Elsevier

Neuropharmacology

Volume 52, Issue 7, June 2007, Pages 1439-1453
Neuropharmacology

Mini-review
Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

https://doi.org/10.1016/j.neuropharm.2007.01.022Get rights and content

Abstract

The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through non-genomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

Introduction

Compounds classified as neurosteroids or neuroactive steroids encompass both natural and synthetic derivatives of the gonadal steroids, progesterone and testosterone, and the adrenal steroid, deoxycorticosterone. Naturally occurring neurosteroids are synthesized from cholesterol in both peripheral organs and in the central nervous system (CNS), primarily by glial cells, and can be classified as positive (enhancing) or negative (blocking) allosteric modulators of the GABAA receptor (for review, Baulieu, 1998; Compagnone and Mellon, 2002; Belelli and Lambert, 2005). Synthetic steroids, including anesthetics such as alphaxalone and ganaxolone (for review, Belelli and Lambert, 2005) and the anabolic androgenic steroids (AAS) (for review, Clark et al., 2004, Clark et al., 2006) also act as allosteric modulators of the GABAA receptor. Reproductive biologists have demonstrated an indisputable role for nuclear hormone receptor-mediated steroid signaling in governing reproductive processes (for review, Course and Korach, 1998) and neuroendocrinologists have firmly established that allosteric modulation γ-aminobutyric acid type A (GABAA) receptors has a critical role in mediating aggression, stress and anxiety; behaviors that are known to vary with hormonal state (for review, Finn et al., 2004, Henderson and Jorge, 2004, Smith, 2004). Less is known about the intersection of allosteric modulation of GABAA receptors and reproductive control, and the purpose of this review is to highlight the literature to date indicating that this mechanism of steroid action is important in neural regulation of reproduction.

Section snippets

Mechanisms of steroid modulation of GABAA receptors

Neurosteroids can be metabolized in the CNS from plasma-derived steroids or directly synthesized in the brain (for review, Baulieu, 1998, Compagnone and Mellon, 2000). A-ring reduced neurosteroids, such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one), THDOC (5α-pregnane-3α,21-diol-20-one) and 3α-diol (5α-androstane-3α,17β-diol) are positive allosteric modulators of the GABAA receptor that augment channel burst durations by increasing the opening frequency (and therefore the relative

Subunit expression in the hypothalamus/basal forebrain

The native GABAA receptor is a pentameric ionotropic transmembrane protein for which sixteen different receptor subunit genes (α1–α6, β1–β3, γ1–γ3, δ, ɛ, π, and θ) have been identified in mammals (for review, Henderson and Jorge, 2004). Subunit composition is regulated with age and development, in a region-specific manner and in response to exposure to both exogenous and endogenous substances. Subunit composition, in turn, determines not only basic biophysical properties of the receptor, but

Neurosteroid and anabolic androgenic steroid levels in the CNS

Concentrations of neurosteroids in the brain have been shown to vary significantly during different developmental epochs, between the sexes, among different brain regions, as a function of hormonal state, and during acute stress (for review, Henderson and Jorge, 2004). For example, concentrations of both pregnenolone sulfate and DHEAS have been detected in human brain tissues at concentrations that are several fold higher than in plasma and are present at different levels in women than in men (

Forebrain and hypothalamic regions regulating the expression of reproductive behaviors

The neural substrates of the hypothalamus/basal forebrain required for the expression of sexual behaviors in rodents have been well documented by lesion studies, anatomical tracer studies, and assessments of c-fos expression associated with hormone treatment and mating behaviors (for review, Meisel and Sachs, 1994, Pfaff et al., 1994, Paredes and Baum, 1997, Blaustein and Erskine, 2002, Hull et al., 2002). For females, activity within the VMN and the midbrain central grey (MCG) facilitates the

Steroid modulation of GABAergic transmission in hypothalamus/basal forebrain

Although neurosteroid modulation of GABAA receptor-mediated responses was first noted in the early 1980s (for review, Lambert et al., 2003), steroid modulation of neurons in neuroendocrine control regions has been assessed only during the past decade. Initial studies concentrated on modulation of GABAA receptor-mediated responses in dissociated embryonic hypothalamic neurons, while more recent reports have examined effects of steroid modulators in defined regions/nuclei of acutely isolated

Steroid modulation of reproductive behaviors

The effects of intrahypothalamic injection/implantation of a number of A-ring reduced progesterone derivatives into estrogen-primed female rats on female sexual behavior was first examined by Beyer and colleagues Rodriguez-Manzo et al., 1986, Beyer et al., 1989). Crystallized 5β,3β-pregnanolone was found to induce intense lordosis when implanted into the mPOA, a result the authors attribute to a depression of mPOA neuronal firing (Rodriguez-Manzo et al., 1986). A later study examining the

Future directions

Nearly all studies to date have focused on the effects of allosteric modulators on synaptic responses in the hypothalamus and the potential consequences of allosteric modulation of these responses may have for neuroendocrine control. Of unexplored, but potentially high significance in understanding modulation of GABAergic tone in the hypothalamus is the impact steroid modulators may have on tonic currents mediated by low concentrations of ambient GABA through high affinity extrasynaptic

Acknowledgements

This work was supported by the NIH (DA/NS14137 and DA18255). I thank Drs. Ann S. Clark, Carlos Penatti and Beth Costine for their review of the manuscript.

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