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    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]
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    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

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    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

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    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.

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    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.

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    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

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    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.

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    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.

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    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

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    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.

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    (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).

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    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.

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    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.

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    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)


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