Modulation of Pulsatile LH Secretion by Baclofen, a Selective GABA&lt;sub&gt;B&lt;/sub&gt; Receptor Agonist, in Ovariectomized Rats

Akema, Tatsuo; Kimura, Fukuko

doi:10.1159/000126221

Cited by 24 publications

(15 citation statements)

References 11 publications

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“…This effect of GABA was reversed by GABA A and GABA B antagonists in females, suggesting the participation of both kinds of receptors [27]. The early increase in LH in OVX knockout females corroborates the participation of GABA B Rs in this response in the mouse and demonstrates that in the absence of estradiol GABA B Rs are active in the control of LH secretion in the OVX wild-type female, as was suggested previously [15] in the rat. A further effect in the initial suppression of LH increase in females is probably exerted through GABA A Rs, since in female GABA B1 –/– mice LH did not increase as early as in males, although other factors may also be playing a role.…”

Section: Discussionsupporting

confidence: 76%

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GABAB1 Knockout Mice Reveal Alterations in Prolactin Levels, Gonadotropic Axis, and Reproductive Function

et al. 2005

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γ-Aminobutyric acid (GABA) has been implicated in the control of hypophyseal functions. We evaluated whether the constitutive loss of functional GABA_B receptors in GABA_B1 knockout (GABA_B1^–/–) mice alters hormonal levels, under basal and stimulated conditions, and reproductive function. The serum hormone levels were measured by radioimmunoassay, the estrous cyclicity was evaluated by vaginal lavages, and the mating behavior was determined by the presence of vaginal plugs. A moderate hyperprolactinemic condition was observed, in which prolactin increase and thyroid-stimulating hormone decrease were similar between genotypes. Basal luteinizing hormone (LH), follicle-stimulating hormone, thyroid-stimulating hormone, and growth hormone levels were similar between genotypes in each sex. Analysis of the gonadotropin axis revealed no differences in puberty onset between female genotypes. In con trast, the estrous cyclicity was significantly disrupted in GABA_B1^–/– female mice, showing significantly extended periods in estrus and shortened periods in proestrus. Reproduction was significantly compromised in GABA_B1^–/– females, with a significantly lower proportion of mice (37.5%) getting pregnant during the first 30 days of mating as compared with wild-type controls (87.5%). Moreover, only 14% of vaginal plug positive GABA_B1^–/– females had successful pregnancies as compared with 75% in the controls. In addition, the postovariectomy LH rise was significantly advanced in GABA_B1^–/– mice, while the response to estradiol feedback was similar in both genotypes. In conclusion, our endocrine analysis of GABA_B1^–/– mice reveals that GABA_B receptors are involved in the regulation of basal prolactin titers. Moreover, the hypothalamic-hypophyseal-ovarian axis is seriously disturbed, with alterations in cyclicity, postcastration LH increase, and fertility indexes. The molecular mechanism underlying these hormonal disturbances remains to be addressed.

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Section: Discussionsupporting

confidence: 76%

“…The latter were originally described by Bowery et al [5] over two decades ago. We and others demonstrated the participation of GABA B Rs in the regulation of prolactin (PRL) and gonadotropin secretion in developing and adult rats [6,7,8,9,10,11,12,13,14,15]. The presence of GABA B Rs in somatotropes has also been described [4].…”

Section: Introductionmentioning

confidence: 99%

GABAB1 Knockout Mice Reveal Alterations in Prolactin Levels, Gonadotropic Axis, and Reproductive Function

et al. 2005

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“…Administration of baclofen (GABA B R agonist; Table 3) to OVX female rats led to a very complex response of the pulsatile properties of LH release, and the extent of these outcomes were dose dependent (Akema and Kimura, 1992). To summarize, the authors found a temporary ablation of LH pulses, followed by an increase in pulse amplitude and inter-pulse interval.…”

Section: Gamma-aminobutyric Acid (Gaba) and The Hpg Axismentioning

confidence: 99%

“…To summarize, the authors found a temporary ablation of LH pulses, followed by an increase in pulse amplitude and inter-pulse interval. Biphasic and triphasic fluctuations in mean LH release were also seen (Akema and Kimura, 1992). …”

Section: Gamma-aminobutyric Acid (Gaba) and The Hpg Axismentioning

confidence: 99%

Chapter 2 Hypothalamic Neural Systems Controlling the Female Reproductive Life Cycle

Maffucci

Gore

2009

International Review of Cell and Molecular Biology

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The hypothalamic-pituitary-gonadal (HPG) axis undergoes a number of changes throughout the reproductive life cycle that are responsible for the development, puberty, adulthood, and senescence of reproductive systems. This natural progression is dictated by the neural network controlling the hypothalamus including the cells that synthesize and release gonadotropin-releasing hormone (GnRH) and their regulatory neurotransmitters. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters in the central nervous system, and as such contribute a great deal to modulating this axis throughout the lifetime via their actions on receptors in the hypothalamus, both directly on GnRH neurons as well as indirectly though other hypothalamic neural networks. Interactions among GnRH neurons, glutamate, and GABA, including the regulation of GnRH gene and protein expression, hormone release, and modulation by estrogen, are critical to age-appropriate changes in reproductive function. Here, we present evidence for the modulation of GnRH neurosecretory cells by the balance of glutamate and GABA in the hypothalamus, and the functional consequences of these interactions on reproductive physiology across the life cycle.

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“…Despite this, knockdown of GABA A Rs in GnRH neurons has minimal effects on fertility [11]. Regarding GABA B Rs, an inhibitory effect on GnRH and LH release has been demonstrated [12–15]. However, much less is known about the regulation of Gnrh1 expression by GABA B R, especially in development.…”

Section: Introductionmentioning

confidence: 99%

Lack of Functional GABAB Receptors Alters Kiss1, Gnrh1 and Gad1 mRNA Expression in the Medial Basal Hypothalamus at Postnatal Day 4

Giorgio

Catalano²,

López³

et al. 2013

Neuroendocrinology

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Background/Aims: Adult mice lacking functional GABA_B receptors (GABA_B1KO) show altered Gnrh1 and Gad1 expressions in the preoptic area-anterior hypothalamus (POA-AH) and females display disruption of cyclicity and fertility. Here we addressed whether sexual differentiation of the brain and the proper wiring of the GnRH and kisspeptin systems were already disturbed in postnatal day 4 (PND4) GABA_B1KO mice. Methods: PND4 wild-type (WT) and GABA_B1KO mice of both sexes were sacrificed; tissues were collected to determine mRNA expression (qPCR), amino acids (HPLC), and hormones (RIA and/or IHC). Results: GnRH neuron number (IHC) did not differ among groups in olfactory bulbs or OVLT-POA. Gnrh1 mRNA (qPCR) in POA-AH was similar among groups. Gnrh1 mRNA in medial basal hypothalamus (MBH) was similar in WTs but was increased in GABA_B1KO females compared to GABA_B1KO males. Hypothalamic GnRH (RIA) was sexually different in WTs (males > females), but this sex difference was lost in GABA_B1KOs; the same pattern was observed when analyzing only the MBH, but not in the POA-AH. Arcuate nucleus Kiss1 mRNA (micropunch-qPCR) was higher in WT females than in WT males and GABA_B1KO females. Gad1 mRNA in MBH was increased in GABA_B1KO females compared to GABA_B1KO males. Serum LH and gonadal estradiol content were also increased in GABA_B1KOs. Conclusion: We demonstrate that GABA_BRs participate in the sexual differentiation of the ARC/MBH, because sex differences in several reproductive genes, such as Gad1, Kiss1 and Gnrh1, are critically disturbed in GABA_B1KO mice at PND4, probably altering the organization and development of neural circuits governing the reproductive axis.

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Modulation of Pulsatile LH Secretion by Baclofen, a Selective GABA<sub>B</sub> Receptor Agonist, in Ovariectomized Rats

Cited by 24 publications

References 11 publications

GABA<sub>B1</sub> Knockout Mice Reveal Alterations in Prolactin Levels, Gonadotropic Axis, and Reproductive Function

GABA<sub>B1</sub> Knockout Mice Reveal Alterations in Prolactin Levels, Gonadotropic Axis, and Reproductive Function

Chapter 2 Hypothalamic Neural Systems Controlling the Female Reproductive Life Cycle

Lack of Functional GABA<sub>B</sub> Receptors Alters <b><i>Kiss1</i></b>, <b><i>Gnrh1 </i></b>and <b><i>Gad1</i></b> mRNA Expression in the Medial Basal Hypothalamus at Postnatal Day 4

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