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Endocrinology Vol. 138, No. 5 1944-1948
Copyright © 1997 by The Endocrine Society

Articles

Possible Role of the {gamma}-Aminobutyric Acid-A Receptor System in the Timing of the Proestrous Luteinizing Hormone Surge in Rats

Dai Mitsushima, Kayoko Jinnai and Fukuko Kimura

Department of Physiology, Yokohama City University School of Medicine, Fukuura, Kanazawa-ku, Yokohama, Japan

Address all correspondence and requests for reprints to: Dr. Dai Mitsushima, Department of Physiology, Yokohama City University School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To examine the role of the {gamma}-aminobutyric acid-A receptor-mediated system in the timing of the proestrous LH surge, we observed the free running activity rhythm and the timing of the LH surge simultaneously in blinded cycling female rats. Blood samples were obtained from unanesthetized freely moving rats through an intraatrial cannula. Five hours after the activity offset on the day of proestrus, bicuculline methiodide (BIC; 50 mg/kg·h) or saline was infused iv for 3 h into the freely moving rats. In the BIC group, the peak time of the surge occurred at 7.9 ± 0.2 h after the activity offset, with a significant advance compared to the peak time in the saline group (i.e. 9.9 ± 0.4 h), but neither BIC nor saline induced a significant phase shift in the circadian activity rhythm. We found that the infusion of BIC on the subjective morning of the proestrous day dissociates the timing of the LH surge from the circadian activity rhythm in rats.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
WE RECENTLY reported that an infusion of the {gamma}-aminobutyric acid-A (GABAA) receptor antagonist bicuculline (BIC) on the morning of proestrus is effective in advancing the timing of the LH surge, but the infusion at other stages in the estrous cycle is not (1, 2). An in vivo microdialysis study indicated that GABA release in the medial preoptic area (MPO), where many LHRH neurons responsible for the LH surge are located (3), expresses daily fluctuation and decreases before the onset of the LH surge (4). In addition, a double labeled electron microscopic study has revealed that GABAergic neurons synapse on the LHRH neurons in the MPO (5). It is, therefore, possible that the disinhibition of LHRH neurons from GABA caused the advancement of the timing of the LH surge in our previous study.

It is also possible, however, that the effect of BIC occurs through the phase shift of the circadian clock. The suprachiasmatic nucleus (SCN), which is known as the circadian clock in rodents, regulates many behavioral and endocrine rhythms (6, 7, 8). The fact that bilateral lesions of the SCN block the LH surge in rats (9, 10, 11) indicates that the timing of the LH surge depends on the function of the SCN. Furthermore, both GABAergic neurons and the GABAA-benzodiazepine receptor complex were observed in the SCN (12, 13), and BIC was effective in blocking the phase delay induced by light or benzodiazepine diazepam (14), raising the possibility that a GABAA receptor-mediated system is involved in the modulation of phase resetting in the SCN. In support of this, daily injections of a short acting benzodiazepine triazolam for 3 days were able to induce changes in the hamster’s free-running activity rhythm as well as in the timing of the LH surge (7).

In the present study, therefore, to determine whether the advancement of the LH surge by the infusion of bicuculline is due to the phase shift of the circadian clock or to the advance in the timing of the LH surge without any effect on the circadian clock, we examined the effects of bicuculline on the timing of the LH surge and on the circadian locomotor activity rhythm in the cycling female rat.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Female Wistar-Imamichi rats were housed in individual plastic cages under constantly controlled environmental conditions (temperature, 23 ± 1 C; lights on, 0500–1900 h). Food and water were available ad libitum in all experimental periods. As it was difficult for us to perform simultaneous blood sampling and measurement of locomotor activity under freely moving conditions in constant dark, the optic nerves of the rats were cut under ether anesthesia around 1900 h on the day when the measurement of spontaneous locomotor activity was begun. Small plastic boards were inserted at the nerve ends to prevent regeneration of the nerve fibers. After the blinding, the rats were housed under continuous regular light (~250 lux).

A vaginal smear was taken daily before the monitoring of locomotor activity and indicated regular 4- to 5-day estrous cycles. Estrous cycles clearly continue in blinded female rats, as we reported previously (15). At the expected subjective day of proestrus, a vaginal smear was taken again at the time of cannulation. When the experiment started 4 h before the activity offset, a vaginal smear was taken after the final blood sampling (6 h after the activity offset).

All animal housing and surgical procedures were in accordance with the guidelines of the institutional animal care and use committee of the Animal Research Center, Yokohama City University School of Medicine (Yokohama, Japan).

Serum LH and locomotor activity determination
Individual female rats were housed in plastic cages (length, 30 cm; width, 45 cm; height, 20 cm) placed on dielectric constant sensors with counters (DAC-200, Dia Medical System Co., Tokyo, Japan; length, 33 cm; width, 50 cm; height, 13 cm). Spontaneous locomotor activity counts were evaluated by changes in the dielectric constant and recorded every 30 min using a printer (DAC-210, Dia Medical System Co.) (16). A double plotted actogram was expressed using the software that we used previously (15). The activity offset time in the optic nerve-sectioned rat was determined by eye-fitting a straight line through the activity offsets over a period of 10 consecutive days. As, unlike in hamsters, the activity onset time was quite variable and unstable in some of the intact female rats, the offset of activity on the subjective morning of proestrus was used as a phase reference point. On the day of proestrus for more than 12 days after the nerve section, sequential blood samplings and BIC infusions were started 5 h after the activity offset time in unanesthetized, freely moving rats through indwelling cardiac cannulas of silicone tubing (Kaneka Medix Co., Osaka, Japan), which had been inserted through the jugular vein on the day of the infusion, as described previously (17). The iv infusion of bicuculline methiodide (BIC; Sigma Chemical Co., St. Louis, MO) dissolved in saline (SAL) at a dose of 50 mg/kg·h or only SAL as a control was performed through the cannula for 3 h with a micropump at a rate of 10 µl/min. Sequential blood samples (200 µl) were obtained at 30- to 60-min intervals to detect the LH surge, and an equal volume of heparinized SAL was replaced after each bleeding. Separated serum samples (50 µl) were mixed with 1% BSA-PBS (50 µl) and stored at -20 C until the assay. After the experiment with BIC or SAL infusion, the activity recording was continued for more than 12 days, and changes in the phase of circadian activity rhythm were evaluated.

The serum LH concentration was measured by RIA with materials supplied by the NIDDK. The reference standard was NIDDK rat NIH RP-3, but the amounts of LH are expressed in terms of NIH LH-S1. The mean minimum detectable amount of LH in four assays was 0.39 ± 0.06 ng/ml. The intra- and interassay coefficients of variation were 4.71% and 6.16%, respectively.

Statistics
To determine the effect of the infusion of BIC or SAL on the LH surge, serum LH concentrations during and after BIC infusion were compared to those at the corresponding times in the control group. Data were analyzed by two-way ANOVA for repeated measures; the between-group factor was treatment (BIC or SAL), and the within-group factor was time. This was followed by post-hoc analysis with the Fisher protected least significant difference test. The two-tailed unpaired t test was used for analysis of the peak time of LH, amplitude of the LH surge, and phase change in locomotor activity. Significance was attained at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Representative individual examples of the circadian rhythm of spontaneous motor activity and the proestrous LH surge are shown in Fig. 1Go. A clear circadian rhythm in activity was present in all rats after the nerve section. The activity phase on the days after the SAL infusion tended to advance slightly, possibly due to the experimental manipulation (Fig. 2Go). The mean (±SE) peak time of the LH surge was 9.93 ± 0.35 h after the time of activity offset in the SAL group (Fig. 2Go). The time course changes in the mean LH concentrations during and after SAL infusion are shown in Fig. 3Go (open circles).



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  		Figure 1. Double plotted actograms of locomotor activity (upper panels) and serum LH profiles (lower panels) in two rats (A and B) infused with BIC or SAL. The 3-h infusion of BIC or SAL on the day of proestrus is indicated by a shaded bar on each activity record. In rat A, blood collections on the day of BIC infusion were performed 13 days after the nerve section, and those on the day of SAL infusion were performed after 25 days. In rat B, blood collections on the day of BIC infusion were performed 27 days after the nerve section, and those on the day of SAL infusion were performed after 15 days.

 


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  		Figure 2. The effect of infusion of BIC or SAL on the time of the peak proestrous LH surge (upper panel) and the phase of circadian locomotor activity (lower panel). A positive number on the x-axis means a phase advance in circadian locomotor activity rhythm. The values are the mean ± SE for seven rats in both groups. **, P < 0.01 vs. SAL group.

 


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  		Figure 3. The effect of infusion of BIC or SAL on serum LH concentrations. BIC (filled circle) or SAL (open circle) was infused from 5–8 h after activity offset as indicated by a shaded bar. The values are the mean ± SE for seven rats in both groups. In some cases, BIC (filled square) was infused from 1–4 h before activity offset, as indicated by a dashed bar. *, P < 0.05; **, P < 0.01 (vs. SAL group).

 
In contrast, the mean peak time of the LH surge was 7.86 ± 0.24 h after the activity offset in the BIC group (Fig. 2Go), although the activity phase after the BIC infusion was similar to that on the days before infusion (Fig. 1Go). In four of seven rats the activity phase was slightly advanced (<30 min), and in the other three it was slightly delayed (<30 min) after the BIC infusion. However, no rat showed an obvious phase advance in the circadian activity rhythm, unlike the LH surge (Fig. 2Go). Two-tailed t test indicated that the peak time of the LH surge was significantly advanced by the BIC infusion (P < 0.01 vs. SAL), whereas the phase changes in circadian locomotor activity in the two groups were not significant (P > 0.05 vs. SAL; Fig. 2Go). It was noticed that the mean peak amplitude of the LH surge induced by BIC was significantly greater than that in the SAL group (P < 0.01 vs. SAL). Time-course changes in the mean LH concentrations during and after the BIC infusion are shown in Fig. 3Go (filled circles).

Infusions of BIC in a different circadian phase were also performed in some rats on the day of proestrus. In the experiment, the same protocol was used, except that the BIC infusion and blood sampling were started 4 h before activity offset. Although no SAL control was performed in this study, no LH surge was observed in any of the four rats examined (Fig. 3Go, filled square). In addition, the circadian phase of locomotor activity was similar to the phase before the infusion (0.42 ± 0.35 h phase delay).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It was found that the peak in the proestrous LH surge occurred at 9.93 ± 0.35 h after the time of the activity offset in rats, although the LH surge was detected on various days after the nerve section. To the best of our knowledge, this is the first report that shows the timing of the LH surge and circadian locomotor activity in the same cycling female rat. The results demonstrate that the timing of the proestrous LH surge in rats is entrained to the circadian activity rhythm.

We also found that the injection of BIC (GABAA receptor antagonist) during the subjective morning of proestrus did not significantly shift the phase of the circadian rhythm in locomotor activity (Fig. 2Go). In contrast, the injection of triazolam, an activator of the GABAA benzodiazepine receptor complex, which was performed in a similar corresponding phase, shifted the phase of activity rhythm (7, 18, 19). Although methodological differences should be examined, it is possible that the exogenous stimulation of benzodiazepine receptor, but not the blockage of GABAA receptor, is effective in changing the phase of the activity rhythm in this clock time.

Conversely, BIC was able to shift the timing of the proestrous LH surge in the nerve-sectioned rat, which was similar to our previous observation in the intact rat (1). These results indicate that the BIC infusion transiently dissociates the timing of the LH surge from the circadian activity rhythm. GABAergic neurons synapse on LHRH neurons in the MPO (5). A dual label in situ hybridization study revealed that the GABAA receptor subunit messenger RNA was colocalized with LHRH messenger RNA in the preoptic area (20). It is, therefore, likely that the disinhibition of LHRH neurons from GABAergic neurons dissociates the timing of the LH surge from the circadian locomotor activity rhythm.

GABA release in the MPO changed daily in estrogen-primed ovariectomized rats (4), suggesting that the GABAergic neurons in the MPO are regulated by a circadian factor. In histological studies, it was indicated that some neurons in the SCN project to neurons containing estrogen receptors (21), and estrogen receptors seem to be concentrated in GABAergic neurons in the preoptic area (22). Taken together, these reports support the hypothesis that the GABAergic neurons that contain estrogen receptors receive neural projections from the SCN to regulate LHRH neurons.

It was reported that both circadian locomotor activity and LH surge generator were regulated by the same multioscillator system (23), but recent reports address another possibility. It was indicated that a diffusible signal from the SCN is important for the generation of circadian locomotor rhythm (24), whereas the reproductive rhythm requires neural efferents (25). It is, therefore, also possible that neural outputs from the clock for the timing of the LH surge might be more sensitive to BIC than the diffusible outputs for circadian locomotor activity. BIC might act within the SCN to selectively disinhibit the release of some other stimulatory signal or to inhibit some other inhibitory signal for LHRH neurons, such as vasoactive intestinal polypeptide (26). Further study is necessary to determine the mechanism of the dissociation.

It was observed in the present study that the amplitude of the LH surge induced by BIC in advance was almost twice as great as that in the SAL group, whereas apparently there was no difference between the BIC-induced and normal surges in amplitude in the light-dark condition (1). Although it is difficult to interpret the results, photic sensation may be related to the GABAergic inhibition of the LH surge. It was reported that in ovariectomized rats, a constant light applied for a short period was effective in reducing the magnitude of the steroid-induced LH surge (27), but further experiments are needed to clarify details.

BIC was able to shift the timing of the LH surge when infused 5 h after, but not 4 h before, activity offset, indicating that GABAergic inhibition of the LH surge generator is phase dependent. However, in estrogen-primed ovariectomized rats, GABA release in the MPO seemed high during the several hours before the LH surge and decreased before the onset of the LH surge (4). We may be able to interpret our results as indicating that GABAergic inhibition is too strong for LHRH neurons to stimulate LH release in response to BIC infusion in early proestrus. In that case, it is possible that a spontaneous decrease in GABAergic tone a few hours before the proestrous LH surge enables BIC to advance the LH surge.

It is also possible that GABAergic inhibition of the LH surge generator is effective only in the critical period (morning of the proestrous day). In the intact female rat, the peak plasma estradiol concentration occurred around noon on the day of proestrus and was much higher than that in the predawn of that day (28). As in vivo microdialysis studies have indicated that estrogen increases the release of GABA in the MPO (29, 30), GABAergic inhibition of LHRH neurons may be greater in the late morning of the day of proestrus than in the predawn of that day. If this interpretation is correct, the GABAergic inhibition seems to be established as occurring at a time between 1 h before and 5 h after activity offset time on the day of proestrus.

A change in pituitary responsiveness to LHRH may also be responsible for the phasic effect of BIC, because an injection of estradiol in the morning of diestrous day 1 does not induce a LH surge in the evening (31). During the estrous cycle, a gradual increase in circulating estrogen is associated with increasing pituitary responsiveness to LHRH, which reaches a maximum on proestrous afternoon (32).

In conclusion, simultaneous locomotor activity recordings and LH measurements demonstrate that the timing of the proestrous LH surge is entrained to the circadian clock in the cycling female rat. Furthermore, it was found that the infusion of BIC transiently dissociates the timing of the LH surge from the circadian activity rhythm.


   Acknowledgments
 
We express our appreciation to Dr. K. Shinohara, Yokohama City University School of Medicine, for valuable comments on this manuscript. We are grateful to the NIDDK and Dr. K. Wakabayashi, Gunma University, for the generous gifts of RIA materials.

Received October 7, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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