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Neurochemical Research, Vol. 23, No. 5, 1998, pp. 675-688 Gonadal Steroids and Neuronal Function* Rafael Alonso1,3 and Ignacio Lopez-Coviella1,2 (Accepted My 7, 1997) Gonadal steroid hormones may affect, simultaneously, a wide variety of neuronal targets, influ- encing the way the brain reacts to many external and internal stimuli. Some of the effects of these hormones are permanent, whereas others are short lasting and transitory. The ways gonadal steroids affect brain function are very versatile and encompass intracellular, as well as, membrane receptors. In some cases, these compounds can interact with several neurotransmitter systems and/or tran- scription factors modulating gene expression. Knowledge about the mechanisms implicated in steroid hormone action will facilitate the understanding of brain sexual dimorphism and how we react to the environment, to drugs, and to certain disease states. KEY WORDS: Steroid hormones; neurotransmitters; plasticity; second messengers; signal transduction; syn- aptic transmission. INTRODUCTION It is sometimes believed that our destiny in life could be influenced by our own endocrine glands. Ob- viously, this hypothesis has never been fully tested. However, there is abundant experimental evidence sug- gesting that endogenous steroid hormones, mainly, al- though not exclusively, from the adrenal and gonadal glands, may exert powerful effects on the central and peripheral nervous system. They include effects on neu- ronal cell development and differentiation, plastic changes in the organization of synaptic connections, and modulation of the efficiency of neuronal signal trans- duction events (1-5). Consequently, it is not surprising that physiological, pharmacological, or pathological 1 Department of Physiology and Research Unit, Canarian University Hospital, University of La Laguna School of Medicine, Santa Cruz de Tenerife, Spain. 2 Department of Psychiatry, Boston University Medical Center, Bos- ton, Massachusetts. 3 Address reprint requests to: Dr. Rafael Alonso. Departamento de Fi- siologia, Facultad de Medicina, Universidad de La Laguna, 38320 Santa Craz de Tenerife, Spain. Tel.: (34-22) 603487. Fax: (34-22) 648457. e-Mail: [email protected]. * Special issue dedicated to Dr. Richard J. Wurtman. 675 changes in circulating levels of steroid hormones may induce important modifications of neuroendocrine re- sponses related to the maintenance of general body ho- meostasis and appearance, behavior, mood states, and even memory (6,7). We would like to review here some of the molecular mechanisms believed to mediate the effects of gonadal steroid hormones and their brain me- tabolites on the central nervous system (CNS). General Characteristics of Steroid Hormone Actions on the CNS Although steroid hormones have been known for quite a long time, the characterization of their effects on brain function has been very difficult. Only in the past few years we have been able to grasp the versatility of some of the mechanisms underlying the wide range of their actions (8-12). To describe some of the ways by which steroids may alter brain function we should, first, consider their origin or how they can be generated; sec- ondly, we should try to characterize the molecular or cel- lular substratum with which they may interact; and finally, it will be necessary to differentiate the extent and temporal course of the responses of brain cells to steroids. 0364-3190/98/0500-0675$15.00/0 C 1998 Plenum Publishing Corporation

Gonadal Steroids and Neuronal Function

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Page 1: Gonadal Steroids and Neuronal Function

Neurochemical Research, Vol. 23, No. 5, 1998, pp. 675-688

Gonadal Steroids and Neuronal Function*

Rafael Alonso1,3 and Ignacio Lopez-Coviella1,2

(Accepted My 7, 1997)

Gonadal steroid hormones may affect, simultaneously, a wide variety of neuronal targets, influ-encing the way the brain reacts to many external and internal stimuli. Some of the effects of thesehormones are permanent, whereas others are short lasting and transitory. The ways gonadal steroidsaffect brain function are very versatile and encompass intracellular, as well as, membrane receptors.In some cases, these compounds can interact with several neurotransmitter systems and/or tran-scription factors modulating gene expression. Knowledge about the mechanisms implicated insteroid hormone action will facilitate the understanding of brain sexual dimorphism and how wereact to the environment, to drugs, and to certain disease states.

KEY WORDS: Steroid hormones; neurotransmitters; plasticity; second messengers; signal transduction; syn-aptic transmission.

INTRODUCTION

It is sometimes believed that our destiny in lifecould be influenced by our own endocrine glands. Ob-viously, this hypothesis has never been fully tested.However, there is abundant experimental evidence sug-gesting that endogenous steroid hormones, mainly, al-though not exclusively, from the adrenal and gonadalglands, may exert powerful effects on the central andperipheral nervous system. They include effects on neu-ronal cell development and differentiation, plasticchanges in the organization of synaptic connections, andmodulation of the efficiency of neuronal signal trans-duction events (1-5). Consequently, it is not surprisingthat physiological, pharmacological, or pathological

1 Department of Physiology and Research Unit, Canarian UniversityHospital, University of La Laguna School of Medicine, Santa Cruzde Tenerife, Spain.

2 Department of Psychiatry, Boston University Medical Center, Bos-ton, Massachusetts.

3 Address reprint requests to: Dr. Rafael Alonso. Departamento de Fi-siologia, Facultad de Medicina, Universidad de La Laguna, 38320Santa Craz de Tenerife, Spain. Tel.: (34-22) 603487. Fax: (34-22)648457. e-Mail: [email protected].

* Special issue dedicated to Dr. Richard J. Wurtman.

675

changes in circulating levels of steroid hormones mayinduce important modifications of neuroendocrine re-sponses related to the maintenance of general body ho-meostasis and appearance, behavior, mood states, andeven memory (6,7). We would like to review here someof the molecular mechanisms believed to mediate theeffects of gonadal steroid hormones and their brain me-tabolites on the central nervous system (CNS).

General Characteristics of Steroid Hormone Actionson the CNS

Although steroid hormones have been known forquite a long time, the characterization of their effects onbrain function has been very difficult. Only in the pastfew years we have been able to grasp the versatility ofsome of the mechanisms underlying the wide range oftheir actions (8-12). To describe some of the ways bywhich steroids may alter brain function we should, first,consider their origin or how they can be generated; sec-ondly, we should try to characterize the molecular or cel-lular substratum with which they may interact; and finally,it will be necessary to differentiate the extent and temporalcourse of the responses of brain cells to steroids.

0364-3190/98/0500-0675$15.00/0 C 1998 Plenum Publishing Corporation

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Fig. 1. Schematic representation of steroid modes of action.

Neuroactive steroid compounds may originate fromvarious sources: a) The endocrine system, mainly theadrenal and sexual glands (13,14); b) The nervous sys-tem itself, where steroids can be synthesized de novo(neurosteroids), or derive from the metabolism of steroidhormones originally present in the blood (15-18); c) Ex-ogenously, from various environmental sources (19).

Brain cells responsive to gonadal steroids mayhave, at least, two types of steroid receptors (Fig. 1): 1)The well known intracellular steroid receptors (20), thatonce activated act as transcription factors and may trig-ger gene expression, and are typically responsible forlate and long-lasting neuronal responses (3,4,21); 2) Therecently described membrane steroid receptors (22-24),which may be coupled directly to membrane ion chan-nels or second messengers systems, and which elicitrapid and transitory changes on neuronal excitability

(25-28). The distinction between these two types of re-ceptors is, in part, artificial, since changes in specific ionconductance may be brought about by the activation ofintracellular or intranuclear steroid receptors (29) and,conversely, the activation of steroid membrane receptorscan regulate gene expression through signal transductionregulation of some transcription factors (30-32). Fur-thermore, in spite of the existence of specific receptorsfor steroids, there is considerable evidence showing thatthese hormones may act, in addition, by directly mod-ulating the responses of particular membrane receptorsto their respective neurotransmitters (39-44). This cross-talk between the endocrine and the nervous systemssometimes implies the co-participation of different neu-rotransmitters or, even, neuronal populations with agiven steroid to evoke a hormonal effect (5,11,12). Yet,in some circumstances, intranuclear steroid receptors can

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be activated independently of their ligands through theactivation of membrane neurotransmitter receptors bytheir physiological agonists, like the dopamine-inducedactivation of nuclear progesterone receptor (37,38).

Considering the wide range of ways by which go-nadal steroid hormones may influence neuronal functionand the high degree of integration between these andthose exhibited by certain neurotransmitter systems, theiractions can take place very rapidly (seconds) or be de-layed (hours, or days), and the nature of their effects bepermanent (2,21,33) or transitory (34-36), depending onthe stage of development of the CNS. It has been gen-erally assumed that permanent or "organizational" ef-fects are mediated by intracellular receptors and that willalways entail a genomic effect. However, this will notexplain why certain brain areas in the adult animal, de-void or with very low number of intracellular steroidreceptors, are functional and morphologically sexuallydimorphic. On the other hand, short, transitory, or "ac-tivational'' effects of steroids, not only may result fromactivation of membrane receptors, but, in fact, involveactivation of intracellular steroid receptors in brain areasrich in these type of receptors, such as it occurs duringthe estrous cycle in the rat. In general, what it seems tobe determinant of permanent vs. transitory changes inthe sexual dimorphism of brain function and structure isthe time at which brain cells are exposed to gonadalsteroids (i.e., the perinatal and prepuberal stages of de-velopment vs. adulthood).

Gonadal Steroid Sources

The primary source of gonadal steroid hormonesare the gonads. However, the secretion of these hor-mones is not uniform throughout life, and it follows wellcharacterized, oscillatory patterns that may vary as ani-mals age (13-15). Since gonadal steroids share the samemetabolic pathway as glucocorticoids and mineralocor-ticoids, the adrenals could be a source of them as well,considerably increasing their levels during stress (45).Brain cells can also synthesize, de novo, their own ster-oids (neurosteroids), and secret them in an autocrine orparacrine fashion (15). Rat brain, for example, has beenshown to have the capacity of synthesizing not only pro-gesterone, but also its immediate precursor pregnenoloneor, even, cholesterol (47). The enzymatic activity nec-essary for the synthesis of progesterone has been foundin various rat brain regions, such as hypothalamus, hip-pocampus, olfactory bulb, striatum, septum, cerebellum,and cortex (15) both in glial cells (mainly astrocytestype-I and oligodendrocytes) (48-51) as well as in neu-rons (8,226).

Regardless of whether gonadal steroids originatewithin the brain, or are taken up from the blood, braincells could transform these hormones into potentiallyneuroactive metabolites. Rat brain has been shown tohave 5a-reductase activity—the enzyme responsible forthe transformation of progesterone to dehydroprogester-one-, both in neurons as well as in glial cells; whereas3a-hydroxysteroid dehydrogenase—which converts de-hydroprogesterone to tetrahydroprogesterone—is alsopresent in brain, but only in astrocytes Type-I (52,53).Thus, it is possible that some actions, initially attribut-able to progesterone on the CNS, could instead be me-diated through one or several of its a-reducedmetabolites (54,55). There is, in addition, enough evi-dence that a similar fate could happen to testosterone.The brain of rats and other animals have the capacity ofconverting it into 5a-reduced metabolites, both in neu-rons and glial cells (53,56). Some glial metabolites couldexert a paracrine modulatory role on certain neuronalpopulations (17). Moreover, neurons can convert testos-terone to estradiol by means of an aromatase enzyme(57,58), the activity of which may fluctuate betweenbrain regions early in life and influence the sexual neu-ronal development of the brain in males.

Finally, various compounds in the environment canbe potentially steroidogenic in nature, since they mayinteract with steroid receptors in cells from many spe-cies, including humans. In some cases, the biologicalstrength of these chemicals is extremely low. However,when animals are exposed to a combination of severalof these products, the resulting effects can be many or-ders of magnitude greater than those derived from ex-posure to anyone of them separately (19).

Genomic Actions of Gonadal Steroids Mediated byIntracellular Receptors

Ligand-activated intracellular steroid receptors altergene expression by interacting with nucleotide se-quences on target genes known as hormone responsiveelements (HRE). Therefore, as a general rule, only braincells that contain both, the receptor and the HRE, aresusceptible to this type of transcriptional regulation bysteroids. However, there are other DNA binding proteinsand transcription factors that can influence this interac-tion between the receptor and the HRE, and neurons willreact differently to steroids, not only depending on thetype of receptor they have, but also on the presence orabsence of these other factors (20,59,60).

Effects of Gonadal Steroids on Neuropeptides andNeurotransmitter Enzymes. In mammals physiologicaloscillations of estradiol and progesterone can affect the

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synthesis of neuropeptides such as vasopresin (61-63),neurotensin (61,65), proopiomelanocortin (66,67), andgalanine (68-70). Although intracellular receptors seemto be responsible for these effects (due to their temporalexpression pattern, and to the presence of receptors insome neuropeptidergic neurons), it can not be ruled outthat some may be transynaptic in nature (i.e., mediatedby steroid receptor-positive interneurons), such as it maybe the case for LHRH-producing neurons in the ratpreoptic area. Estradiol enhances the synthesis of LHRHin these neurons by a positive feedback mechanism thatimplies increased LHRH mRNA transcription (71), inspite of the fact that they have extremely low levels ofintracellular estrogen receptors (72). This has led to thehypothesis that the effects of estrogens on LHRH syn-thesis and release is mediated through either adrenergic,serotonergic, dopaminergic, or peptidergic neurons inclosed proximity to LHRH cells, positive for intracel-lular estrogen receptors by autoradiography (36).

One of the neuronal systems that control the secre-tion of LHRH, the tuberoinfudibular dopaminergic neu-rons of the arcuate nucleus that project to the medianeminence (TIDA), is a classic example of a brain areacontrolled by genomic actions of gonadal steroids(36,85,86). These neurons contain estradiol (87) andprogesterone (88,89) intracellular receptors, and also ex-press tyrosine hydroxylase (TH). In ovariectomized rats,estradiol administration reduces TH-mRNA transcriptionin the arcuate nucleus by a negative feedback mecha-nism that coincides 1 to 4 hours later with changes indopamine turnover and TH activity in the median emi-nence (90-93). In these neurons, progesterone can alsodiminish TH activity in the median eminence (94,95)and, in addition, reduce the number of TH-mRNA pos-itive cells and total TH-mRNA levels in the arcuate nu-cleus (96,97). However, progesterone can also have alate and opposite effect on these neurons (believed to bedependent on prior estradiol exposure), characterized byboth increased TH-mRNA content and TH activity inthe arcuate and the median eminence, respectively(98,99).

Enhanced estradiol and progesterone blood levelsmay also have long-lasting genomic effects on cholin-ergic neurons in the basal forebrain region. These in-clude elevations in cholineacetyltransferase (ChAT)activity (73-75); greater number of immunoreactiveChAT positive neurons (76); and increase in ChAT-mRNA content (77). In the rat, some of these effectsresemble those that physiologically occur during the es-trous cycle (78). Although certain basal forebrain neu-rons in the septal area express intracellular estrogen andprogesterone receptors, it is not known whether gonadal

steroids act directly on cholinergic neurons or on thetarget neurons where they project. It has been shown thatestrogens, on one hand, can increase brain derived neu-rotrophic factor (BDNF) and nerve growth factor (NGF)mRNA levels in these targets areas, and the expressionof their receptors on septohippocampal cholinergic neu-rons, on the other (76-81). This, in fact, could be a uni-versal mechanism by which a genomicestrogen-dependent action could influence brain plastic-ity and neuronal survival, since estrogen receptors areexpressed in neurons that also contain mRNA for severalneurotrophins and, additionally, estrogen responsive el-ements have been shown to be present in genes codingfor some neurotrophins (82-84).

Genomic Effects of Estrogens on Postsynaptic Neu-rotransmitter Receptors. Estrogens can affect the sensi-tivity and level of expression of postsynaptic receptorsfor various neurotransmitters, including serotonergic(5HT1, and 5HT2A) (6,100,101), adrenergic (40,102,103),dopaminergic (104-19), GABAA (10), peptidergic (113-115), and opiate receptors (111,112). Furthermore, es-trogens can also regulate the expression of their recep-tors (116-121). These long-lasting effects generallyoccur in brain regions rich in intracellular estrogen re-ceptors, and vary according to the functional state of theneurons in question.

Non-Genomic Actions of Gonadal SteroidsMediated by Membrane Receptors

Non-genomic actions of gonadal steroids are char-acterized by being fast (milliseconds to minutes), insen-sitive to transcriptional or protein synthesis inhibition,and reproducible by immobilized and non-permeablesteroids or, in vitro, when using isolated cell membraneswithout nuclei (for reviews see McEwen, 1991 (10);Wehling, 1994 (22), Baulieu and Robel, 1995 (28); Or-chinik and McEwen, 1995 (11)). On the CNS, physio-logical concentrations of estradiol and/or progesteronemay alter neuronal excitability (122-127), neuropeptiderelease (109,128-134), and cell membrane ultrastructureand endoexocytotic activity (2,135,136). The use oflarger concentrations of these steroids may lead to lessspecific effects which are dependent on their physico-chemical interactions with the lipid barrier (22).

Various hypothesis have been suggested to explainthe molecular mechanism by which these membrane ef-fects may take place, such as changes in membraneproperties (ex., membrane permeability or fluidity, pro-tein mobility, etc.), or direct interactions with membraneproteins that induce changes in their allosteric properties(ex., receptors, ion channels, enzyme systems, etc.).

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However, until now, none of these hypothesis seems tobe entirely satisfactory (137,138). In non-neuronal cells,for instance, gonadal steroids can induce rapid changesin Ca2+ permeability and its accumulation inside the cell,or modulation of other second messenger systems which,in turn, mediate hormonal effects (137-143).

Membrane Steroid Receptor Identification. Al-though the existence of membrane receptors for estro-gen, progesterone, and testosterone on brain cells hasbeen assumed on the basis of membrane specific bindingsites for these hormones (144,145) and on rapid effectsassociated with changes on second messenger systemsfollowing their administration, it has not yet been pos-sible to clone any of these putative membrane receptors.Recently the use of radiolabeled steroids associated tobovine serum albumin (that do not cross cell mem-branes) has permitted the study of the interactions be-tween steroids and cell membranes, reducingconsiderably the amount of background initially implicitin this type of studies (132,141,146-154).

Rapid Actions of Gonadal Steroids on Neurosecre-tion. It is difficult to separate rapid effects of gonadalsteroids on neurotransmitter release mediated by mem-brane receptors from those mediated by intracellular re-ceptors, since sometimes the later can also occur quiterapidly. In vitro, high concentrations of progesterone,similar to those occurring in female rats under physio-logical conditions, can originate rapid changes on therelease of neurotransmitters such as LHRH(130,147,155,156), dopamine (131-133), or acetylcho-line (157). One of the mechanisms supposedly impli-cated include increase in intracellular Ca2+

concentrations, which could also mediate the actions ofestradiol on dopamine turnover in the striatum and nu-cleus accumbens (109), or its release measured by invivo voltametry (134,158).

Steroid Modulation of Ligand-Activated Ion Chan-nels Mediating Neuronal Excitability. Since the discov-ery that alfaxalone (5a-pregnane-3a-ol-ll,20-dione; asynthetic steroid with anesthetic properties) was a strongpotentiator of GABAA depolarization of brain slices(160,161), other endogenous steroid molecules with areduced A ring (pregnanes) have, also, been shown toproduce sedative, anesthetic, and ansiolytic effects rap-idly after their administration (162-165). Although themolecular mechanisms mediating these effects are notfully known, it has been hypothesized that steroids mayact like barbiturates (166,167). Studies carried on non-neuronal preparations have shown that physiologicalconcentrations (~1 nM) of these compounds can in-crease GABA-dependent chloride currents in a stereo-specific way (23,168-173), prolonging the opened state

of chloride channels and increasing their opening fre-quency (171-174). Although the modulation of GABAA

receptor by steroids is influenced by receptor subunitcomposition, attempts to relate these effects with a spe-cific subunit of the GABAA receptor complex havefailed. However, in some species of aquatic invertebratesthe existence of a p subunit in the GABAA receptor com-plex makes these animals insensitive to this type of ster-oids (175).

Gonadal steroids can also modulate the effects ofexcitatory neuro-transmitters. In some brain regions,characterized by low levels of intracellular steroid re-ceptors, these actions appear to be mediated by inter-actions between the steroid and a membrane component.In ovariectomized rats, the administration of physiolog-ical doses of estradiol increases the excitatory responseof cerebellar Purkinje cells to iontophoretical applicationof glutamate receptor agonists (176), whereas progester-one, alone or combination with estradiol, has the oppo-site effect, and increases the inhibitory response toGAB A (177). The modulation of these responses by go-nadal steroids happens within minutes of their adminis-tration, in some cases immediately following theiriontophoretical application (126), and occurs in the pres-ence of protein synthesis inhibitors. However, sincethese effects last hours (178), it has been suggested thatthey may imply plastic changes in synaptic efficiencymediated by intracellular signals dependent on postsyn-aptic receptor activation.

In the hippocampus, an area associated with learn-ing and memory as well as with functional and structuralchanges during aging (179), gonadal hormone actionscan be genomic, mediated by intracellular steroid recep-tors (12,113,180,181), or non-genomic and dependent onmembrane receptors. For example, in hippocampal brainslices, 17p-estradiol (but not the 17a-isomer) causes de-polarization of CA1 pyramidal cells without modifyingtheir late hyperpolarization nor their accommodativeproperties (183), and enhances the excitatory responsesof these neurons to glutamatergic Schaffe collateral stim-ulation by specific agonists (127). These actions are fast(1-2 minutes) and entirely reversible. In cultured hip-pocampal neurons, progesterone produces a rapid facil-itation of membrane currents, and increases the activityof individual channels and the entry of Ca2+ after NMD Areceptor activation (184,185). Direct evidence that someof these effects imply the interaction of the steroid witha membrane component has been obtained from exper-iments utilizing cell membrane patches from young rats.In these experiments, pregnenolone sulphate, but not17B-estradiol, can directly modulate the activity of glu-tamatergic NMDA receptors coupled to cationic

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channels, increasing their probability to opening in re-sponse to specific agonists applied both on the outsideas well as on the inside face of the patches (186).

Steroid Interactions with Second Messenger Sys-tems. There are several reports in the literature showingthat some steroid actions may be mediated directlythrough second messenger systems coupled to G pro-teins (guanine nucleotide binding proteins) (227). In hy-pothalamic slices from ovariectomized guinea pigs, thedepolarization produced by 17B-estradiol induced in-crease in potassium conductance is enhanced by phos-phodiesterase inhibitors and adenylate cyclase activators,and reproduced by cAMP analogues (187). Similarly, inhippocampal CA1 neurons in culture, the increase inkainate induced currents by 17(3-estradiol is potentiatedby the same compounds as before, and completely elim-inated by the application of protein kinase A (PKA) in-hibitors, or reduced by GTP analogues which block theGTPase cycle or activate G proteins (43). In addition,several neurosteroids derived from pregnenolone andsynthesized, de novo, in the brain from cholesterol canmodulate specific Ca2+ currents in guinea pig CA1 neu-rons in culture, by acting directly on the membrane viaa mechanism coupled to G proteins sensitive to pertusis(PTX) toxine that lead to activation of protein kinase C(PKC) (188).

In other systems, inhibitory actions of steroid hor-mones on metabotropic receptors have been also re-ported. Thus, progesterone coupled to serum albuminreduces the accumulation of cAMP generated by a1-ad-renoceptors agonists in preoptic area and mediobasal hy-pothalamic slices from ovariectomized rats (189).Similarly, in arcuate nucleus slices from ovariectomizedguinea pigs, estradiol decreases the hyperpolarization re-sulting from the actions of opiate agonists, probably bya direct interaction with G proteins (190). Since mostionotropic and metabotropic receptors contain subunitscapable of being phosphorylated by various protein ki-nases (191,192), thus causing an increase in agonists in-duced currents (193,194), these findings would suggestthat certain rapid actions of gonadal hormones on neu-ronal excitability are mediated through steroid interac-tion with a membrane site coupled to G proteins, ordirectly on them. This, in turn, will originate a cascadeof intracellular signals which, eventually, will modulatethe neuronal response to a variety of synaptic inputs.

Signal Integration and Neuromodulation bySteroids

In the past few years, it has been considered thatgenomic-intracellular receptor mediated and non-ge-

nomic-membrane mediated steroid actions are notindependent of each other, and that a high degree ofcross-talk exists between these two types of signals.However, in the first case steroid effects on cells can lastlong periods in the absence of the hormone, whereas inthe second case it has to be present at the level of themembrane for its action to take place. Both mechanismsare probably active in the same cell, and participate inthe control of its excitability and capacity of response.Thus, the cellular effects of estradiol and/or progesteroneon several neuronal systems are facilitated if the animalsare previously treated with the same hormone(113,115,127,134,187,195). From a functional point ofview, it is reasonable to propose that basal or oscillatorychanges of steroid hormone levels are responsible for apermissive, organizational action through classic intra-cellular receptors, whereas tonic changes and acute hor-mone surges are aimed at provoking specific responses.Thus, a relatively reduced number of chemical signalswill originate a wide variety of cellular responsesthrough several related mechanisms, providing the targetcell with a great capacity of adaptation. It should bepointed out that steroid hormones can interact, not onlywith the classical HRE, but also with other transcriptionfactors such as the AP-1 site (203), involved in cell pro-liferation (197), and that classic intracellular steroid re-ceptors can be activated in the absence of their ligands(204), or even by neurotransmitters such as dopamine(205-208).

Finally, membrane actions of steroids and the gen-eration of second messengers molecules can convergewith other intracellular signals that result in activationof gene transcription. Thus, in some non-neuronal cells,the increase in cAMP levels originated by estradiol canin turn activate the cAMP response element (CRE)(198). In the brain, estradiol can act rapidly and stimu-late the phosphorylation of CRE binding protein (CREB)(199,200). For some neurons lacking intracellular steroidreceptors, these mechanisms may constitute a way bywhich steroids could regulate gene transcription. It hasbeen postulated that, in some cases, these actions couldbe synergistic with other second messenger systems that,independently, also regulate CREB, such as Ca2+-cal-moduline protein kinase or PKA (201), and that they areinvolved in long lasting events that affect neuronal plas-ticity, learning, and memory (202). Therefore, since inCA1 hippocampal neurons, implicated in long term po-tentiation events: a) activation of PKA increases the re-sponse of glutamate receptors (191,194); b) estrogensmodulate Ca2+ influx and kainate induced currentsthrough the cAMP-PKA cascade (13); c) estrogens reg-ulate the proliferation of dendritic spines and the ex-

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pression of NMDA receptors (180-182,209,210); and d)some actions of estrogens require the synergistic partic-ipation of some excitatory amino acids (12), it wouldnot be surprise that estrogenic hormones could activelyparticipate in plastic neuronal changes leading to longterm memory formation (179,211-214).

Development of Steroid Sensitive Areas in the Brain

Sexual differentiation of the rat brain is believed tohappen during late fetal and early postnatal life (215).At embryonic day (ED) 15-16 the fetal rat testes havethe enzymes necessary for the production of testoster-one, and testosterone levels rise sharply from El8 on-wards (216). Circulating testosterone levels during thefirst few days of postnatal life are approximately 15-foldhigher in male than in female rats (216). During devel-opment, the aromatization of testosterone secreted by thetestes and its conversion to estradiol is necessary for themasculinization of the brain in males.

In spite of high levels of gonadal hormones fromapproximately ED 15, estrogen receptors in rat brain arenot detected before ED21, after which they increase rap-idly in the perinatal period (218). This raises the ques-tion of what role gonadal steroids may be playing fromED15 to ED21. The receptors for these hormones arefound first in the limbic system (hypothalamus, preopticarea, and amygdala), and later on the cerebral cortex.Development of cortical estrogen receptors is delayed afew days, but then they increase rapidly reaching similarlevels as those found in the limbic system by postnatalday (PD) 6 (218). In the hypothalamus estrogen receptorlevels peak between PD8 and PD15, whereas in theamygdala they remain relatively constant apart from asmall increase around PD10. In the septum/preoptic area,the levels of these receptors increase steadily throughoutthe entire postnatal period. In the cortex, receptor levelsincrease between days PD3 and PD10 and then declineand remain low from PD15 onwards (219,220). More-over, although the expression of estrogen receptormRNA could be an indication of the presence of thereceptor in a given brain area, it has been shown thatneurons expressing this mRNA not always exhibit li-gand-binding capacity for estrogen, suggesting addi-tional developmentally-regulated differences inpostranscriptional processing of estrogen receptors in thevarious brain regions (221). In general, it does not seemto exist a sex difference in brain estrogen receptor levels,although the occupation of estrogen receptors shows amarked sex difference in some brain areas but not inothers (217,218). Levels of exchangeable cell nuclearestradiol are higher in males as compared to females in

limbic areas (even though receptor occupation by estra-diol in male limbic nuclei is only at 10% of their ca-pacity); yet no sex differences are apparent in corticalestrogen receptor occupation (217). These findings alsoagree with reports that aromatization of testosterone toestradiol occurs in limbic areas but not in cortex of new-born rat brains. Therefore, these findings could suggestthat in some brain areas the sexual differentiating effectsof testosterone in males could be exerted by its conver-sion to estrogen, whereas in others could be the resultof testosterone acting directly or through other metabo-lites yet to be identified. However, the appearance oftestosterone receptors does not necessarily parallels intime that of estrogen receptors, or even follows the peakof the circulating levels of this hormone. In the preop-tic/septal area, receptors for testosterone appear afterthose for estrogen and progestin (224). During the lastfew days of fetal life, there is less than one-tenth of theadult levels of testosterone receptors in brain. Afterbirth, they increase dramatically between PD7 and PD15and by PD25 they do not yet reach adult levels (224).

In relation to progesterone, it is known that serumprogesterone levels, secreted in large amounts duringpregnancy and by the adrenal cortex of the fetus, fallabruptly during the perinatal period (222). Levels of thishormone remain low during the first 10 days of postnatallife and then gradually increase. Developmental studiesof brain progestin receptors indicate that their levels in-crease rapidly after birth (223). In cortex, progestin re-ceptors peak between PD8 and PD10 and slowlydecrease thereafter to reach adult levels by PD25. In thehypothalamus and the preoptic area, the amounts ofthese receptors increase steadily throughout the postnatalperiod (223).

CONCLUSION

The analysis of the interactions between the endo-crine and the nervous system has greatly contributed tocharacterize the molecular mechanisms involved in cell-to-cell communication. On one hand, the brain can con-trol the release of hormones into the circulation, thuslinking environmental, behavioral, and experience-de-pendent changes with body function. On the other, hor-mones secreted from the peripheral endocrine glands canhave powerful feedback effects on brain architecture andsynaptic function (1,2,12). As a result, steroid hormonescan affect the way we feel, the way we think, and eventhe way we remember (6,7). During critical periods ofbrain development, some actions of gonadal steroids arepermanent and responsible of brain sexual dimorphisms

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(2,8,21). During adult life, their actions are transitoryand can affect neurotransmission and remodelling ofsynaptic connections (42). At the synaptic level, steroidinduced plasticity is expressed through modulation ofthe amount of neurotransmitter released, the sensitivityof postsynaptic receptors, and the production of secondmessengers that may, in turn, activate intracellular sig-nals and gene transcription. These effects may occur inseveral brain regions simultaneously, and will allow ste-roid transynaptic coordination of various neuronal netsimplicated in the expression of a particular behavior, orin the regulation of several neuroendocrine responses. Itmust be emphasized that some brain regions associatedwith cognitive processes and memory are among thosesusceptible of being influenced by gonadal hormonesboth during the critical periods of early development, aswell as throughout life. Whether this, in part, may ex-plain why certain neurodegenerative diseases affect dif-ferently men and women remains an open question(225).

ACKNOWLEDGMENTS

Supported in part by DGICYT (PM 92-0160 and PB94-0590) andby GAC (92/069 and 93/002).

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