Date post: | 04-Jun-2018 |
Category: |
Documents |
Upload: | florin-daniel |
View: | 220 times |
Download: | 0 times |
of 19
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
1/19
Neuroactive steroid regulation of neurotransmitter release in the CNS:
Action, mechanism and possible significance
Ping Zheng *
State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032,
Peoples Republic of China
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2. Regulation of neurotransmitter release by neuroactive steroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.1. Pregnenolone and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.2. Pregnenolone sulfate and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
2.2.1. PREGS and glutamate release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
2.2.2. PREGS and GABA release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.2.3. PREGS and acetylcholine release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.2.4. PREGS and norepinephrine release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2.2.5. PREGS and dopamine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2.3. Progesterone and neurotransmitter release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2.3.1. PROG and glutamate release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2.3.2. PROG and norepinephrine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2.3.3. PROG and dopamine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2.3.4. PROG and serotonin release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.4. Allopregnanolone and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.4.1. ALLO and glutamate release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.4.2. ALLO and GABA release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Progress in Neurobiology 89 (2009) 134152
A R T I C L E I N F O
Article history:
Received 29 August 2008Received in revised form 11 March 2009
Accepted 2 July 2009
Keywords:
Neuroactive steroid
Neurotransmitter release
Synaptic transmission
A B S T R A C T
Neuroactive steroids refer to steroids that are capable of regulating neuronal activities. Neuroactive
steroids, synthesized either de novo in the nervous tissue or in the peripheral endocrine glands or as
synthetic steroids, have exhibited numerous important modulatory effects on brain functions and brain
diseases. At thecellular level, in additionto theeffect on postsynaptic receptors, mostneuroactivesteroids,
including pregnenolone, pregnenolone sulfate, progesterone, allopregnanolone, dehydroepiandrosterone,
dehydroepiandrosterone sulfate, testosterone and estradiol, have modulatory effects on the release of
multiple neurotransmitters like glutamate, GABA, acetylcholine, norepinephrine, dopamine and 5-HT.
Many of these effects occur in the brain regions involved in learning and memory, emotion, motivation,
motor andcognition.Moreover, theeffectsare rather complicated,maybedependingon many factors such
as types of neuroactive steroids, brain regions and presynaptic functional states. The mechanisms are also
complicated. Many of them involve rapid non-genomic effects on presynaptic receptors and ion channels
like sigma-1 receptor,a1 receptor, nicotine receptor, D1 receptor, NMDA receptor, GABAA receptor and L-type Ca2+ channels. These effects have made neuroactive steroids important regulators of synaptic
transmission in the central nervous system and constitute the major basis for many important actions of
neuroactive steroids on brain functions and brain diseases.
2009 Elsevier Ltd. All rights reserved.
Abbreviations: CNS, central nervous system; HPLC, high-performance liquid chromatography; PPF, paired pulse facilitation; PREG, pregnenolone; P450scc, cholesterol side-
chain cleavage enzyme; PKC, protein kinase C; PREGS, pregnenolone sulfate; mEPSCs, miniature excitatory postsynaptic currents; ACh, acetylcholine; NBM, nucleus basalis
magnocellularis; NE, norepinephrine; DA, dopamine; PROG, progesterone; 3b-HSD, 3b-hydroxysteroid dehydrogenase; ALLO, allopregnanolone; DHEA, dehydroepian-
drosterone; P450c17, P450 17ahydroxylase; P450aro, aromatase; AD, Alzheimers disease.
* Tel.: +86 21 54237437; fax: +86 21 64174579.
E-mail address: [email protected].
Contents lists available at ScienceDirect
Progress in Neurobiology
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / p n e u r o b i o
0301-0082/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2009.07.001
mailto:[email protected]://www.sciencedirect.com/science/journal/03010082http://dx.doi.org/10.1016/j.pneurobio.2009.07.001http://dx.doi.org/10.1016/j.pneurobio.2009.07.001http://www.sciencedirect.com/science/journal/03010082mailto:[email protected]8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
2/19
2.4.3. ALLO and acetylcholine release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.4.4. ALLO and norepinephrine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.4.5. ALLO and dopamine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.5. Dehydroepiandrosterone and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.6. Dehydroepiandrosterone sulfate and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.6.1. DHEAS and glutamate release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2.6.2. DHEAS and acetylcholine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2.6.3. DHEAS and norepinephrine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2.7. Testosterone and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2.8. Estradiol and neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1462.8.1. Estradiol and glutamate release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
2.8.2. Estradiol and GABA release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
2.8.3. Estradiol and acetylcholine release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.8.4. Estradiol and norepinephrine release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.8.5. Estradiol and dopamine release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
3. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
1. Introduction
Neuroactive steroids refer to steroids that are capable of
regulating neuronal activities. Based on the source or productionsite, neuroactive steroids can be classified into two categories:
exogenous steroids (synthetic steroids) and endogenous ster-
oids. The latter is subdivided into hormonal steroid (steroids
produced by endocrine glands) and neurosteroid (steroids
produced by the nervous tissue (Melcangi et al., 2008)(Fig. 1).
The hormonal steroid mainly includes the ovary-produced
steroids (estradiol and progesterone), the testis-produced
steroid (testosterone) and the adrenal-produced steroids (glu-
cocorticoid and dehydroepiandrosterone) (Rhodes et al., 2004;
Scharfman and MacLusky, 2006), whereas the neurosteroid,
synthesized in neuronal and glial cells, mainly has pregnenolone,
dehydroepiandrosterone, progesterone, allopregnanolone and
their sulfate esters, such as pregnenolone sulfate and dehy-
droepiandrosterone sulfate (Baulieu, 1998). In addition, anumber of synthetic neuroactive steroids, such as alphaxalone
and steroid-3a-hydroxy-5b-pregnan-20-one hemisuccinate,have been developed recently, which share their endogenous
counterparts characteristic of modulating neuronal activities
(Melcangi et al., 2008).
Neuroactive steroids, synthesized either de novo in the nervous
tissue or in the peripheral endocrine glands or as syntheticsteroids, have exhibited numerous important modulatory effects
on brain functions andbrain diseases (Melcangi et al., 2008). Under
physiological conditions, neuroactive steroids can affect a broad
spectrum of behavioral functions, such as sexual and feeding
behavior, responses to stress, emotion, memory and cognition
(Melcangi and Mensah-Nyagan, 2008; Frye, 2001; Serra et al.,
2000; Darnaudery et al., 2002; Johansson et al., 2002; Vallee et al.,
1997). Under pathophysiological conditions, they also play
important roles in the pathology and treatment of neurological
and psychiatric disorders like epilepsy, premenstrual syndrome,
schizophrenia, depression, anxiety, multiple sclerosis and other
neurodegenerative diseases (Marx et al., 2006; Pisu and Serra,
2004; MacKenzie et al., 2007; Morrow, 2007; Backstrom et al.,
1983; Landgren et al., 1987).At the molecular level, neuroactive steroids can bind to
intracellular receptors that act as transcription factors and regulate
gene expression. Neuroactive steroids can also act at an array of
Fig. 1.Categories of neuroactive steroids.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152 135
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
3/19
neurotransmitter receptors and voltage-dependent ion channels,
especially GABAA, NMDA, AMPA, kainate, glycine, serotonin,
sigma-1, nicotinic and muscarinic acetylcholine receptors (Rup-
precht et al., 2001; Strous et al., 2006; Dubrovsky, 2006 ) as well as
T-type Ca2+ channel, high-voltage activated Ca2+ channel, Na+
channel, Ca2+-activated K+ channel and anion channels (Joksovic
et al., 2007; Pathirathna et al., 2005; Todorovic et al., 2004; rbandi-
Tonkabon et al., 2004; Nakashima et al., 1999, 1998; ffrench-
Mullen et al., 1994; Ffrench-Mullen and Spence, 1991; Cheng et al.,
2008; Carrer et al., 2003; Kelly et al., 2002).
At the cellular level, studies show that neuroactive steroids can
modulate neuronal excitability (Fatehi and Fatehi-Hassanabad,
2008; Grassi et al., 2007; Benarroch, 2007; Smith and Woolley,
2004; Inghilleri et al., 2004; Smith et al., 2002; Joels, 1997; Teyler
et al., 1980), although it remains to be investigated. In addition,
neuroactive steroids can modulate almost all kinds of classical
synaptic transmission, including glutamatergic, GABAergic, cho-
linergic, noradrenergic, dopaminergic and serotonergic synaptic
transmission, by altering the responsiveness of postsynaptic
receptors or the presynaptic release of neurotransmitter (Abdrach-
manova et al., 2001; Shen et al., 2000; Belelli et al., 2006; Gibbs
et al., 2006; Mitsushima et al., 2008, 2003; Darnaudery et al., 2000,
1998; Gilad et al., 1987; Perez-Neri et al., 2008; Laconi et al., 2007;
Peris et al., 1991; Kimet al., 2003, 2002; Belmaret al., 1998; Farmeret al., 1996; Young et al., 1994; Hyatt and Tyce, 1984 ). Meanwhile,
neuroactive steroids also have a modulatory effect on synaptic
plasticity at glutamatergic and GABAergic synapses (Wang et al.,
2008; Sabeti et al., 2007; Sliwinski et al., 2004; Chen et al., 2007;
Smith and McMahon, 2005; Hsu et al., 2003; McEwen, 1994;
Pavlides et al., 1993). These effects have made neuroactive steroids
important regulators of synaptic transmission in the central
nervous system (CNS) and constitute the major basis for many
important actions of neuroactive steroids on brain functions and
brain diseases. Especially, the effect of neuroactive steroids on
neurotransmitter release has received a great deal of attention
because neurotransmitter release is the first step in synaptic
transmission and is very important to insure effective synaptic
transmission. Moreover, it appears, based on the literature, thatthis effect is rathercomplicated, maybe depending on many factors
such as types of neuroactive steroids, brain regions and functional
states. However, previous review articles involve only a part of
reports about the effect of neuroactive steroids on neurotrans-
mitterrelease,although a numberof reviews have summarized the
synthesis, action, mechanism and function of neuroactive steroids
(Melcangi et al., 2008; Akk et al., 2007; Gibbs et al., 2006; Strous
et al., 2006; Dubrovsky, 2005; Rupprecht, 2003; Stoffel-Wagner,
2003; Mitchell et al., 2008; Lambert et al., 2003; Valenzuela et al.,
2008).
In this review, we shall summarize the reports on the action of
neuroactive steroids (mainly pregnenolone sulfate, progesterone,
allopregnanolone, dehydroepiandrosterone sulfate, estradiol and
testosterone) on the release of classical neurotransmitters (mainlyglutamate, GABA, acetylcholine, norepinephrine, dopamine and
serotonin) and illustrate the complexity of this effect, which may
depend on many factors, such as types of neuroactive steroids,
brain regions and presynaptic functional states. We also detail the
already studied mechanism by which neuroactive steroids
modulate neurotransmitter release. Finally, we discuss the
possible significance for these effects.
2. Regulation of neurotransmitter release by neuroactive
steroids
Themethods used in literature to study theeffect of neuroactive
steroids on neurotransmitter release involved both in vivo and in
vitro techniques. The most frequently applied in vivo technique
was microdialysis combined with high-performance liquid chro-
matography (HPLC), which allowed continuous sampling of
neurotransmitter release in awake, freely moving or in anesthe-
tized animals. The in vitro technique mainly included radioactively
labeled and electrophysiological techniques. When using the
radioactively labeled technique, CNS preparations were first
preincubated with the labeled neurotransmitter to make the cells
uptake it and then the stimulation-evoked release of labeled
neurotransmitter from the superfused preparation was measured.
When using the electrophysiological technique, the frequency of
spontaneous postsynaptic currents and the ratio of the paired
pulse facilitation (PPF) are usually used as the index of presynaptic
neurotransmitter release. Among them, the interpretation of PPF is
somewhat complicated. The PPF experiment involves the activa-
tion of presynaptic excitatory input to the recorded cell with two
consecutive stimuli of identical intensity at a short interval
(usually 3050 ms). Under this condition the response to the
second stimulus is generally greater than that to the initial
stimulus (so called paired pulse facilitation). PPF is proposed to
result from a transient increase in the neurotransmitter release in
the second response, which is most likely due to the effect of
residual Ca2+ in the presynaptic terminal after the initial response
(Katz and Miledi, 1968; Zuckerand Regehr, 2002). Therefore, PPF is
a phenomenon reflecting presynaptic function. Moreover, thesituation leading to thechangein PPF after a treatment can be used
to judge whether the modulation is stimulatory or inhibitory on
neurotransmitter release and whether the treatment has an action
on basal neurotransmitter release. The criteria are (1) if a
treatment increases both the first and second response, but the
increase percentage in the first response is larger than that in the
second one, this will lead toa decrease in PPF and thus suggest that
the action of the treatment is stimulatory on neurotransmitter
release (Chen and Regehr, 1997; Neugebauer et al., 2003); (2) if a
treatment decreases both the first and second response, but the
decrease percentage in the first response is smaller than that in the
second one, this will lead to an increase in PPF and thus suggest
that the action of the treatment is inhibitory on neurotransmitter
release (Coelho et al., 2000; Dunwiddie and Haas, 1985; Sun et al.,2005); (3) if a treatment only has an increasing action on the
second response, but has no effect on the first one, this will lead to
an increase in PPF and thus suggest that the treatment has a
stimulatory effect on facilitated neurotransmitter release, but has
no effect on spontaneous release (Partridge and Valenzuela, 2001;
Thomas et al., 2005; Schiess and Partridge, 2005; Gottschalk et al.,
1998); (4) if a treatment changes (increases or decreases) both the
first andsecond response andthe changepercentage is similar, this
will not change PPF and thus suggest that the site of the action of
the treatment is at postsynaptic site rather than at presynaptic site
(Huang et al., 2001).
2.1. Pregnenolone and neurotransmitter release
Pregnenolone (PREG) is synthesized from cholesterol by the
cholesterol side-chain cleavage enzyme (P450scc) and then is
metabolized into different neuroactive steroids (Sierra, 2004). In
contrast to the abundance of reports on the regulation of
neurotransmitter release by a variety of metabolites of PREG,
few studies have investigated the effects of PREG on neurotrans-
mitter release.Nuwayhid and Werling (2003)reported that PREG
inhibited NMDA-stimulated [3H] DA release in the striatum. Both
the sigma-1 antagonist DuP734 and the sigma-2 antagonist Lu28-
179 could completely reverse this inhibition, suggesting that PREG
inhibited NMDA-stimulated [3H] DA release via sigma receptors
(Nuwayhid and Werling, 2003). In addition, the PKCb inhibitorLY379196 could also completely reverse this inhibition, suggesting
that the sigma receptor coupled-PKCb pathway was involved in
P. Zheng/ Progress in Neurobiology 89 (2009) 134152136
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
4/19
the effect of PREG (Nuwayhid and Werling, 2003). This finding
supports that PREG is one possible candidate for endogenous
ligand at sigma receptors. Interestingly, other studies showed that
PREG itself was ineffective, but its metabolites, pregnenolone
sulfate and allopregnanolone, could potentiate glutamate release
in the prelimbic cortical (Dong et al., 2005) and hippocampal slices
(Chen and Sokabe, 2005) and K+-induced [3H]-NE release from the
cortical slices (Belmar et al., 1998), respectively, suggesting that in
some instances, the conversion of PREG into its metabolites was
required to produce some effects.
2.2. Pregnenolone sulfate and neurotransmitter release
Pregnenolone sulfate (PREGS) is synthesized from PREG by the
enzyme sulfotransferase and is one of the most important
neurosteroids (Compagnone and Mellon, 2000). PREGS has
multiple important effects on brain functions such as cognitive
enhancing, promnesic, antistress and antidepressant effects. At the
cellular level, in addition to the effect on postsynaptic receptors,
PREGSalso has significant regulatory effects on the release of many
important neurotransmitters such as glutamate, GABA, ACh, NE
and DA (Fig. 2). Moreover, in most cases, the effect is stimulatory,
but the mechanism appears to be complicated.
2.2.1. PREGS and glutamate release
Glutamate is widely distributed through the CNS and as the
principal excitatory neurotransmitter plays an important role in a
number of CNS functions such as motor, emotion and cognition
(Meldrum, 2000; Javitt, 2004). The effect of PREGS on glutamate
release in the hippocampus, prefrontal cortex and striatum has
been examined. The results showed that PREGS had a complicated
effect on glutamate release, depending on developmental period,
brain region and functional state.
2.2.1.1. Hippocampus.
2.2.1.1.1. In immature neurons. In cultured hippocampal neurons
from neonatal rats and hippocampal slices from postnatal day 34
(P3P4) rats, the effect of PREGS on spontaneous glutamaterelease
was evaluated using the frequency of miniature excitatory
postsynaptic currents (mEPSCs) as the index of spontaneous
glutamate release. The result showed that PREGS dose-depen-
dently increased the frequency of mEPSCs (Meyer et al., 2002;
Mameli et al., 2005; Carta et al., 2003), suggesting that PREGS could
promote presynaptic spontaneous glutamate release in immature
neurons of the hippocampus. This statement was consistent with
the result of the PPF experiment, which showed that PREGS
increased both the first and second response, but the increase
percentage in the first response (due to an increase in spontaneous
glutamate release) was larger than that in the second one, thus
leading to a reduction in PPF (Mameli et al., 2005; Meyer et al.,
2002).
About the receptor mechanism of the effect of PREGS, it has
been proposed that it is through activation of sigma-1 receptors.
The evidence supporting this statement was that the sigma-1
receptor antagonists, haloperidol and BD-1063, could block the
PREGS-induced increase in mEPSC frequency and the sigma-1
receptor agonist pentazocine could mimick the effect of PREGS
(Meyer et al., 2002). The downstream mechanism of the activation
of sigma-1 receptorsby PREGS was thought to involve Gi/o proteins
and intracellular Ca2+ because the Gi/oprotein inhibitor pertussis
toxin and the Ca2+ chelator BAPTA could block the effect of PREGS
(Meyer et al., 2002). However, a lack of an involvement of sigma-1receptors in the mechanism of the PREGS-induced increase of
mEPSC frequency was also observed (Mameli et al., 2005). In
addition, the role of NMDA receptors in the effect of PREGS in
cultured hippocampus neurons and neonatal hippocampus slices
was completely different: NMDA receptors were not required for
the presynaptic actions of PREGS in cultured hippocampal neurons,
but they were required in neonatal slices (Meyer et al., 2002).
Significance: The effects of PREGS on spontaneous glutamate
release in immature hippocampus neurons may have an impact on
synaptic development in the hippocampus and may contribute to
the maturation and/or maintenance of hippocampus synapses
(Meyer et al., 2002) because studies have demonstrated that
spontaneous glutamate release is essential for the maintenance of
synaptic neuronal networks (Verhage et al., 2000).
Fig. 2. Effect of PREGS on neurotransmitter release. (+) promote release; (
) inhibit release; (*
) no effect.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152 137
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
5/19
2.2.1.1.2. In mature neurons. It was reported that the PREGS-
induced increase of spontaneous glutamate release in P3P4
neurons of the hippocampus was undetectable by P6 (Mameli
et al., 2005). This was consistent with the result that PREGS had no
effect on the first EPSC in PPF experiment of mature neurons
(Thomas et al., 2005; Partridge and Valenzuela, 2001; Schiess and
Partridge, 2005; Schiess et al., 2006; Thomas et al., 2005). These
results suggest that PREGS has no effect on spontaneous glutamate
release in mature neurons. However, some other studies showed
that PREGS could promote spontaneous glutamate release in
mature hippocampus (Chen and Sokabe, 2005; Dong et al., 2005).
In addition, in mature hippocampal neurons a number of studies
showed that PREGS could increase the amplitude of the second
EPSC, but had no effect on the first one (Thomas et al., 2005;
Partridge and Valenzuela, 2001; Schiess and Partridge, 2005;
Schiess et al., 2006; Thomas et al., 2005), suggesting that PREGS
could promote facilitated glutamate release in mature hippocam-
pal neurons. Interestingly, the concentration of PREGS that
promotes facilitated glutamate release was much lower than that
of promoting spontaneous glutamate release.
However, the effect of PREGS on spontaneous and facilitated
glutamate release in the mature hippocampus was through a
common receptor mechanism, namely, via activation of sigma-1
receptor (Dong et al., 2005; Schiess and Partridge, 2005). Inaddition, a mechanism that PREGS first sensitized presynaptic
a7nAChR and then activated L-type calcium channels to promotefacilitated glutamate release was also proposed (Chen and Sokabe,
2005).
Significance: PPF in the hippocampus is a form of short-term
synaptic plasticity and is thought to be a model for learning and
memory processes (Dobrunz and Stevens, 1999). Facilitated
glutamate release is the key step in PPF. Thus, the promoting
effect of PREGS on facilitated glutamate release in the mature
hippocampus may underlie the influence of PREGS on learning and
memory.
2.2.1.2. Prefrontal cortex.
2.2.1.2.1. Spontaneous glutamate release. In the prefrontal cortex,the results from our lab showed that PREGS dose-dependently
increased the frequency of mEPSCs (Dong et al., 2005), suggesting
that PREGS could promote spontaneous glutamate release in the
prefrontal cortex.
Further receptor mechanism study showed that the effect of
PREGS was only partially blocked by the sigma-1 antagonist
haloperidol and AC915 (Dong et al., 2005). This resultwas different
from that in the hippocampus, where these two sigma-1
antagonists could completely block the effect of PREGS (Dong
et al., 2005; Meyer et al., 2002), suggesting that in the prefrontal
cortex the receptor mechanism of the effect of PREGS on
spontaneous glutamate release was more complicated. We further
tested the role of dopaminergic D1 receptors and adrenergic a1receptors in the effect of PREGSin the prefrontal cortex. The results
showed that the D1 receptor antagonist SCH23390 had no
significant influence on the PREGS effect, but the a1 receptorantagonist prazosin could completely block the effect of PREGS
(Dong et al., 2005), suggesting that the activation ofa1receptorsplays a key role in the effect of PREGS in the prefrontal cortex.
Moreover, our further study suggests that the downstream signal
transduction pathways of the activation ofa1receptors by PREGSappears to involve two aspects, one may be mediated by the a1receptor signal transduction pathway and the other may be
mediated through synergizing the activation ofs1receptor signaltransduction pathway bya1receptors (Fig. 3)(Dong et al., 2005).Interestingly, although the effect of PREGS on spontaneous
glutamate release is similar in the prefrontal cortex and
hippocampus, the receptor mechanism activated by PREGS
appears to be different in these two brain regions (Fig. 3) (Dong
et al., 2005).
Significance: The prefrontal cortex is an important brain region
involved in cognitive function (Seamans et al., 1995). The
functional activity of the prefrontal cortex is dictated by many
factors. Among them, the spontaneous excitatory synaptic activityis a fundamental event in synaptic transmission and has an
important effect on the excitability of the postsynaptic cells (Lang,
2003; Jones and Woodhall, 2005). Therefore, the finding that
PREGS can significantly promote spontaneous glutamate release in
the prefrontal cortex provides experimental evidence for under-
standing the mechanism of the action of PREGS on cognitive
function.
2.2.1.2.2. Evoked glutamate release. The work from our lab showed
that PREGS at the concentration of 1 mM that had no effect onspontaneous glutamate release could inhibit electrical stimulus-,
dopamine- and 5-HT-evoked presynaptic glutamate release (Sun
et al., 2005), suggesting that at lower concentration, PREGS might
selectively inhibit evoked glutamate release.
To study the mechanism underlying the inhibitory effect ofPREGS on evoked glutamate release, we tested the role of Gi-
protein in the effect of PREGS. The result showed that the G i-
protein inhibitor NEM could abolish the effect of PREGS ( Sun et al.,
2005), suggesting that the activation of Gi-protein played an
important role in the effect of PREGS on evoked glutamate release.
However, how PREGS activates Gi-proteins remains to be studied.
Significance: Abnormally enhanced presynaptic glutamate
release in the prefrontal cortex has been reported to play an
importantrole in the pathophysiology of neuropsychiatric diseases
(Adams and Moghaddam, 1998; Moghaddam et al., 1997;
Fig. 3. The mechanism of the effect of PREGS on spontaneous glutamate release in the prefrontal cortex and hippocampus.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152138
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
6/19
Moghaddam and Adams, 1998). Thus, the inhibition of evoked
glutamate release in the prefrontal cortex by PREGS may have
significant functional consequence for some neuropsychiatric
diseases.
2.2.1.3. Striatum. In the striatum, we demonstrated that PREGS at
the concentration that could promote spontaneous glutamate
release in the hippocampus and prefrontal cortex had no effect on
the frequency of mEPSCs (Dong et al., 2005), suggesting that PREGS
had no effect on spontaneous glutamate release in the striatum.
2.2.2. PREGS and GABA release
GABA is themain inhibitory transmitter of thecentral nervous
system and plays an important role in brain functions by
maintaining the balance of excitation and inhibition (Miles,
2000; Otis et al., 1991). The effect of PREGS on presynaptic GABA
release was studied in the hippocampus. Teschemacher et al.
(1997)using the frequency of miniature inhibitory postsynaptic
currents (mIPSCs) in the presence of TTX (to block action
potential)as a index of action potential-independent spontaneous
GABA release, found that PREGS decreased the frequency of
sIPSCs, suggesting that PREGS could inhibit action potential-
independent spontaneous GABArelease in the hippocampus. This
result was consistent to that obtained by Mtchedlishvili andKapur (2003). Moreover, Mtchedlishvili and Kapur (2003) studied
the effect of PREGS on the action potential-dependent and
independent components of sIPSCs (spontaneous inhibitory
postsynaptic currents) without TTX and found that PREGS could
inhibit both the two components of sIPSCs, suggesting that in
addition to the inhibition of action potential-independent
spontaneous GABA release, PREGS also could inhibit action
potential-dependent one.
Mtchedlishvili et al. studied the mechanism of the inhibitory
effect of PREGS on spontaneous GABA release in the hippocampus.
They found that the sigma-1 receptor antagonists haloperidol and
BD-1063 could block the effect of PREGS on the frequency of
sIPSCs; the sigma-1 receptor agonist SKF 10047 could mimick the
effect of PREGS; the Gi/oprotein inhibitor pertussis toxin pertussistoxin could antagonize the effect of PREGS (Mtchedlishvili and
Kapur, 2003). These results suggest that PREGS inhibit sponta-
neous GABA release in the hippocampus via activation of Gi/oprotein-coupled sigma-1 receptors. This mechanism was similar to
that of promoting effect of PREGS on spontaneous glutamate
release in the hippocampus, meaning that PREGS inhibited
spontaneous GABA release and promoted spontaneous glutamate
release in the hippocampus via a similar mechanism, namely, via
activation of Gi/oprotein-coupled sigma-1 receptors.
Significance: Spontaneous GABA release has been postulated to
contribute to a tonic inhibition of neuronal excitability (Otis et al.,
1991). Therefore, the inhibitory effect of PREGS on spontaneous
GABA release suggests that this neurosteroid may play a role in
modulating background excitability in the hippocampus. Inaddition, as a disinhibitory effect by suppressing spontaneous
release of GABA can facilitate long-term potentiation in CA1
pyramidal neurons (Carlson et al., 2002), this PREGS-mediated
disinhibition in the hippocampus may allow long-term potentia-
tion to occur and thus facilitate learning and memory mediated by
the hippocampus.
2.2.3. PREGS and acetylcholine release
Acetylcholine (ACh) is a neurotransmitter widely distributed in
the central and peripheral nervous system. In the central nervous
system, its distribution mainly includes the neocortex and
amygdala, which are innervated by cholinergic projection neurons
of nucleus basalis magnocellularis (NBM) and the hippocampus,
which is innervated by cholinergic projection neurons of the
medial septum (George et al., 2006). In addition, the striatum,
nucleus accumbens, and olfactory tubercle contain cholinergic
interneurons. Functionally, both basalo-cortical and septo-hippo-
campal cholinergic pathways have been implicated in the
regulation of cognitive processes (attention, memory), whereas
striatal cholinergic interneurons have been mainly implicated in
motor process (Mayo et al., 2003). The effect of PREGS on ACh
release in the hippocampus and other brain regions was
investigated by on-line microdialysis in freely moving rats.
2.2.3.1. Hippocampus. Intracerebroventricular injection of PREGS
could stimulate ACh release in the hippocampus (Vallee et al.,
1997; Darnaudery et al., 2000). Moreover, when direct local
injection of PREGS into the medial septum nucleus, where the cell
bodies of cholinergic neurons projecting to the hippocampus were
localized, PREGS still could produce this promoting effect in the
hippocampus (Darnaudery et al., 2002), suggesting that the action
of PREGS at the cell bodies of cholinergic neurons in the medial
septum nucleus might be one of the important mechanisms for its
effect in the hippocampus.
Significance: The ACh systemin the hippocampus is known tobe
involved in theregulation of memoryprocesses (Mayo et al., 2003).
Therefore, the promoting effect of PREGS on ACh release in the
hippocampus may be beneficial to improvement of memory. Thisstatement has been supported by the result that after intracer-
ebroventricular injection of PREGS or infusion of PREGS into the
medial septumnucleus, both an enhancement of hippocampal ACh
release and an improvement of memory performances occurred for
the same doses of PREGS (Darnaudery et al., 2000, 2002). In
addition, this effect of PREGS on ACh release may be of value for
reinforcing depressed cholinergic transmission in certain age-
related memory disorders. This speculation was supported by the
result that the memory deficit of cognitively impaired aged rats
could be improved after either intraperitoneal or bilateral
intrahippocampal injection of PREGS (Vallee et al., 1997).
2.2.3.2. Other brain regions. The effect of PREGS on ACh release in
the frontal cortex, amygdala and striatum was also investigated bymicrodialysis. The result obtained in the frontal cortex and
amygdala was similar to that in the hippocampus, that is, it could
dose-dependently increase ACh release in the frontal cortex and
amygdala (Darnaudery et al., 1998). Moreover, PREGS adminis-
tration at the level of cholinergic cell bodies in the NBM also
increased ACh release in the projection areas of those neurons, the
basolateral amygdala and frontoparietal cortex (Pallares et al.,
1998). However, intracerebroventricular administration of PREGS
had no effects on ACh release in the striatum (Darnaudery et al.,
1998).
Significance: The functional significance of the effect of PREGS
on the ACh release in the frontal cortex and amygdala may be
different. Themain function of the ACh systemin thefrontal cortex
has been shown to be implicated in the modulation of cognitiveprocesses (Mayo et al., 2003). Therefore, it is possible that the
increasing effect of PREGS on ACh release in the frontal cortex
produces an improving effect on cognitive processes. This
speculation was supported by the result that a significant positive
correlation was found between spatial memory improvement and
the ACh levels in the frontal cortex after PREGS (Pallares et al.,
1998). However, the effect of PREGS on the ACh release in the
amygdala may not be related to modulation of cognitive processes
because the main function of the ACh system in the amygdala has
been reported to alter fear-related behavioral responses (Power
and McGaugh, 2002). This point was supported by the result that
no positive correlation between spatial memory improvement and
the ACh levels in the amygdala was observed after PREGS (Pallares
et al., 1998). Thus, it is possible that the functional significance of
P. Zheng/ Progress in Neurobiology 89 (2009) 134152 139
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
7/19
the effect of PREGS on the ACh release in the amygdala may be
related to its influence on fear-related behavioral responses.
2.2.4. PREGS and norepinephrine release
Norepinephrine (NE) is a neurotransmitter that is important
for attentiveness, emotions, sleeping, dreaming and learning
(Berridge and Waterhouse, 2003). The cell bodies of noradrener-
gic neurons mainly locate in the locus coeruleus and they are a
primary source for an extensive NE network in the forebrain,
including the hippocampus, amygdala and neocortex (van
Stegeren, 2008). The effect of PREGS on NE release in the
hippocampus was studied in slices and synaptosomes using the
radioactively labeled NE. The result showed that PREGS had no
effect on the spontaneous release of [3H] NE,but could inhibit the
NMDA-induced NE release in a concentration-dependent manner
in hippocampal slices (Monnet et al., 1995). Cannizzaro et al.
(2003) using hippocampal synaptosomes obtained a similar
result to that in the slices. Further mechanism study demon-
strated that the sigma-1 receptor antagonist haloperidol and BD-
1063and the Gi/o inhibitor pertussis toxin couldabolish the effect
of PREGS on the NMDA-induced NE release, suggesting that
PREGS inhibited the hippocampal NMDA-induced NE release via
activation of Gi/o protein-coupled sigma-1 receptors (Monnet
et al., 1995).Significance: NMDA receptors have been found to exist on
noradrenergic axon terminals in the hippocampus (Raiteri et al.,
1992; Pittaluga and Raiteri, 1992a,b). This presynaptic NMDA
receptor mediates enhancement of NE release and may play roles
in neuronal excitability and long-term potentiation in the
hippocampus (Pittaluga and Raiteri, 1992a,b). Thus, the inhibitory
effect of PREGS on the NMDA-induced NE release in the
hippocampus may play some role in epilepsy and in the process
of learning and memory.
2.2.5. PREGS and dopamine release
Dopamine (DA) is a neurotransmitter that plays important roles
in cognition, motivation, reward, motor activity, prolactin produc-
tion and sex behavior (Schultz, 2007; Nieoullon, 2002). Dopami-nergic neurons originate in three major sites: the substantia nigra,
the ventral tegmental area and the hypothalamus and project to
large areas of the brain through four major pathways: mesocortical
pathway (from the ventral tegmental area to the prefrontal
cortex); mesolimbic pathway (from the ventral tegmental area to
the nucleus accumbens); nigrostriatal pathway (from the sub-
stantia nigra to the striatum) and tuberoinfundibular pathway
(from the arcuate nucleus of the hypothalamus to the median
eminence of pituitary gland) (Dominguez and Hull, 2005; Alcaro
et al., 2007). In addition, less dense aggregations of DA neurons
inhabit the supramammillary region and preoptic area of the
hypothalamus, the dorsal raphe and the periaqueductal grey
(Alcaro et al., 2007). The effect of PREGS on DA release in the
nucleus accumbens and hypothalamus was studied by means of
microdialysis. Barrot et al. (1999) found that intracerebroven-
tricular injection of PREGS dose-dependently increased DA release
in the nucleus accumbens and could double DA release induced by
morphine. However, PREGS had no effect on DA release from the
hypothalamus (Murray and Gillies, 1997).
Significance: DA system in the nucleus accumbens is considered
oneof theprincipal biological substrates of motivation, rewardand
rapid antidepressant action (Mogenson et al., 1980; Carlezon and
Thomas, 2009; Plaznik and Kostowski, 1987). Thus, the stimulant
effect of PREGS on DA release in the nucleus accumbens may
mediate some of the behavioral effects of this steroid on
motivation and reward. This speculation was supported by the
facts that the PREGS-induced increase in DA release was similar tothe one induced by natural reinforcers such as palatable food and
this steroid could amplify the effect of other rewarding stimuli
such as morphine (Barrot et al., 1999). In addition, this effect may
also mediate the antidepressant action of PREGS observed in other
studies (Reddy et al., 1998; Urani et al., 2001).
2.3. Progesterone and neurotransmitter release
Progesterone (PROG) is synthesized from pregnenolone by the
enzyme 3b-hydroxysteroid dehydrogenase (3b-HSD) in theovaries or de novo in the brain (Rupprecht and Holsboer, 1999).
There is increasing evidence indicating that PROG, besides its
effects on reproductive behavior and gonadal function, has
profound psychotropic effects. At cellular level, in addition tothe effect on postsynaptic receptors, the effect of PROG on
neurotransmitter release, especially on DA release, has been
examined in a number of studies (Fig. 4).
Fig. 4. Effect of PROG on neurotransmitter release. (+) promote release; (
) inhibit release; (*
) no effect.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152140
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
8/19
2.3.1. PROG and glutamate release
In the prefrontal cortex, we examined the effect of PROG on
spontaneous and evoked glutamate release using the frequency of
sEPSCs as the index of glutamate release (Feng et al., 2004). We
found that PROG had no effect on spontaneous glutamate release,
but could dose-dependently inhibit the DA-evoked glutamate
release. Moreover, this effect appeared to have some extent of
selectivity because PROG had no effect on 5-HT-evoked one.
The mechanism of the inhibitory effect of PROG on the DA-
evoked glutamate release might involve many aspects. Our results
that the effect of PROG on DA-evoked glutamate release was rapid
and the PROG receptor antagonist RU486 had no influence on the
inhibitory effect of PROG on DA-induced glutamate release (Feng
et al., 2004) suggested that genomic mechanism might not be
involved in the effect of PROG. In addition, our result that GABAAreceptor antagonist could not block the inhibitory effect of PROG
(Feng et al., 2004) suggested that the enhancement of the
inhibitory synaptic transmission might not be the main mechan-
ismof thePROG effect. Moreover, ourresult also showedthat PROG
had no inhibitory effect on DA D1 receptor agonist-induced
increase in glutamate release (Feng et al., 2004). These results
strongly suggested that a novel mechanism involved in actions at
upstream of D1 receptors for the effect of PROG on DA-induced
glutamate release might exist. In this aspect, our further studyshowed that PROG might produce its effect via blocking sigma-1
receptors, inhibiting the sigma-1/D1 receptor synergism and then
inhibiting DA-evoked glutamate release (Fig. 5) (Feng et al., 2004).
Significance: It has been known that the effect of DA on the
excitatory synaptic transmission in the prefrontal cortex plays an
important role in the physiology of cognition and the pathophy-
siology of neuropsychiatric diseases (Tzschentke, 2001). Thus, the
finding that PROG significantly inhibits the DA-induced increase in
glutamate release in the prefrontal cortex reveals a new
mechanism for the PROG involvement of cognition and neurop-
sychiatric diseases.
2.3.2. PROG and norepinephrine release
In rat cerebral cortex slices, the effect of PROG on K+-inducedrelease of [3H]-NE was studied during the oestrous cycle or 7 days
after ovariectomy or on the fifth day of pregnancy. The result
showed that PROG reduced the K+-induced [3H]-NE release in all
the stages of the cycle, but did not modify the reduced release
found after ovariectomy or pregnancy or the release induced from
male slices (Pinter and Belmar, 1993). Further mechanism study
showed that the a2-adrenergic receptor antagonist yohimbineblocked the effect of PROG (Pinter and Belmar, 1993), suggesting
that PROG might produce its effect via activation ofa2-adrenergicreceptor. In the hippocampus, PROG had no effect on NMDA-
evoked NE release (Monnet et al., 1995).
Significance: NE has been reported to be able to modulate
neuronal excitability in the cerebral cortex (McCormick et al.,
1991). Thus, the inhibitory effect of PREGS on K+-induced NE
release in the cerebral cortex may play some role in the
modulatory effect of PROG on the excitability of the cerebral
cortex.
2.3.3. PROG and dopamine release
2.3.3.1. Striatum. In ovariectomized female rats (to exclude the
action of endogenous estrogen) and male rats, in vivo microdialysis
studies showed that PROG could increase spontaneous DA release
in the striatum, suggesting that PROG could promote spontaneous
DA release in the striatum independently of estrogens and sex
(Petitclerc et al., 1995). In ovariectomized estrogen-primed female
rats, PROG still could promote spontaneous striatal DA release
(Dluzen and Ramirez, 1989a,b). However, PROG had no effect on
stimulated striatal DA release in ovariectomized female rats andintact male rats. Only when ovariectomized female rats or
castrated male rats were treated with estrogen, could PROG
enhance stimulated striatal DA release (Becker and Rudick, 1999;
Dluzen and Ramirez, 1989a,b, 1990). These results suggest that
estrogen priming is necessary for PROG to enhance stimulated
striatal DA release both in female and male rats. This statement
was consistent with the result that PROG modified the induced DA
release in the striatum in an estrous cycle-dependentway (Cabrera
et al., 1993). However, an inhibitory effect of PROG on NMDA-
stimulated [3H] DA release (Nuwayhid and Werling, 2003) or an
opposite effect at low and high dose on high K+-induced DA release
(Cabrera et al., 1993), or dual effect of PROG upon dopamine
release (facilitation followed by inhibition) (Dluzen and Ramirez,
1984), or an opposite effect upon the amphetamine-evoked DArelease as a function of its mode of infusion (Dluzen and Ramirez,
1987) were also reported in the striatum.
The mechanism for the effect of PROG on DA release remains to
be studied. Studies showed that the addition of TTX to the
superfusion medium abolished the effect of PROG (Dluzen and
Ramirez, 1989a,b), suggesting that this effect was action potential-
dependent. In addition, immobilized PROG linked to bovine serum
albumin was used to examine whether the effect of PROG upon DA
release might be attributable to an action at surface membrane
site. The result showed that this immobilized PROG still had the
effect (Dluzen and Ramirez, 1989a,b), suggesting that the action of
PROG on DA release was mediated primarily through an action at
surface membrane site. Further studies showed that the action of
PROG on NMDA receptors in the membrane of dopaminergic nerveterminals might mediate the promoting effect of PROG on DA
release because NMDA receptor antagonists could block the effect
ofPROG onDA release (Cabrera and Navarro, 1996). In addition,the
mechanism for the inhibitory effect of PROG on NMDA-stimulated
DA release was proposed to be via activation of sigma receptors
and PKC (mainly PKCb)(Nuwayhid and Werling, 2003).Significance: The effect of PROG on striatal DA release may
mediate some of the sex and reproductive cycle-dependent
differences in sensorimotor functions observed in rodents and in
humans (Hampson and Kimura, 1988; Beatty, 1979). Indeed,
women were observed to have enhanced performance on tasks
during periods of the menstrual cycle when PROG was elevated
(Petitclerc et al., 1995). In addition, the promoting effect of PROG
on striatal DA release may have clinical relevance in neurologicalFig. 5.The mechanism of the effect of PROG on DA-evoked glutamate release in the
prefrontal cortex.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152 141
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
9/19
disordersthat involve thestriatum, such as Parkinsons disease and
other dyskinesias.
2.3.3.2. Hypothalamus. In the preoptic area of the hypothalamus,
PROG could promote DA release. Declining levels of PROG around
the time of parturition were associated with decreased dopami-
nergic activity in the preoptic area (Lonstein et al., 2003). By
contrast, increased levels of circulating PROG facilitated DA release
in the preoptic area (Matuszewich et al., 2000). Increased DA
release following PROG was dependent on the priming dose of
estradiol. In response to PROG, ovariectomized female rats primed
with a low dose of estradiol showed an increase in DA release,
whereas priming with a higher dose of estradiol showed neither
(Matuszewich et al., 2000).
Significance: It has beenknown thatchanges in DArelease in the
preoptic area of the hypothalamus could significantly influence
maternal behavior (Lonsteinet al., 2003). Manipulations of DAergic
activity could affect many aspects of maternal behavior in rats
(Numan and Nagle, 1983). Elevated DA release in the preoptic area
of the hypothalamus during copulation in rats was critical for their
sexual motivation and performance (Hull et al., 1999; Matusze-
wich et al., 2000), which was in some ways similar to maternal
motivation and performance (Stern, 1990; Lonstein et al., 2003).
Thus, the promoting effect of PROG on DA release in the preopticarea of the hypothalamus may mediate some of the influence of
PROG on maternal behavior.
2.3.4. PROG and serotonin release
The effects of PROG on 5-HT release in the ventromedial
hypothalamus, preoptic area and midbrain central grey were
studied using in vivo microdialysis in ovariectomized rats
pretreated with estradiol. Subcutaneous injection of PROG could
significantly reduce 5-HT release in the ventromedial hypothala-
mus and midbrain central grey, whereas 5-HT release in the
preoptic area didnot change significantlyafter PROG (Farmeret al.,
1996). However, an increase in 5-HT release in the preoptic area
after PROG was also reported (Johnson and Crowley, 1986).
Significance: The ventromedial hypothalamus and midbraincentral grey has been implicated in the control of lordosis behavior
(Sakuma and Pfaff, 1979). In particular, 5-HT in these two brain
regions has been proposed to play an inhibitory role on lordosis
behavior (Renner et al., 1987). Therefore, the inhibitory effect of
PROG on 5-HT release in the ventromedial hypothalamus and
midbrain central grey might release these sites from a tonic
inhibitory serotonergic influence on lordosis behavior and thus
facilitate lordosis behavior. In addition, it has been shown that
specific depletion of 5-HT in the preoptic area can result in a
blockade of the LH surge (Johnson and Crowley, 1986). Thus, the
promoting effect of PROG on 5-HT release in the preoptic area may
be involved in the LH surge induced by PROG.
2.4. Allopregnanolone and neurotransmitter release
Allopregnanolone (ALLO) is synthesized from progesterone by
the enzyme 5areductase and 3a-hydroxysteroid dehydrogenase(3aHSD) (Compagnone and Mellon, 2000). ALLO is one of the mostimportant neurosteroids in the brain and has been shown to be
involved in modulating neuroendocrine axes, stress and cognitive
function. At cellular level, in addition to the effect on postsynaptic
receptors, ALLO also has modulatory effects on the release of a
number of neurotransmitters (Fig. 6).
2.4.1. ALLO and glutamate release
In the prefrontal cortex, our work showed that ALLO had no
effects on spontaneous glutamate release, but significantly
inhibited the depolarizing agent and electrical stimulus-evoked
glutamate release (Hu et al., 2007), suggesting that the effect of
ALLO glutamate release was neuronal activity-dependent, that is,
when presynaptic terminals were at rest state,ALLO had no effects,
but if the terminals were stimulated, ALLO had an inhibitory effect
on glutamate release. In addition, our study also showed that this
effect of ALLO appeared to have some extent of selectivity for brain
regions because ALLO hadno effectin thestriatum(Huet al.,2007).
To explore the mechanism for the inhibitory effect of ALLO on
evoked glutamate release,we first observed theeffect of ALLO on the
depolarizing agent-evoked PKA activation. The result showed that
ALLO could significantly inhibit the depolarizing agent-evoked PKA
activation (Hu et al., 2007). However, ALLO had no direct inhibitory
effect on the activated PKA because ALLO had no effects on the PKA
activator forskolin-evoked activation of PKA (Hu et al., 2007).
Moreover, our further results suggested that the ALLO-mediated
inhibition of the high K+-evoked PKA activation was most probably
through the inhibition of L-type Ca2+ channels, but not through N-
and P/Q-type Ca2+ channels because L-type Ca2+ channel antago-
nists, but not the N- and P/Q-type Ca2+ channel antagonist, blocked
the effectof ALLO(Huet al.,2007). In addition, ourresults that ALLO
inhibited theL-typeCa2+channelagonist-evoked increasein thePKA
activity, intrasynaptosomal Ca2+ concentration and frequency of
sEPSCs as well as L-type Ca2+ channel antagonists could block the
effect of ALLO on depolarization-evoked glutamate release furthersupported that ALLO inhibited the evoked glutamate release via
the inhibition of L-type Ca2+ channels in the prefrontal cortex
(Hu et al., 2007).
Significance: It was reported that some pathophysiologic stimuli
such as stress and psychostimulants could significantly elevate the
expression of L-type Ca2+ channels in the cerebral cortex
(ntkiewicz-Michaluk et al., 1990, 1993, 1994a,b, 1995; Mamczarz
et al., 1994, 1999) and this elevation had been proposed to be
involved in etiology of a variety of psychiatric disorders such as
schizophrenia, morphine abstinence and neuroleptic withdrawal
(ntkiewicz-Michaluk et al., 1994a,b, 1995, 1997, 1993; Mamczarz
et al., 1994, 1999; ntkiewicz-Michaluk, 1999). Moreover, the
glutamate release in the medial prefrontal cortex is also important
in etiology of a variety of psychiatric disorders (Adams andMoghaddam, 1998; Moghaddam et al., 1997; Moghaddam and
Adams, 1998). Therefore, the finding that ALLO inhibits the L-type
Ca2+ channel activation-evoked glutamate release in the prefrontal
cortex is of significance for understanding the possible antipsy-
chotic effect of ALLO.
2.4.2. ALLO and GABA release
In the preoptic area of the hypothalamus, studies showed that
ALLO could enhance the frequency of mIPSCs in a dose-dependent
manner (Haage and Johansson, 1999; Uchida et al., 2002; Haage
et al., 2002), suggesting that ALLO could promote spontaneous
GABA release. However, when using high K+ to evoke depolariza-
tion-induced presynaptic GABA release, ALLO had little or an
inhibitory effect on the frequency of mIPSCs (Haage et al., 2002). Inaddition, in the hippocampus,Tauboll et al. (1993) reported that
ALLO also inhibited high K+-induced GABA release in a semi-
quantitative immunocytochemical study.
The mechanism for the promoting effect of ALLO on sponta-
neous GABA release in the preoptic area has been studied. Haage
et al. (2002)found that the effect of ALLO was strongly dependent
on the external Cl concentration, suggesting that the ALLO might
promote spontaneous GABA release via first activation of
presynaptic GABAA receptors and then increasing presynaptic
Cl permeability. This statement is supported by the observations
that ALLO can directly activate GABAA receptor (Haage and
Johansson, 1999) and the GABAA receptor agonist muscimol can
mimick the effect of ALLO on the sIPSC frequency ( Haage et al.,
2002). In addition, external Ca
2+
was needed for ALLO-facilitated
P. Zheng/ Progress in Neurobiology 89 (2009) 134152142
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
10/19
release of GABA because ALLO failed to increase the mIPSC
frequency in Ca2+-free external solution (Uchida et al., 2002). Also,
theenhancementof GABA release by ALLO might require a high Cl
concentration in the presynaptic terminal maintained by Na+-
dependent, bumetanide-sensitive mechanisms (e.g., Na+K+Cl
cotransporter) because the Na+K+Cl cotransporter blocker
bumetanide, which could abolish the high Cl concentration in
the presynaptic terminal, could block the effect of ALLO ( Uchida
et al., 2002). Finally, the facilitation of GABA release from thepresynaptic terminals by ALLO disappeared in Ca2+-free extra-
cellular solution (Uchidaet al., 2002), suggesting that external Ca2+
was needed for the effect of ALLO.
Significance: The medial preoptic area of the hypothalamus has
been suggested to play a central role in the control of gonadal
steroid production and secretion (Haage et al., 2002). Most of the
gonadotropin-releasing hormone (GnRH)-producing cell bodies
are situated within the medial preoptic area (Chappel, 1985) and
the GABAergic inputs to GnRH-producing neurons have been
known to play an important role in regulation of the secretion of
GnRH (Leonhardt et al., 1995). Thus, the promoting effect of ALLO
on spontaneous GABA release at the GnRH-producing neuron is of
significance for understanding the effect of PROG on GnRH
secretion.
2.4.3. ALLO and acetylcholine release
Dazzi et al. studied the effect of ALLO on basal and stress-
induced Ach release in various brain regions of freely moving rats
by means of microdialysis. The result showed that intracerebro-
ventricular injection of ALLO inhibited basal ACh release in the
prefrontal cortex and hippocampus in a dose-dependent manner,
but not in the striatum (Dazzi et al., 1996). ALLO also could
completely prevent the increase in the hippocampal ACh release
induced by foot-shock stress (Dazzi et al., 1996).Significance: It has been known that cortical and hippocampal
ACh plays an important role in cognition, memory and stress (Brito
et al., 1983; Decker and McGaugh, 1991; Dutar et al., 1995). Thus,
the effect of ALLO on ACh release in the prefrontal cortex and
hippocampus suggests that ALLO may play a role in modulation of
these processes.
2.4.4. ALLO and norepinephrine release
In the cerebral cortex, the effect of ALLO on basal and K+-
induced [3H] NE release was studied. The result showed that ALLO
could potentiate basal [3H] NE release (Belmar et al., 1998). This
effect was dependent upon the estrous cycle, since the effect was
significant during estrus and diestrus I, but was less pronounced
during diestrus II, proestrus and after 7 days of ovariectomy
Fig. 6.Effect of ALLO on neurotransmitter release. (+) promote release; () inhibit release; (*) no effect.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152 143
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
11/19
(Belmar et al., 1998). ALLO also could potentiate K+-induced [3H]
NE release during estrus (Belmar et al., 1998). The mechanism for
the potentiating effect of ALLO on NE release has been proposed to
involve noradrenergic alpha-2 receptors (Belmar et al., 1998).
Significance: NE is a neurotransmitter that can modulate
neuronal excitability in the cerebral cortex (McCormick et al.,
1991). Thus, the promoting effect of ALLO on NE release in
cerebral cortex may play some role in the effect of ALLO on the
excitability of cerebral cortex. In addition, the dependence of the
effect of ALLO on NE release on estrous cycle may underlie some
of the sex and reproductive cycle-dependent differences in
modulating cortical functions after exposure to endogenous or
exogenous ALLO.
2.4.5. ALLO and dopamine release
2.4.5.1. Striatum. In striatal slices,Cabrera et al. (2002)found that
ALLO increased the NMDA-evoked [3H] DA release from estrus
rats; this effect was not observed in diestrus rats; the ovariectomy
abolished the facilitatory effect of ALLO on NMDA-evoked [3H] DA
release; subcutaneous administration of a combination of exo-
genous estrogen and progesterone, but not with estrogen alone,
restored the facilitatory effect of ALLO on the DA release. In in vivo
experiments,Laconi et al. (2007)reported that ALLO significantlydecreased the striatal DA release in the estrus, but increased it in
the ovariectomy group primed with estrogen and progesterone.
These results suggest that ALLO is able to modulate DA release in
the striatum in an ovarian-hormone-fluctuation-dependent man-
ner.
Significance: It has been proposed that the presynaptic NMDA
receptor-evokedDA release in the striatum plays an importantrole
in the sensorimotor functions (Krebs et al., 1991; Kretschmer,
1999). Therefore, the promoting effect of ALLO on NMDA-induced
striatal DA release may contribute to the influence of ALLO on
sensorimotor functions. In addition,the dependence of the effect of
ALLO on striatal DA release upon ovarian-hormones may underlie
some of the sex and reproductive cycle-dependent differences in
sensorimotor functions after exposure to ALLO.
2.4.5.2. Nucleus accumbens. The effect of ALLO on DA release in the
nucleus accumbens was studied by means of microdialysis in
freely moving rats. The result showed that ALLO dose-dependently
increased the release of DA (Rouge-Pont et al., 2002). Furthermore,
this steroid also dose-dependently increased the morphine
induced-DA release (Rouge-Pont et al., 2002). However, Motzo
et al. (1996)reported that ALLO reduced DA release in the nucleus
accumbens and completely prevented the increase in DA release in
the nucleus accumbens induced by foot-shock stress.
Significance: DA release in the nucleus accumbens plays an
important role in reward processes, motivation and mood
(Mogenson et al., 1980; Salamone, 1996). Thus, the modulatory
effect of ALLO on DA release in the nucleus accumbens may play arole in its effect on behavior in response to natural reinforcers and
to drugs of abuse (Finn et al., 1997). In addition, it has been
proposed that a decrease in DA activity in the nucleus accumbens
(Plaznik and Kostowski, 1987) is one of the neurobiological
substrates of depression. Thus, this effect of ALLO may provide a
neurobiological substrate for the interaction between ALLO and
depression.
2.4.5.3. Prefrontal cortex. In the prefrontal cortex, Motzo et al.
(1996) reported that ALLO inhibited basal DA release in the
prefrontal cortex in a dose-dependent manner. This result was
consistent with that reported byDazzi et al. (2002), who showed
that in freely moving rats, depletion of cortical ALLO by finasteride
markedly increased foot shock induced-DA release in the
prefrontal cortex. Moreover, finasteride significantly enhanced
the stimulatory effect of anxiogenic drug FG 7142 on DA release in
the prefrontal cortex (Dazzi et al., 2002), suggesting that
endogenous ALLO might inhibit the anxiogenic drug-induced DA
release in the prefrontal cortex.
Significance: It has been known that cortical dopaminergic
neurons contribute to the modulation of emotion (Cancela et al.,
2001; Jentsch et al., 2000), while cortical concentration of ALLO
changes markedly during various physiological and pathological
conditions such as the menstrual cycle, pregnancy,menopause and
mood disorders (Dazzi et al., 2002). Thus, the effect of ALLO on DA
release in the prefrontal cortex may play roles in connecting the
change in ALLO concentration and altered emotional state under
these conditions.
2.4.5.4. Hypothalamus. The effect of intracerebroventricular injec-
tion of ALLO on DA release was studied in the medial basal
hypothalamus and preoptic area of the hypothalamus in ovar-
iectomized rats primed with estrogen and progesterone. The result
showed that in vitro [3H]-DA release from the medial basal
hypothalamus and preoptic area was lower in rats injected with
ALLO in comparison with vehicle-treated rats (Laconi and Cabrera,
2002). This effect may be responsible for the inhibition of
luteinizing hormone release and the reduced reproductive activityobserved in female rats after ALLO (Laconi and Cabrera, 2002).
2.5. Dehydroepiandrosterone and neurotransmitter release
Dehydroepiandrosterone (DHEA) is synthesized from pregne-
nolone by the enzyme cytochrome P450 17a hydroxylase(P450c17) (Mensah-Nyagan et al., 1999).
DHEA has multiple effects on neuronal survival, brain
development and cognition. However, few studies examined
theeffect of DHEA on neurotransmitterrelease. Bothinvitro and in
vivo, DHEA increased basal [3H] glutamate release without
affecting the K+-stimulated release from synaptosomes of rat
forebrain (Lhullier et al., 2004a,b). In addition, Lhullier et al.
studied theeffect ofDHEAon glutamate release in theforebrainatdifferent ages. They found that there was an increase in basal and
K+-stimulated [3H] glutamate release in rats at 12 months old,
when comparedto otherages, butthere wasan inhibitoryeffect of
DHEA on basal [3H] glutamate release in 12-month-old rats
(Lhullier et al., 2004a,b).
Significance: Theglutamatergic systemin theforebrain hasbeen
proposed to be involved in plastic processes related to learning and
memory (Izquierdo and Medina, 1997). Thus, it is possible that
DHEA, by increasing glutamate release, can strengthen the
physiological glutamatergic tonus, consequently improving the
memory of inhibitory avoidance task. This speculation was
consistent with the result Lhullier et al. (2004a,b) obtained in
behavioral experiments. In addition, the inhibitory effect of DHEA
on basal [3
H] glutamate release in 12-month-old rats may berelated to its reported protective role against excitotoxicity caused
by overstimulation of the glutamatergic system (Lhullier et al.,
2004a,b).
2.6. Dehydroepiandrosterone sulfate and neurotransmitter release
Dehydroepiandrosterone sulfate (DHEAS) is synthesized from
DHEA by the enzyme sulfotransferase (Mensah-Nyagan et al.,
1999). DHEAS is one of the most important neurosteroids. DHEAS
has been found to have multiple important effects such as memory
enhancing, antidepressant, anxiolytic and antiaggression effects.
At cellular level, in addition to the effect on postsynaptic receptors,
DHEAS also could modulate the release of a number of
neurotransmitters (Fig. 7).
P. Zheng/ Progress in Neurobiology 89 (2009) 134152144
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
12/19
2.6.1. DHEAS and glutamate release
2.6.1.1. Prefrontal cortex. Using the frequency of mEPSCs as the
index of spontaneous glutamate release, we found that DHEAS
could dose-dependently increase the frequency of mEPSCs (Dong
et al., 2007), suggesting that DHEAS could promote spontaneous
glutamate release in the prefrontal cortex.
The mechanism of the effect of DHEAS on spontaneousglutamate release in the hippocampus was proposed to be via
activation of presynaptic sigma-1 receptors (Meyer et al., 2002).
However, in the prefrontal cortex the sigma-1 receptor antagonist
only partially blocked the effect of DHEAS (Dong et al., 2007),
suggesting that a more complicated mechanism for the effect of
DHEAS on glutamate release might be involved in the prefrontal
cortex. Our further study showed that blocking DA D1 receptor or
its downstream signaling molecules (AC and PKA) with a specific
antagonist could completely abolish the effect of DHEAS (Dong
et al., 2007), suggesting that in addition to the sigma-1 receptor
that plays a partial role in the effect of DHEAS, the activation of D1
receptor plays a key role in the effect of DHEAS on spontaneous
glutamate release in the prefrontal cortex.
Significance: The prefrontal cortex is an important brain regioninvolved in cognition (Seamans et al., 1995). The glutamate-
mediated synapticinputsto theprefrontalcortex arevery important
for the function of the prefrontal cortex (Ishikawa and Nakamura,
2003; Nelson et al., 2002; Hempel et al., 2000). Therefore, the result
that DHEAS can significantly increase glutamate release in the
prefrontal cortex provides some experimental evidence for under-
standing the action of DHEAS on cognitive function.
2.6.1.2. Hippocampus. Using the frequency of mEPSCs as the index
of spontaneous glutamate release, Meyer et al. (2002) reported
that DHEAS could significantly increase the frequency of mEPSCs,
suggesting that DHEAS could promote spontaneous glutamate
release in the hippocampus. This result was confirmed by our
similar experiment (Dong et al., 2007). Further mechanism studyshowed that the sigma-1 receptor antagonist could completely
block the effect of DHEAS in the hippocampus (Meyer et al., 2002;
Dong et al., 2007), suggesting that DHEAS produced its effect via
activation of sigma-1 receptor.
Significance: Glutamate release in the hippocampus has been
known to play an importantrole in learning andmemory (Bliss and
Collingridge, 1993; Kano, 1995). Thus, the promoting effect of
DHEAS on glutamate release in the hippocampus may mediate its
influence on learning and memory.
2.6.2. DHEAS and acetylcholine release
The effect of DHEAS on the release of ACh from the
hippocampus of anesthetized rats was examined using in vivo
microdialysis. DHEAS significantly increased ACh release in the
hippocampus (Rhodes et al., 1996). This result was consistent with
that reported byRhodes et al. (1997) who found that the increased
plasma DHEAS concentrations by non-steroidal steroid sulfatase
inhibitor accompanied an increase in hippocampal ACh release.
Significance: It has been known that hippocampal ACh is closely
associated with memory function (Gold, 2003). The increased
release of ACh in the hippocampus following a treatment can
improve memory (Gold, 2003). Thus, the promoting effect ofDHEAS on ACh release in the hippocampus may be one mechanism
for its memory enhancing effect.
2.6.3. DHEAS and norepinephrine release
In the hippocampal slices, DHEAS had no effect on the basal or
the high K+-evoked [3H] NE release. However,in thepresence of the
dopamine D2 receptor antagonists spiperone and sulpiride, DHEAS
could produce a marked facilitation of the high K+-evoked [3H] NE
release in a dose-dependent manner and this facilitation could be
reversed by L- and N-type C2+ channel blockers. In addition,
Monnet et al. reported that DHEAS could potentiate NMDA-evoked
release of [3H] NE from hippocampal slices. The sigma-1 receptor
antagonists andthe Gi/o protein inhibitor couldcompletely prevent
the effect of DHEAS on NMDA-evoked [3H] NE release (Monnetet al., 1995), suggesting that DHEAS promoted NMDA-evoked NE
release via activation of Gi/oprotein-coupled sigma-1 receptor.
Significance: NE has been reported to play an important role in
themodulation of the function of thehippocampusand thus has an
important influence on learning and memory (van Stegeren, 2008;
Harley, 2007). Thus, the effect of PREGS on the K+- and NMDA-
induced NE release in the hippocampus may play some role in its
effect on learning and memory.
2.7. Testosterone and neurotransmitter release
Testosterone is synthesized from androstenediol by the enzyme
3 beta-hydroxy-steroid dehydrogenase (3bHSD) (Mellon et al.,
2001). Testosterone is the major male gonadial hormone and isresponsible for the male sexual characteristics. Testosterone also
has significant effects on brain functions like memory and
cognition. However, few studies have examined the effect of
testosterone on neurotransmitter release.
It was reported that testosterone was necessary for the
precopulatory increase in DA release in the medial preoptic area
(Hull et al., 1997, 1995). Testosterone enhanced DA release by
upregulating nitric oxide synthesis in the medial preoptic area
(Hull et al., 1997). Moreover, testosterone replacement restored
both sexual behavior and the precopulatory DA release from the
medial preoptic area in most castrated male rats (Putnam et al.,
2003, 2001) and in aged male rats (Sato et al., 1998).
Significance: The medial preoptic area (MPOA) is an important
integrative site for male sexual behavior (Putnam et al., 2003). DA
Fig. 7. Effect of DHEAS on neurotransmitter release. (+) promote release; () inhibit release; (*) no effect.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152 145
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
13/19
in MPOA can facilitate male sexual behavior and is released in the
presence of a receptive female and during copulation (Bitran and
Hull, 1987; Melis et al., 2003). Thus, the promoting effect of
testosterone on DA release in the MPOA may contribute to sexual
motivation and copulatory proficiency.
2.8. Estradiol and neurotransmitter release
Estradiol is synthesized from testosterone by the enzyme
aromatase (P450aro) (Mensah-Nyagan et al., 1999). Estradiol is the
major gonadial steroid hormone in females and exerts various
physiological actions throughout the body. Besides the classic role
in reproduction, its neuroactive properties such as the effects on
brain injury, stress, emotion and cognition have become one of the
major focuses. At the cellular levels, a number of studies examined
the effect of estradiol on neurotransmitter release (Fig. 8).
2.8.1. Estradiol and glutamate release
In cultured hippocampal neurons, using HPLC and fluorescence
technique,Yokomaku et al. (2003) found that pretreatment with
estradiol for 24 h caused a dose-dependent increase in high K+-
evoked glutamate released, but basal release was not affected.
In a mechanism study,Yokomaku et al. (2003)found that both
ICI182,780, an estrogen receptor antagonist, and tamoxifen, which
antagonized the estrogen receptor-mediated cellular event, could
block the glutamate release potentiated by estradiol, suggesting
that estradiol exerted this effect through the estrogen receptor. A
further intracellular signaling pathway study suggests that
activation of both the MAPK pathway and PI 3-kinase is necessary
for the estradiol-potentiated glutamate release (Yokomaku et al.,
2003). Moreover, the results they obtained suggested that estradiol
enhanced the high K+-induced release of glutamate through
potentiation of the exocytotic machinery (Yokomaku et al., 2003).
Significance: It has been known that glutamate has crucial roles
in neuronal plasticity of the hippocampus and thus plays an
important role in learning and memory (Bliss and Collingridge,
1993; Kano, 1995). Thus, the promoting effect of estradiol on
glutamate release may mediate its influence on learning and
memory. Moreover, this influence may occur both in female and
male because in male the brain can also synthesize estradiol by the
enzymeP450aro,which is expressedin various regions of thebrain
(McEwen et al., 1997).
2.8.2. Estradiol and GABA release
In the striatum, pretreatment with estrodial significantly
attenuated K+-induced GABA release (Hu et al., 2006). This
inhibitory effect of estrodial on GABA release might mediate the
promoting effect of estrodial on DA release observed in other
Fig. 8. Effect of estrodial on neurotransmitter release. (+) promote release; (
) inhibit release; (*
) no effect.
P. Zheng/ Progress in Neurobiology 89 (2009) 134152146
8/13/2019 Neuroactive Steroid Regulation of Neurotransmitter Release
14/19
studies (Xiao and Becker, 1998; Xiao et al., 2003) because
GABAergic inputs to DA terminals formed an inhibitory tone on
DA release and thus through inducing a decrease in this inhibitory
tone, estradiol might enhance DA release (Hu et al., 2006). This
finding is of significance for understanding how estradiol
modulates neuronal activity in the striatum.
In the hippocampus, kainite could induce a marked reductionin
K+-evoked [3H] GABA release. Estrodial could prevent this kainite-
induced reduction in GABA release (Ortiz et al., 2001). Kainite-
induced reduction in GABA release is proposed to be one
mechanism that mediates the KA-induced neuronal damage and
death (Ortiz et al., 2001). Thus, prevention of the kainite-induced
GABA release by estrodial may be one of the mechanisms
accounting for the protective effects of estrodial.
2.8.3. Estradiol and acetylcholine release
2.8.3.1. Hippocampus. In ovariectomized female rats, estradiol did
not alter baseline release of ACh (Marriott and Korol, 2003), but
couldsignificantly increase K+-stimulated ACh release (Gibbs et al.,
2004; Gabor et al., 2003). Moreover, estradiol could potentiate the
increase in hippocampal ACh release during place training
(Marriott and Korol, 2003).
Significance: It has been known that the hippocampal choli-nergic system plays an important role in learning and memory
(Gold, 2003). Moreover, the release of ACh in the hippocampus is
positively correlated with good performance on a variety of
hippocampus-dependent tasks in rats (Chang and Gold, 2003).
Thus, the augmentation of hippocampal ACh release by estrodial
may mediate the effect of estrodial on learning and memory.
2.8.3.2. Frontal cortex. In ovariectomized female rats, estradiol had
no effect on basal ACh release, but could increase fenfluramine
(serotonin releasing agent)-induced ACh release in the frontal
cortex (Matsuda et al., 2002). Moreover, estradiol also could
potentiate 8-OH-DPAT (5-HT1A receptor agonist)-induced cortical
ACh release. However, it had no effect on DOI (5-HT2A/2C receptor
agonist)-induced cortical ACh release (Matsuda et al., 2002).Significance: Hippocampal cholinergic function has been
implicated in learning and memory (Gold, 2003). In Alzheimers
disease (AD) brain, a significant deficiency of ACh anda decrease in
activity of enzyme choline acetyltransferase (ChAT) have been
detected (Davies and Maloney, 1976; Sims et al., 1983). The
nucleus basalis, a main source of cholinergic projection to the
cerebral cortex, is known to be affected in AD ( Coyle et al., 1983).
Previousstudies suggest that estradiolmay have positive effects on
cognitive functions through stimulating cholinergic neurons
(Matsuda et al., 2002). Thus, the effect of estradiol on cortical
ACh release provides a direct biochemical evidence for this action
on cholinergic neurons. Moreover, the indirect effect of estradiol
via 5-HT on ACh release could herald new strategies for the
prevention and treatment of AD.
2.8.4. Estradiol and norepinephrine release
Paul et al. (1979) found that estradiol could produce a
concentration-dependent increase in NE release in the intact
hypothalamus. Estradiol treatment also could increase NE release
in the preoptic area of the hypothalamus, but only in diabetic
animals (Karkanias et al., 1998). However, an inhibitory effect
(Hyatt and Tyce, 1984a) or no effect (Ramirez and Carrer, 1982) of
estradiol on NE release in the hypothalamus was also reported.
Significance: Hypothalamic circuits utilizing NE play an
important role in the regulation of female reproductive behavior.
Especially, noradrenergic inputs from the locus coeruleus to
luteinizing hormone-releasing hormone neurons in the hypotha-
lamus are essential for triggering the preovulatory surge mechan-
isms for gonadotrophins and prolactin (Szawka et al., 2007;
nselmo-Franci et al., 1997). Thus, estrodial may modulate female
reproductive behavior in part by modulation of NE release in the
hypothalamus.
2.8.5. Estradiol and dopamine release
2.8.5.1. Striatum. When depleting endogenous estrodial by ovar-
iectomy, the basal release of DA in the striatum decreased and this
decrease could be reversed by chronic replacement of estrodial(Becker, 1990a,b; Ohtani et al., 2001). Estradiol could also
potentiate amphetamine-, KCl-, cocaine- and L-DOPA-evoked
striatal DA release (McDermott et al., 1994; Becker and Rudick,
1999; Xiao and Becker, 1998; Peris et al., 1991; Becker, 1990a,b;
Becker and Beer, 1986; Becker and Ramirez, 1981). Moreover, prior
treatment with estrodial could result in a significant enhancement
of the effect of acute administration of estrodial on amphetamine-
induced striatal DA release (Becker and Rudick, 1999). However,
estrodial did not affect striatal DA release in males (Becker,
1990a,b). In addition,McDermott (1993)