Elsevier

Neuroscience Research

Volume 46, Issue 4, August 2003, Pages 399-405
Neuroscience Research

Review article
Sexual dimorphism in the GABAergic control of gonadotropin release in intact rats

https://doi.org/10.1016/S0168-0102(03)00099-3Get rights and content

Abstract

GABA is a potent regulator of gonadotropin release both in male and female rats. We reported 24 h profiles of GABA release in the medial preoptic area (MPO) where gonadotropin-releasing hormone (GnRH) surge generator resides in female rats. In this article, we review the sex difference in 24 h profiles of GABA release. GABA release is high and episodic in male rats without any time dependency, but female rats showed a surge-like secretion of GABA in the early morning of the proestrous day. GABA release rapidly decreased until the afternoon of the day of proestrus followed by the preovulatory luteinizing hormone (LH) surge. The peak time of GABA episodes changes with estrous cycle in female rats. Fitting with the double cosinor method demonstrated that the acrophase of the GABA release in proestrous female rats occurs in the early morning, whereas the acrophases in diestrous females, estrous females and males occur at various time of day. Proestrous female rats showed significant difference in the peak time and acrophase of the GABA release compared with other estrous stages of female and male rats. These results demonstrated further sexual dimorphism of GABA release in the MPO, suggesting that coupling between the GABA release and the circadian clock may be a determining factor in the sex difference of the hypothalamo-pituitary-gonadal (HPG) axis in rats.

Section snippets

Sexual dimorphism in gonadotropin release

There is a distinct sex difference in the hypothalamo-pituitary-gonadal (HPG) axis in rats. Female rats have a luteinizing hormone (LH) surge in the afternoon of proestrus (Butcher et al., 1974), while male rats do not show any LH surge (Kalra and Kalra, 1977). The sex difference at the level of hypothalamus stands out in estrogen-primed gonadectomized rats. Estradiol treatment causes a daily surge-like secretion of LH in gonadectomized female rats, while it continuously suppresses serum LH

Neurotransmitters participating in the control of GnRH–LH axis

A number of neuroendocrinological studies have suggested that many neurotransmitters are involved in the control of GnRH neurons. We proposed that there are two subgroups of GnRH neurons in female rats, the GnRH surge generator and GnRH pulse generator, which generate gonadotropin surge and sustain pulsatile secretion of gonadotropin, respectively (Kimura and Funabashi, 1998). The GnRH pulse generator exists in both sexes of rats, but the GnRH surge generator exists only in female rats.

Many

GABA as a potent and direct GnRH-regulating neurotransmitter

Although there is no doubt that multiple neurotransmitter systems participate in the regulation of GnRH neurons, abundant neuroendocrinological evidence suggests a potential role of GABA in regulating GnRH neurons. First, histological studies demonstrated direct GABAergic regulation of the GnRH neurons in rats: GnRH neurons express some specific subunits forming the GABAa receptor (He et al., 2000b, Jung et al., 1998, Petersen et al., 1994, Sim et al., 2000) and receive synaptic inputs from

GABA release in the MPO of cycling female rats

We have reported the 4 day profile of the GABA release in the MPO of cycling female rats (Mitsushima et al., 2002). We found that GABA release in the MPO was closely associated with the serum estradiol concentration: on the day of diestrus 1, the serum estradiol concentration and the GABA release are low (Butcher et al., 1974, Mitsushima et al., 2002). On the day of diestrus 2, the serum estradiol concentration is slightly increased, and the GABA release declines in the afternoon. In the

Circadian signal to regulate the GABA release of female rats

Nevertheless, circulating estrogen is not the sole factor controlling the GABA release, since GABA release significantly decreases in the afternoon in a high estrogen milieu (i.e. diestrus 2 and proestrus). We recently monitored the GABA release in ovariectomized rats 3–5 days after implantation of a capsule containing 17β-estradiol. The serum estradiol concentration was kept at approximately 75 pg/ml, which is similar to the peak concentration in proestrous female rats (Fig. 1). Ovariectomized

GABA release in the MPO of male rats

We have recently reported the 24 h profile of GABA release in intact male rats (Tin-Tin-Win-Shwe et al., 2002). Unexpectedly, the GABA release level in intact male rats was as high as the morning level in proestrous female rats, and an episodic release pattern was observed throughout the day. Two to six episodic GABA releases were found per day and no surge-like secretion of LH was observed. Since serum LH and testosterone concentration changes episodically (Ellis and Desjardins, 1982), the

Peak time and acrophase of the GABA release

Peak time in each rat was defined as the time when the sample showed maximum concentration of GABA or LH as shown in upper panel of Fig. 2. In diestrus 2 and estrous rats, individual peak time was observed at various times of the day. Although diestrus 1 or male rats tended to show peaks in the afternoon, the peak time in diestrus 1 or male rats was not significantly different from that in diestrus 2 or estrus rats. But proestrous female rats consistently showed increase of GABA release in the

Cause of the sexual difference in the GABA release

The question arises as to what causes the sexually dimorphic profile in GABA release. The sexual dimorphism of the GABA release may simply reflect sex difference in the gonad or circulating hormone milieu, or it may be due to the sex difference in hypothalamic neuronal circuitry caused by neonatal androgen exposure (Orikasa et al., 2002, McEwen, 1994). To further determine the cause of the sex difference, we performed in vivo microdialysis studies in gonadectomized male and female rats.

Acknowledgements

This work was supported by a Grant-in-Aid for Encouragement of Young Scientists from the Ministry of Education, Cultute, Sports, Science and Technology of Japan to D. Mitsushima.

References (64)

  • D. Mitsushima et al.

    The maturation of GABAa receptor-mediated control of luteinizing hormone secretion in immature male rats

    Brain Res.

    (1997)
  • D. Mitsushima et al.

    Fos expression in gonadotropin-releasing hormone neurons by naloxone or bicuculline in intact male rats

    Brain Res.

    (1999)
  • D. Mitsushima et al.

    GABA release in the medial preoptic area of cyclic female rats

    Neuroscience

    (2002)
  • I.F. Palm et al.

    Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesions of the suprachiasmatic nucleus

    Neuroscience

    (1999)
  • J.W. Witkin

    Increased synaptic input to gonadotropin-releasing hormone neurons in aged, virgin, male Sprague–Dawley rats

    Neurobiol. Aging

    (1992)
  • R.L. Butcher et al.

    Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17β throughout the 4-day estrous cycle of the rat

    Endocrinology

    (1974)
  • W.P. Chen et al.

    Sexual dimorphism in the synaptic input to gonadotropin releasing hormone neurons

    Endocrinology

    (1990)
  • P.M. Conn
  • G.B. Ellis et al.

    Male rats secrete luteinizing hormone and testosterone episodically

    Endocrinology

    (1982)
  • G. Fink et al.

    Serotonergic 5-HT2A receptors important for the oestradiol-induced surge of luteinising hormone-releasing hormone in the rat

    J. Neuroendocrinol.

    (1999)
  • G. Flügge et al.

    Evidence for estrogen-receptive GABAergic neurons in the preoptic/anterior hypothalamic area of the rat brain

    Neuroendocrinology

    (1986)
  • M.E. Freeman
  • T. Funabashi et al.

    Bicuculline infusion advances the timing of Fos expression in LHRH neurons in the preoptic area of proestrous rats

    Neuroreport

    (1997)
  • T. Funabashi et al.

    Gonadotropin-releasing hormone exhibits circadian rhythm in phase with arginine-vasopressin in co-cultures of the female rat preoptic area and suprachiasmatic nucleus

    J. Neuroendocrinol.

    (2000)
  • D.R. Grattan et al.

    Antiandrogen microimplants into the rostral medial preoptic area decrease γ-aminobutyric acidergic neuronal activity and increase luteinizing hormone secretion in the intact male rat

    Endocrinology

    (1996)
  • F. Halberg

    Chronobiology

    Annu. Rev. Physiol.

    (1969)
  • S. Han et al.

    Effect of GABA on GnRH neurons switches from depolarization to hyperpolarization at puberty in the female mice

    Endocrinology

    (2002)
  • D. He et al.

    Change in the number of GABAa receptor positive GnRH neurons in immature and mature male rats

    Jpn. J. Physiol.

    (2000)
  • S.R. Henderson et al.

    Effect of oestradiol-17β exposure on the spontaneous secretion of gonadotrophins in chronically gonadectomized rats

    J. Endocrinol.

    (1977)
  • A.E. Herbison et al.

    Effect on luteinizing hormone secretion of GABA receptor modulation in the medial preoptic area at the time of proestrous luteinizing hormone surge

    Neuroendocrinology

    (1991)
  • T.L. Horvath et al.

    Luteinizing hormone-releasing hormone and gamma-aminobutyric acid neurons in the medial preoptic area are synaptic targets of dopamine axons originating in anterior periventricular areas

    J. Neuroendocrinol.

    (1993)
  • H. Jarry et al.

    Amino acid neurotransmitter release in the preoptic area of rats during the positive feedback actions of estradiol on LH release

    Neuroendocrinology

    (1992)
  • Cited by (0)

    View full text