Withdrawal properties of a neuroactive steroid: implications for GABAA receptor gene regulation in the brain and anxiety behavior
Introduction
Classic actions of steroid hormones involve binding of the steroid molecule to a cytosolic receptor protein, with ensuing genomic effects which typically require a latency of hours to days [1]. However, more recent data has suggested the existence of neuroactive steroids which are defined as hormones which produce rapid actions on neuronal substrates within the central nervous system (CNS) [2]. They include classes of hormones which act as modulators of traditional neurotransmitter receptor molecules to either enhance or depress neuronal activity [3]. In many cases, such hormones are produced by endocrine sources across naturally occurring hormonal rhythms, i.e. the menstrual or circadian cycles [4], or in response to stress or olfactory cues [5], [6]. As steroids are naturally lipophilic molecules which are bound to carrier proteins in the circulation, in most cases, they easily pass the blood-brain barrier where they gain access to neuronal and glial populations. In other cases, neurosteroids are metabolized in the brain from precursor ‘parent’ compounds originating from endocrine sources, such as progesterone (P) [7]. Finally, more recently has come the discovery of ‘neurosteroids,’ which are formed de novo within the CNS from cholesterol via side chain cleavage enzyme [2], [8].
Section snippets
3α,5α-THP
One such neurosteroid is 3α,5α-THP (3α-OH-5α-pregnan-20-one, 3α-OH-DHP or ‘allopregnanolone,’ Fig. 1). Produced from circulating progesterone via two enzymatic conversions (5α reductase and 3α-hydroxy oxidoreductase, Fig. 2), this steroid can be converted both in the periphery as well as within the CNS [7] where levels parallel those of progesterone. 5α- and 5β-reductase enzyme activities are localized to both neurons as well as glia in the CNS [7]. 3α- and 3β-hydroxy additions also occur
GABAR pharmacology
The GABAR is a pentameric receptor protein associated with a chloride ion channel (Fig. 3), and mediates the action of GABA, the primary inhibitory neurotransmitter in the brain [20]. The subunits comprising the receptor come from a pool of as many as 6α, 4β, 4γ, δ, ϵ, π, 3ρ and θ subunits, which yield a multitude of receptor isoforms [20]. The most common isoform is 2α, 2β and 1γ, although other stoichiometries exist [21]. The particular combination of subunits would yield receptors with
Synaptic currents
GABAR in areas of the brain such as the hippocampus, part of the limbic circuitry important for emotional expression, and the cerebellum, an important center for control of motor coordination, have been well-characterized in terms of their specific subcellular localization with regard to synaptic input. Many GABAR subunit subtypes, including the α2 and γ2, are believed to be localized exclusively to the synapse [27]. Others, such as the δ and α5, are believed to reside exclusively in the
Behavioral properties
These positive GABA-modulatory effects of 3α,5α-THP, as described above, are similar to those reported for benzodiazepine tranquilizers and sedatives. Correspondingly, the behavioral properties of this steroid are also similar to those exhibited by benzodiazepine tranquilizers and sedatives, in that administration of 3α,5α-THP can reduce anxiety [7], [39], reduce seizure activity [40], [41], [42], [43], produce sedation [44], and at high doses can act as a general anesthetic [45]. One
Long-term exposure to steroids and withdrawal effects
Progesterone and its metabolites are elevated for 11–12 days during the luteal phase of the menstrual cycle [48] and for nine months during pregnancy before declining precipitously during the premenstrual [50] and postpartum periods, further justifying investigation of longer term hormone exposure and withdrawal effects on GABAR function. Initial studies from the present laboratory established that withdrawal from neuroactive steroids (Fig. 4), such as 3α,5α-THP or 3α,5β-THP, following chronic
Chronic neurosteroid exposure
A number of studies have suggested that chronic exposure to neuroactive steroids, such as 3α,5α-THP result in altered GABAR pharmacology, which in some cases was associated with subunit changes. These changes are comparable to what has been reported for other GABA-modulatory drugs such as the BDZs and ethanol [20]. In early studies, micromolar concentrations of 3α,5α-THP were shown to decrease GABA current recorded from neocortical neurons in culture after 5 days exposure [67]. In addition,
Conclusion
Global activation of circuits in the brain by GABA-modulatory steroids such as 3α,5α-THP would be expected to decrease neuronal activity leading to reduced anxiety, suppression of seizure activity, anticonvulsant, sedative and, at high doses, anesthetic effects. However, chronic exposure to and withdrawal from these steroids could then produce ensuing changes in GABAR isoform through upregulation of gene transcription of the α4 subunit. These changes would yield altered sensitivity to
Acknowledgments
The authors are grateful for the helpful assistance provided by Dr. Maria Gulinello, Dr. Fu Chun Hsu, Qi Hua Gong, Xinshe Li, and Ronald Markowitz. This work was supported by NIH grants R01 AA 12958 and R01 DA 09618, as well as a pharmaceutical contract from Merck.
References (74)
Neurosteroidsa novel function of the brain
Psychoneuroendocrinology
(1998)Female sex steroidsfrom receptors to networks to performance - actions on the sensorimotor system
Prog Neurobiol
(1994)- et al.
Neurosteroidsbiosynthesis and function of these novel neuromodulators
Frontiers in Neuroendocrinol
(2000) - et al.
Locally applied progesterone metabolites alter neuronal responsiveness in the cerebellum
Brain Res Bull
(1987) - et al.
GABA-dependent modulation of the Cl− ionophore by steroids in rat brain
Eur J Pharmacol
(1987) - et al.
Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells
J Biol Chem
(1990) - et al.
Long-term plasticity of postsynaptic GABAA-receptor function in the adult braininsights from the oxytocin neurone
Trends Neurosci
(2000) - et al.
Plasticity in fast synaptic inhibition of adult oxytocin neurons by switch in GABA(A) receptor subunit expression
Neuron
(1997) - et al.
The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat
Behav Brain Res
(1999) - et al.
Anxiolytic effects of the neuroactive steroid pregnanolone (3α-OH-5β-pregnan-20-one) after microinjection in the dorsal hippocampus and lateal septum
Brain Res
(1999)
Anticonvulsant profile of the progesterone metabolite 5 α-pregnan-3 α-ol-20-one
Eur J Pharmacol
Anti-seizure effects of progesterone and 3alpha,5alpha acid and perforant pathway models of epilepsy
Psychoneuroendocrinology
Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice
Neuropharmacology
Progesterone metabolite allopregnanolone in women with premenstrual syndrome
Obstet Gynecol
Progesterone withdrawal decreases latency to and increases duration of electrified prod buriala possible rat model of PMS anxiety
Pharmacol Biochem Behav
Progesterone withdrawal IIpro-convulsant effects
Brain Res
Cyclic withdrawal from endogenous and exogenous progesterone increases kainic acid and perforant pathway induced seizures
Pharmacol Biochem Behav
Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor a4 subunit
FEBS Lett
Physiological modulation of GABA(A) receptor plasticity by progesterone metabolites
Eur J Pharmacol
Chronic treatment with diazepam or abecarnil differently affects the expression of GABAA receptor subunit mRNAs in the rat cortex
Neuropharmacology
Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on α-subunit isoform
Biophys J
Chronic neurosteroid treatment attenuates single cell GABAA response and its potentiation by modulators in cortical neurons
Brain Res
Down-regulation of the GABA receptor subunit mRNA levels in mammalian cultured cortical neurons following chronic neurosteroid treatment
Brain Res Mol Brain Res
Gamma-aminobutyric acidA receptor regulationheterologous uncoupling of modulatory site interactions induced by chronic steroid, barbiturate, benzodiazepine, or GABA treatment in culture
Brain Res
Specific subunit mRNAs of the GABAA receptor are regulated by progesterone in subfields of the hippocampus
Brain Res Mol Brain Res
Short-term exposure to a neuroactive steroid increases a4 GABAA receptor subunit levels in association with increased anxiety
Brain Res
Introduction
Neurosteroids3a-OH-5a-pregnan-20-one and its precursors in the brain plasma and steroidogenic glands of male and female rats
Endocrinology
The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations
Br J Pharmacol
Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat
PNAS
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids
PNAS
Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor
Science
Neurosteroid regulation of GABAA receptor-single channel kinetic properties of mouse spinal cord neurons in culture
J Physiol
Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids
Br J Pharmacol
Diazepam and (-)-pentobarbitalfluctuation analysis reveals different mechanisms for potentiation of GABA responses in cultured central neurons
PNAS
Activation of peripheral mitochondrial benzodizepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat
Psychopharmacology
Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol
J Neurosci
Cited by (87)
Can animal models resemble a premenstrual dysphoric condition?
2022, Frontiers in NeuroendocrinologyNeurosteroids
2020, Hormonal Signaling in Biology and Medicine: Comprehensive Modern EndocrinologyAllopregnanolone-based treatments for postpartum depression: Why/how do they work?
2019, Neurobiology of StressCitation Excerpt :GABAARs incorporating the α4 subunit, which is known to partner with the δ subunit, has also been shown to be regulated by steroid hormones and neurosteroids (for review see (Smith et al., 2007)). These receptors have been shown to be altered during puberty (Shen et al., 2007) and in hormone withdrawal models (Smith et al., 1998, 2006, 2007; Smith, 2002). Alterations in GABAARs in hormone withdrawal models has particular potential relevance to postpartum depression.
Neurosteroids: Biosynthesis, Molecular Mechanisms, and Neurophysiological Functions in the Human Brain
2019, Hormonal Signaling in Biology and Medicine: Comprehensive Modern EndocrinologyNeuroendocrine pathways underlying risk and resilience to PTSD in women
2019, Frontiers in NeuroendocrinologyCitation Excerpt :These studies indicate that P4’s ability to modulate fear extinction recall in E2-treated OVX rodents is biphasic and dependent on the time interval between P4 replacement and fear extinction training (Graham and Daher, 2016). This notion that timing from maximal P4 concentrations is important for its influence on affective symptoms is further highlighted by data in women showing that withdrawal from high levels of P4/allopregnanolone during the menstrual cycle and in the postpartum period are associated with increased depressive symptoms (Smith, 2002). Although concentrations of allopregnanolone also fluctuate with those of P4 across the menstrual and estrus cycles, much less research has directly manipulated allopregnanolone levels in preclinical models to assess the neuroactive steroid’s influence on fear responses.
Effects of neonatal and adolescent neuroactive steroid manipulation on locomotor activity induced by ethanol in male wistar rats
2017, Behavioural Brain Research