabeled dendrites in these motoneuronal cell groups and contain large amounts of spherical and a few dense core vesicles. It is concluded that the NRA is well developed in the monkey and that there exists a direct pathway from the NRA to lumbosacral motoneurons in this species. The finding that the NRA projects to a somewhat different set of motoneuronal cell groups compared with other species fits the concept that it is not only involved in expiration-related activities but also in species specific receptive and submissive behavior.

Abdominal Muscles↗

PubMed2000

Monosynaptic projections from the lateral periaqueductal gray to the nucleus retroambiguus in the rhesus monkey: implications for vocalization and reproductive behavior.

The periaqueductal gray (PAG) is known to be essential for vocalization and reproductive behavior. The PAG controls components of these behaviors by means of projections to the nucleus retroambiguus (NRA), a group of premotor neurons in the caudal medulla oblongata. In the accompanying study (VanderHorst et al., 2000 [accompanying study]), the NRA and its lumbosacral projections have been identified in the rhesus monkey. The present light and electron microscopical tracing study describes the PAG-NRA pathway in primates. To locate midbrain neurons projecting to the NRA, wheat germ agglutinin horseradish peroxidase (WGA-HRP) was injected into the NRA in six monkeys. To determine the distribution pattern of PAG axons in the medulla oblongata, WGA-HRP was injected into the PAG and adjacent tegmentum in three additional monkeys. In one of these three monkeys, biotinylated dextran amine and cholera toxin subunit b were injected into the lumbosacral cord to retrogradely identify NRA neurons. The results show that a compact group of neurons in the medial part of the lateral PAG at the intercollicular level sends a dense projection to the NRA. The projection is bilateral with a clear ipsilateral predominance. At the ultrastructural level, there are monosynaptic contacts between PAG fibers and NRA neurons, including NRA neurons that project to the lumbosacral cord. The synaptic contacts were primarily asymmetrical and the labeled terminal profiles contained spherical and dense core vesicles. It is concluded that there exists a strong and direct PAG-NRA pathway in the rhesus monkey. Because NRA neurons projecting to the lower lumbar cord are included, the PAG-NRA projection is likely to be involved not only in vocalization but also in other behaviors, such as receptive posture.

Animals↗

PubMed2000

N-methyl D,L-aspartate induces the release of luteinizing hormone-releasing hormone in the prepubertal and pubertal female rhesus monkey as measured by in vivo push-pull perfusion in the stalk-median eminence.

The role of the excitatory amino acid glutamate, N-methyl D-aspartate (NMDA) receptor agonist, in stimulating in vivo luteinizing hormone-releasing hormone (LHRH) release in the stalk-median eminence of conscious prepubertal and pubertal female rhesus monkeys was evaluated using push-pull perfusion. In Exp 1, the effects of i.v. bolus injection of N-methyl D,L-aspartate (NMA) on LHRH release were examined. Injection of NMA induced an increase in LHRH release in all maturational stages of monkeys. Although the LHRH response to NMA tended to be larger in the older groups, only the duration of the LHRH response in the midpubertal group was significantly longer than that in the prepubertal group. In Exp 2, the effects of direct infusion of NMA (0.1, 1, and 100 microM) into the stalk-median eminence on LHRH release were similarly examined. NMA infusion stimulated LHRH release in pubertal monkeys, whereas it did not induce any consistent changes in LHRH release in prepubertal monkeys except for the highest dose. These data suggest that: 1) the systemic injection of NMA is more effective than direct infusion of NMA; and 2) the prepubertal LHRH neurosecretory system is capable of responding to NMDA, although the responsiveness may undergo developmental changes. Therefore, stimulation of NMDA receptors may contribute to the pubertal changes in the LHRH neurosecretory activity.

Animals↗

PubMed2000

The role of neuropeptide Y in the progesterone-induced luteinizing hormone-releasing hormone surge in vivo in ovariectomized female rhesus monkeys.

Progesterone induces a LHRH surge in estrogen-primed ovariectomized rhesus monkeys, with a concomitant increase in the pulse frequency of neuropeptide Y (NPY) release. However, the role for NPY in the positive feedback action of progesterone on LHRH release in primates is unknown. The present study examines the effect of an antisense oligodeoxynucleotide for NPY messenger RNA (AS NPY) on the progesterone-induced LHRH surge in vivo using push-pull perfusion. The AS NPY was directly infused into the stalk-median eminence (S-ME), whereas perfusates were collected for assessment of LHRH release. For a control, a scrambled oligodeoxynucleotide was infused. The results indicate that 1) the scrambled oligodeoxynucleotide did not interfere with the progesterone-induced LHRH surge, 2) whereas AS NPY blocked the progesterone-induced increase in LHRH release, and 3) no LHRH surges were induced by oil as a control for progesterone, but the AS NPY also reduced LHRH release in oil controls. These data suggest that 1) AS NPY infusion into the S-ME results in reduction in LHRH release; and 2) NPY release in the S-ME is important for the positive feedback effects of progesterone on LHRH release in estrogen-primed ovariectomized monkeys.

Animals↗

PubMed1999

Intracellular Ca(2+) oscillations in luteinizing hormone-releasing hormone neurons derived from the embryonic olfactory placode of the rhesus monkey.

To understand the mechanism of pulsatile luteinizing hormone-releasing hormone (LHRH) release, we examined whether cultured LHRH neurons exhibit spontaneous intracellular Ca(2+) ([Ca(2+)](i)) signaling. The olfactory placode and the ventral migratory pathway of LHRH neurons from rhesus monkey embryos at embryonic ages 35-37 were dissected out and cultured on glass coverslips. Two to five weeks later, cultured cells were labeled with fura-2 and examined for [Ca(2+)](i) signaling by recording changes in [Ca(2+)](i) every 10 sec for 30-175 min. Cells were fixed and immunostained for LHRH and neuron-specific enolase. In 20 cultures, 572 LHRH-positive cells exhibited [Ca(2+)](i) oscillations at an interpulse interval (IPI) of 8.2 +/- 0.7 min and a duration of 88.8 +/- 2.9 sec. LHRH-negative neurons in culture exhibited only occasional [Ca(2+)](i) oscillations. In 17 of 20 cultures with LHRH-positive cells, [Ca(2+)](i) oscillations occurred synchronously in 50-100% of the individual cells, whereas [Ca(2+)](i) oscillations in cells in the remaining three cultures did not synchronize. Strikingly, in 12 of 17 cultures the synchronization of [Ca(2+)](i) oscillations repeatedly occurred in complete unison at 52.8 +/- 3.0 min intervals, which is similar to the period observed for LHRH release, whereas in 5 of 17 cultures the less tight synchronization of [Ca(2+)](i) oscillations repeatedly occurred at 23.4 +/- 4.6 min intervals. IPI of [Ca(2+)](i) oscillations in cells with tight synchronization and less tight synchronization did not differ from IPI in cells without synchronization. The results indicate that LHRH neurons derived from the monkey olfactory placode possess an endogenous mechanism for synchronization of [Ca(2+)](i) oscillations. Whether synchronization of [Ca(2+)](i) oscillations relates to neurosecretion remains to be investigated.

Activity Cycles↗

PubMed1999

An increase in glutamate release follows a decrease in gamma aminobutyric acid and the pubertal increase in luteinizing hormone releasing hormone release in the female rhesus monkeys.

Previously we have shown that release of gamma-aminobutyric acid (GABA) in the stalk-median eminence (S-ME) is high in prepubertal monkeys and that a decrease in GABA release triggers the onset of puberty. However, it is still unclear how disinhibition of the luteinizing hormone releasing hormone (LHRH) neuronal system from GABA input is followed (or accompanied) by an increase in stimulatory signals, such as glutamatergic input to LHRH neurons. To clarify the temporal relationship between the reduction of the GABAergic inhibitory signal and the enhancement of the glutamatergic stimulatory signal in the control of LHRH release at the onset of puberty, we conducted two experiments using a push-pull perfusion method. In the first experiment, we measured developmental changes in release of LHRH, GABA, and glutamate in the S-ME. LHRH levels were very low in prepubertal monkeys, increased to higher levels in early pubertal monkeys, with the highest LHRH levels occurring in mid-pubertal monkeys. As we previously observed, GABA levels were high in prepubertal monkeys and then decreased in early- and mid-pubertal monkeys. In contrast, glutamate levels were very low in prepubertal monkeys, increased dramatically in early pubertal monkeys, and then slightly decreased in mid-pubertal monkeys, although mid-pubertal levels remained much higher than prepubertal levels. In the second experiment, we measured GABA, glutamate and LHRH in the same samples obtained from prepubertal monkeys which were infused with an antisense oligodeoxynucleotide (AS) for glutamic acid decarboxylase (GAD) 67 mRNA into the S-ME. GAD67 is a catalytic enzyme for GABA synthesis from glutamate, and AS GAD67 mRNA interferes with GAD67 synthesis. Infusion of the AS GAD67 induced a decrease in GABA release, which subsequently resulted in an increase in LHRH release. Surprisingly, glutamate release also increased several hours after the decrease in GABA release, and the increased LHRH release continued. These data are interpreted to mean that a decrease in GABA synthesis by interference with GAD67 synthesis and the reduction of GABA release in the S-ME trigger an increase in LHRH release, but that a subsequent increase in glutamate release in the S-ME further contributes to the pubertal increase in LHRH release at the onset of puberty. The data further support our hypothesis that GAD plays an important role in the mechanism of the onset of puberty.

Animals↗

PubMed1999

Effects of pulsatile infusion of the GABA(A) receptor blocker bicuculline on the onset of puberty in female rhesus monkeys.

In order to test the hypothesis that GABA is an inhibitory neurotransmitter restricting the release of LHRH before puberty, we examined the effects of pulsatile infusion of the GABA(A) receptor blocker, bicuculline, on the timing of puberty. Eleven female monkeys at 14-15 months of age were implanted with a stainless steel cannula into the base of the third ventricle above the median eminence. Five monkeys received bicuculline infusion every 2 h at a dose of 1 microM with a gradual increase to 100 microM in 10 microl using a portable infusion pump. The remaining 6 monkeys received similar infusions of saline. An additional 11 colony monkeys without cannula implantation were used for controls. Results indicate that bicuculline infusion advances the timing of puberty. The age of menarche (17.8+/-0.5 months) in the bicuculline infusion animals was significantly earlier than that in the saline controls (28.2+/-2.3, P < 0.001) as well as in colony controls (30.6+/-0.9, P < 0.001). The age of first ovulation (30.5+/-3.3 months) in bicuculline-treated animals was much younger (P < 0.001) than that in both controls (44.8+/-1.8 and 44.7+/-1.2, respectively). Bicuculline also accelerated the growth curve. These results suggest that the reduction of tonic GABA inhibition of LHRH neurons advances the onset of puberty.

Aging↗

PubMed1999

A role of gamma-amino butyric acid (GABA) and glutamate in control of puberty in female rhesus monkeys: effect of an antisense oligodeoxynucleotide for GAD67 messenger ribonucleic acid and MK801 on luteinizing hormone-releasing hormone release.

Previously we have shown that gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter restricting the pubertal increase in LHRH release in juvenile monkeys, and that interfering with GABA synthesis with an antisense oligodeoxynucleotide (AS) for glutamic acid decarboxylase (GAD67) mRNA results in an increase in LHRH release in prepubertal monkeys. GAD67 is a catalytic enzyme that synthesizes GABA from glutamate. To further clarify the role of GABA in puberty, we examined whether the inhibition of LHRH release by GABA continues after the onset of puberty and whether input from glutamatergic neurons plays any role in the onset of puberty when GABA inhibition declines, using a push-pull perfusion method. In Study I, the effects of the AS GAD67 mRNA on LHRH release in pubertal monkeys (34.3 +/- 1.5 months of age, n = 8) were examined, and the results were compared with those in prepubertal monkeys (18.5 +/- 0.4 months, n = 12). Direct infusion of AS GAD67 (1 microM) into the stalk-median eminence (S-ME) for 5 h stimulated LHRH release in both prepubertal and pubertal monkeys. However, the increase in LHRH release in pubertal monkeys was significantly (P < 0.01) smaller than that in prepubertal monkeys. Infusion of a scrambled oligo as a control was without effect in either group. In Study II, to examine the possibility that an increase in glutamate tone after the reduction of an inhibitory GABA tone contributes to the AS GAD67-induced LHRH increase, the effects of the NMDA receptor blocker MK801 (5 microM) on LHRH release were tested in monkeys treated with AS GAD67. MK801 infusion into the S-ME during the treatment of AS GAD67 (1 microM) suppressed the AS GAD67-induced LHRH release in both age groups. MK801 alone did not cause any significant effect in either group. The data are interpreted to mean that GABA continues to suppress LHRH release after the onset of puberty, although the degree of suppression is weakened considerably after the onset of puberty, and that the increased LHRH release after AS GAD67 treatment may be partly due to an increase in glutamate tone mediated by NMDA receptors, as well as due to the decrease in GABA release following the decrease in GAD synthesis. Taken together, the present results suggest that GAD may play an important role in the onset and progress of puberty in nonhuman primates.

Animals↗