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Modulation of amino acid neurotransmitter actions by other neurotransmitters: some examples.

Developments in the field of central neurotransmission indicate that amino acids serve as important and widespread transmitters throughout the central nervous system. There are increasing indications from recent experimental studies that several of the other central neurotransmitters may exert potent effects on central neurons by modulating the actions of amino acids. Noradrenaline and serotonin have received particular attention as potential modulators, and a wide variety of actions has been reported for them. Modulatory actions have been reported at both pre- and post-synaptic levels, including both short- and long-term effects and facilitation or inhibition of amino acid actions. Selectivity has been found both for specific receptor subtypes of the neuromodulator and for specific effects of amino acids. Examples of such selectivity are modification of actions of an amino acid with little effect on spontaneous activity or membrane properties of the target cell, or in comparison to the actions of other neurotransmitters, or even other selective amino acid analogs. Modulatory actions on amino acids have also been reported for several other neurotransmitters including acetylcholine and various peptides. Recent studies of angiotensin II demonstrate that when iontophoretically applied, it can potently and selectively block the depolarizing action of glutamate on locus coeruleus neurons. It is possible that physiological influences of these various transmitter substances are expressed through modification of amino acid actions, rather than through direct effects on central neurons.

Amino Acids

Effect on various putative neurotransmitters on the secretion of corticotrophin-releasing hormone from the rat hypothalamus in vitro-a model of the neurotransmitters involved.

The effect of incubating the hypothalamus of adult male rats with various neurotransmitters upon the release of corticotrophin-releasing hormone (CRH) was studied. The CRH activity in the incubation medium was assayed in 48 h median eminence-lesioned rats and the corticosteroidogenesis of excised adrenals in vitro was used as the end-point. 5-Hydroxytryptamine (100 pg/ml-10ng/ml) caused a dose-dependent release of CRH which was antagonized by methysergide (30-100 ng/ml). The response to 5-hydroxytryptamine was also inhibited by hexamethonium and atropine which indicated that it was acting through a cholinergic interneurone. Melatonin (10 ng) did not alter the basal release of CRH but inhibited the action of both 5-hydroxytryptamine (10 ng) and acetylcholine (3 pg). Thus it appears that both 5-hydroxytryptamine and melatonin play a role in the control of CRH release. Noradrenaline blocked the release of CRH induced by both acetylcholine and 5-hydroxytryptamine and presumably this inhibition was caused by direct action on the CRH neurone. gamma-Aminobutyric acid (GABA) also inhibited the release of CRH and may also be involved in the regulation of CRH secretion. The inhibitory neurotransmitters, noradrenaline, GABA and melatonin, act via independent receptor mechanisms. A model based on the above data is presented.

Acetylcholine

The distribution of neurotransmitters and neurotransmitter-related enzymes in the dorsomedial telencephalon of the pigeon (Columba livia).

Immunoreactivity to four neurotransmitters/transmitter-related enzymes was found in the dorsomedial telencephalon (hippocampal region) of the pigeon. Putative afferent fibers containing choline acetyltransferase-like, serotonin-like, and tyrosine hydroxylase-like immunoreactivity were seen in a fiber tract passing through the septo-hippocampal junction and along the medial wall of the hippocampal region. The most intensive labeling of neuropil and terminals of all four substances was found in the dorsomedial area of the hippocampal region. Glutamic acid decarboxylase-like immunoreactivity was seen in sparsely scattered cells throughout the region. These results are discussed in relation to hypotheses about the boundaries and subdivisions of the hippocampal region of the pigeon.

Afferent Pathways

3,4-Dihydroxyphenylethylamine, L-3,4-dihydroxyphenylalanine and 3,4,5-trihydroxyphenylalanine: oxidation and binding to membranes. A comparative study of a neurotransmitter, a precursor and a neurotransmitter candidate in primitive nervous systems.

At neutral (7.0) and slightly basic (8.2) pH, L-3,4-dihydroxyphenylalanine (L-DOPA), 3,4,5-trihydroxyphenylalanine (5-OH-DOPA) and 3,4-dihydroxyphenylethylamine (dopamine) undergo autoxidation. The binding of radiolabeled oxidation products of L-DOPA, 5-OH-DOPA and dopamine to membrane proteins was compared by a filtration procedure. Membranes from tentacles of the sea anemone Metridium senile bind significantly more 5-OH-DOPA than L-DOPA and dopamine. Membranes from rat brain and brains from the three-spined stickleback Gasterosteus aculeatus, bind significantly more dopamine than L-DOPA and 5-OH-DOPA. Membranes from Metridium contain an o-diphenol O2: oxidoreductase (tyrosinase). In the absence of inhibitors, enzymatic oxidation causes a fiftyfold increase in binding of L-DOPA and a more than tenfold increase in binding of dopamine, whereas the binding of 5-OH-DOPA only is increased by 10%. It is concluded than 5-OH-DOPA more easily undergo autoxidation than L-DOPA and dopamine, but its quinone form is probably less reactive with membrane proteins. The suitability of tyrosinase-mediated biosynthesis of L-DOPA and 5-OH-DOPA versus tyrosine hydroxylase-mediated biosynthesis of L-DOPA and dopamine in primitive nervous systems and in the vertebrate CNS is discussed on the basis of the cytotoxic potential through irreversible binding to membrane proteins of oxidation products of the catechol compounds formed.

Animals

Receptor-mediated regulation of calcium channels and neurotransmitter release.

Ca2+ influx into the nerve terminal is normally the trigger for the release of neurotransmitters. Many neurons possess presynaptic receptors whose activation results in changes in the quantity of neurotransmitter released by an action potential. This paper reviews studies that show that presynaptic receptors can regulate the activity of Ca2+ channels in the nerve terminal, resulting in changes in the influx of Ca2+ and in neurotransmitter release. Neurons possess several different types of voltage-sensitive Ca2+ channels. Ca2+ influx through N-type channels appears to trigger transmitter release in many instances. In other cases Ca2+ influx through L channels can influence transmitter release. Neurotransmitters can inhibit N channels through a G protein-mediated transduction mechanism. The G proteins are frequently pertussis toxin substrates. Inhibition of N channels appears to involve changes in their voltage dependence. Neurotransmitters can also regulate neuronal K+ channels. Activation of these K+ channels can lead to a reduction in Ca2+ influx and neurotransmitter release; these effects are also mediated by G proteins. Thus neurotransmitters may often regulate both presynaptic Ca2+ and K+ channels. These two effects may be synergistic mechanisms for the regulation of Ca2+ influx and neurotransmitter release.

Animals

Amino acid precursors of monoamine neurotransmitters and some factors influencing their supply to the brain.

There is evidence that changes in the concentrations of the monoamine neurotransmitters within the brain are associated with changes in mental processes, with disorders of control of movement and with certain neuropsychiatric diseases. These neurotransmitters are synthesized in the brain from aromatic amino acid precursors that have to be obtained from the circulating blood. In this study some factors which alter the rates of entry of four amino acids (the important neurotransmitter precursors L-tyrosine and L-tryptophan, as well as L-phenylalanine and L-histidine) into the brain have been studied and the findings considered in relation to conditions in which the quantities of one or more of the monoamine neurotransmitters formed within the cerebral cells may be either too large or too small. Thus too little neurotransmitter will be formed if competition between amino acids for the carriers transporting them into the cerebral cells causes the exclusion of a large proportion of any of the aromatic amino acid precursors from the brain. ,or example, L-tryptophan is partially excluded from the brain if a raised level of any one of several other amino acids is maintained in the circulation. Of these, L-phenylalanine inhibits the transport of L-tryptophan into the brain most effectively, while aromatic amino acids in general exclude L-tryptophan more effectively than do other neutral amino acids. Over-production of one or more of the monoamine neurotransmitters is likely to occur when there is too much of one of the aromatic amino acid precursors in the brain cells as a result of abnormally high uptake from the blood, or as a result of their release by an excessive breakdown of the protein within these cells. Underproduction of neurotransmitters may occur in certain disease states, such as some aminoacidurias or Parkinsonism. We have listed some conditions associated with altered mental states or motor disability in which over- or under-production of monoamine neurotransmitters may occur and have tried to relate the findings in human disease with our experimental results.

Amino Acids, Essential

Differential modulation of spontaneous and evoked neurotransmitter release from hair cells: some novel hypotheses.

It has been generally accepted that even in the absence of mechanical stimulation of the transductional elements, a resting depolarizing current exists which is ultimately responsible for the spontaneous release of neurotransmitter. Movement of the transductional elements modulates this resting current and thereby the evoked release of neurotransmitter occurs. Recent data from our laboratory and others have led us to question whether the relationship between spontaneous and evoked neurotransmitter release is as simple as stated. Indeed, a variety of experimental manipulations appear to influence the two modes of release differently. Examination of our results and the results of others has led us to four hypotheses: 1. the two modes of neurotransmitter release are processed differently by the hair cells; 2. cyclic AMP is involved in spontaneous but not evoked neurotransmitter release; 3. there is a positive feedback step involving an excitatory amino acid and its receptor on the hair cell in evoked neurotransmitter release and; 4. different pools of calcium are involved according to the mode of release. Accordingly, there may be several biochemical steps between the transductional movement of the stereocilia at the apex of the hair cells and the ultimate release of the neurotransmitter at the base of these cells. Some of these biochemical steps are different depending on whether the mode of release is spontaneous or evoked. These biochemical steps may amplify or at least interact with the biophysical processes previously described in the hair cells.

Acetylcholine

Appearance of putative amino acid neurotransmitters during differentiation of neurons in embryonic turtle cerebral cortex.

Pyramidal and nonpyramidal neurons can be recognized early in the development of the cerebral cortex in both reptiles and mammals, and the neurotransmitters likely utilized by these cells, glutamate and gamma-aminobutyric acid, or GABA, have been suggested to play critical developmental roles. Information concerning the timing and topography of neurotransmitter synthesis by specific classes of cortical neurons is important for understanding developmental roles of neurotransmitters and for identifying potential zones of neurotransmitter action in the developing brain. We therefore analyzed the appearance of GABA and glutamate in the cerebral cortex of embryonic turtles using polyclonal antisera raised against GABA and glutamate. Neuronal subtypes become immunoreactive for the putative amino acid neurotransmitters GABA and glutamate early in the embryonic development of turtle cerebral cortex, with nonpyramidal cells immunoreactive for GABA and pyramidal cells immunoreactive for glutamate. The results of controls strongly suggest that the immunocytochemical staining in tissue sections by the GABA and glutamate antisera corresponds to fixed endogenous GABA and glutamate. Horizontally oriented cells in the early marginal zone (stages 15-16) that are GABA-immunoreactive (GABA-IR) resemble nonpyramidal cells in morphology and distribution. GABA-IR neurons exhibit increasingly diverse morphologies and become distributed in all cortical layers as the cortex matures. Glutamate-immunoreactive (Glu-IR) cells dominate the cellular layer throughout development and are also common in the subcellular layer at early stages, a distribution like that of pyramidal neurons and distinct from that of GABA-IR nonpyramidal cells. The early organization of embryonic turtle cortex in reptiles resembles that of embryonic mammalian cortex, and the immunocytochemical results underline several shared as well as distinguishing features. Early GABA-IR nonpyramidal cells flank the developing cortical plate, composed primarily of pyramidal cells, shown here to be Glu-IR. The earliest GABA-IR cells in turtles likely correspond to Cajal-Retzius cells, a ubiquitous and precocious cell type in vertebrate cortex. Glutamate-IR projection neurons in vertebrates may also be related. The distinctly different topographies of GABA and glutamate containing cells in reptiles and mammals indicate that even if the basic amino acid transmitter-containing cell types are conserved in higher vertebrates, the local interactions mediated by these transmitters may differ. The potential role of GABA and glutamate in nonsynaptic interactions early in cortical development is reinforced by the precocious expression of these neurotransmitters in turtles, well before they are required for synaptic transmission.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Immunoelectron microscopic localization of neurotransmitters in the cochlea.

This paper presents the works and methods of our respective laboratories using electron microscopic immunocytochemistry to identify and localize cochlear neurotransmitters. Antibodies to various prospective neurotransmitters and associated enzymes have been used to study the ultrastructural localization of several candidates for olivocochlear efferent neurotransmitters previously suggested by light microscopic immunocytochemistry. Antibodies against enkephalins label lateral olivocochlear efferent fibers. Antibodies against choline acetyltransferase (ChAT) (an enzyme marker for acetylcholine) label a major population of both lateral and medial efferent fibers and terminals, whereas antibodies to gamma-aminobutyric acid (GABA) label what might be a small subpopulation of both the lateral and medial efferent systems. The GABA-like immunostained medial efferent fibers are preferentially located in the upper turns of the guinea pig cochlea, particularly the third turn. Immunoelectron microscopy shows that neither GABA nor ChAT immunolabels all medial efferent terminals, regardless of cochlear turn. All the different types of immunolabeled efferent terminals have been observed to make characteristic synaptic contacts; lateral efferent terminals on afferent dendrites and medial efferent terminals on outer hair cells and occasionally on type II afferent dendrites. Other types of contacts involving GABA-like, and sometimes met-enkephalin-like, immunostained fibers are occasionally seen particularly in the upper turns of the cochlea. Immunoelectron microscopic results suggest that both medial and lateral efferent systems might be further subdivided on the basis of differences in neurotransmitters. Future trends of immunocytochemical research on cochlear neurotransmitters are proposed, particularly colocalization studies, which show a complex pattern of coexistence of neurotransmitters in the lateral efferent system.

Animals

Neurotransmitters and neuromodulators and their mediation by cyclic nucleotides.

An effort has been made here to devise criteria allowing discrimination between neurotransmitters, modulators and mediators. However, after consideration of several technical pitfalls in studies of these criteria, and examination of the properties of two examples of neuroactive agents (norepinephrine and endorphins) often referred to as "modulators", it is still difficult to classify these agents in all cases. Thus, in most central targets where NE-fibers are known to terminate, the synaptic actions of NE appear to have properties of both a neuromodulator and a neurotransmitter. Although much more research needs to be pursued, the opioid peptides may be neuromodulators for some neurons (spinal cord neurons) and neurotransmitters for others (myenteric plexus and spinal cord neurons). It may be that classification of such peptide agonists will need to be done on a cell-by-cell basis, with the endogenous peptides subserving a multi-faceted role in central and peripheral neuronal communication. As more and more endogenous ligands and transmitter-like substances are extracted from brain, it begins to appear that the language of neuronal communication is much richer than originally imagined from responses of spinal neurons to the fast-acting classical neurotransmitters. Indeed, it may evolve that the "deviant" forms of communication or transmission are more the rule than the exception. In the final analysis, each neurotransmitter may possess its own "fingerprint" of holistic actions attesting to the unique individuality of neuron types and their neurotransmitters. Such individualities might be expected to accomplish more sophisticated integrative operations, and hence behaviors, than could simple rapid "yes" or "no" messages.

Acetylcholine

The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release.

This article focuses on the role of protein phosphorylation, especially that mediated by protein kinase C (PKC), in neurotransmitter release. In the first part of the article, the evidence linking PKC activation to neurotransmitter release is evaluated. Neurotransmitter release can be elicited in at least two manners that may involve distinct mechanisms: Evoked release is stimulated by calcium influx following chemical or electrical depolarization, whereas enhanced release is stimulated by direct application of phorbol ester or fatty acid activators of PKC. A markedly distinct sensitivity of the two pathways to PKC inhibitors or to PKC downregulation suggests that only enhanced release is directly PKC-mediated. In the second part of the article, a framework is provided for understanding the complex and apparently contrasting effects of PKC inhibitors. A model is proposed whereby the site of interaction of a PKC inhibitor with the enzyme dictates the apparent potency of the inhibitor, since the multiple activators also interact with these distinct sites on the enzyme. Appropriate PKC inhibitors can now be selected on the basis of both the PKC activator used and the site of inhibitor interaction with PKC. In the third part of the article, the known nerve terminal substrates of PKC are examined. Only four have been identified, tyrosine hydroxylase, MARCKS, B-50, and dephosphin, and the latter two may be associated with neurotransmitter release. Phosphorylation of the first three of these proteins by PKC accompanies release. B-50 may be associated with evoked release since antibodies delivered into permeabilized synaptosomes block evoked, but not enhanced release. Dephosphin and its PKC phosphorylation may also be associated with evoked release, but in a unique manner. Dephosphin is a phosphoprotein concentrated in nerve terminals, which, upon stimulation of release, is rapidly dephosphorylated by a calcium-stimulated phosphatase (possibly calcineurin [CN]). Upon termination of the rise in intracellular calcium, dephosphin is phosphorylated by PKC. A priming model of neurotransmitter release is proposed where PKC-mediated phosphorylation of such a protein is an obligatory step that primes the release apparatus, in preparation for a calcium influx signal. Protein dephosphorylation may therefore be as important as protein phosphorylation in neurotransmitter release.

Amino Acid Sequence

Studies on neurotransmitter-stimulated phospholipid metabolism with cerebral tissue suspensions: a possible biochemical correlate of synaptogenesis in normal and undernourished rats.

The phenomenon of neurotransmitter-stimulated incorporation of 32Pi into phosphatidic acid and inositol phosphatides (neurotransmitter effect) in developing brain was studied in vitro as a possible measure of synaptogenesis. While the neurotransmitter effect was not observed with brain homogenates, highly consistent and significant effects were noted with brain tissue suspensions obtained by passing the tissue through nylon bolting cloth. The magnitude of the effect decreased with the increase in mesh number. Maximum stimulations obtained with the 33 mesh adult brain cortex preparations (mean +/- S.E.M. of 6 experiments) were 203 +/- 8%, 316 +/- 17% and 150 +/- 8% with 10(-3) M acetylcholine (ACh) + 10(-3) M eserine; 10(-2) M norepinephrine (NE) and 10(-2) M serotonin (5-HT), respectively. Experiments with developing rat brain at 7, 14 and 21 days of age showed that the neurotransmitter effects due to ACh, NE and 5-HT increase progressively in different regions of the brain but that there are marked regional differences. It is suggested that the neurotransmitter effect is a valid biochemical correlate of synaptogenesis. In rats undernourished from birth to 21 days of age, by increasing the litter size, the neurotransmitter effect with ACh, NE or 5-HT was not altered in the cortex but was significantly reduced in the brain stem. In cerebellum the effects due to ACh and NE were significantly altered, while that with 5-HT was unaffected. It is concluded that cholinergic, adrenergic and serotonergic synapses are relatively unaffected in the cortex but are significantly affected in the brain stem by undernutrition. In the cerebellum of undernourished rats the adrenergic and cholinergic, but not serotonergic systems, are altered.

Acetylcholine

Changes in selected brain neurotransmitters and their metabolites in the lamb after thyroidectomy during the last two trimesters of gestation or the early neonatal period.

To evaluate in a development context the effect of congenital hypothyroidism on concentrations of the neurotransmitters norepinephrine, dopamine, and serotonin (5HT) in selected brain areas of the ovine fetus, we studied the effect of thyroidectomy at three ages on the concentrations of these neurotransmitters and their major metabolites, homovanillic acid and 5-hydroxyindoleacetic acid. Fetuses underwent thyroidectomy at 90-95 or 105-115 d gestation (term = 147-150 d) or 1-5 d after birth. Approximately 25 d after thyroidectomy, at d 120-125 or 130-135 of gestation or 25-30 d after birth, respectively, the ewes were killed and fetal brains removed. Neurotransmitters and their metabolites were measured by HPLC with electrochemical detection. Thyroidectomy in the 2nd trimester increased 5HT in five brain areas: anterior hypothalamus, dorsal medial hypothalamus, pons, medulla, and cerebellum. Thyroidectomy in the 3rd trimester increased 5HT in the pons and medulla, increased norepinephrine in the dorsal medial hypothalamus and pons, and increased homovanillic acid in the posterior hypothalamus. Thyroidectomy in the newborn period decreased NE in the anterior hypothalamus, ventral medial hypothalamus, and midbrain, decreased 5-hydroxyindoleactic acid in the posterior hypothalamus, lateral hypothalamus, dorsal medial hypothalamus, and ventral medial hypothalamus, and decreased homovanillic acid in the dorsal medial hypothalamus and ventral medial hypothalamus. From these data we conclude the following: 1) Hypothyroidism causes changes in neurotransmitter concentrations only in selected brain areas of the ovine fetus, rather than causing generalized and similar changes in all brain areas; and 2) 5HT 5-hydroxyindoleacetic acid concentrations are affected more often than the other neurotransmitters evaluated, perhaps because the 5HT neurotransmitter system is developing at these times.

Animals

Alteration in the function of cerebral neurotransmitter receptors during the establishment of alcohol dependence: neurochemical aspects.

Chronic alcohol treatment induces a variety of effects on the metabolism of neurotransmitters and the function of their receptors. Recent studies on alcohol dependence and/or functional tolerance to alcohol have clearly demonstrated that neurotransmitter-gated and receptor-coupled ion channels, as well as neurotransmitter receptor coupled with intracellular mediator systems, such as phosphatidylinositides and cyclic nucleotide-generating systems, are invariably suppressed during alcohol dependence. Future studies on the central actions of alcohol and on alcohol dependence should therefore be directed at the molecular changes in synaptic membrane-bound components such as neurotransmitter receptors, as well as on neurotransmitter release and relevant membrane-bound enzymes.

Alcoholism

Interrelationship between retinal ischaemic damage and turnover and metabolism of putative amino acid neurotransmitters, glutamate and GABA.

Conditions causing a reduction of oxygen availability (anoxia), such as stroke or diabetes, result in drastic changes in ion movements, levels of neurotransmitters and metabolites and subsequent neural death. Currently, there is no clinically available treatment for anoxia induced neural cell death resulting in drastic and permanent central nervous system dysfunction. However, there have been some exciting developments in experimentally induced anoxic conditions where several classes of drugs appear to significantly reduce neural cell death. This report aims to provide the foundations for understanding both the basic mechanisms involved in retinal ischaemic damage and experimental treatments used to prevent such damage. We discuss the normal release, actions and uptake of the fast retinal neurotransmitters, glutamate and GABA, in the vertebrate retina. Immunocytochemistry is used to demonstrate that both glutamate and GABA are found in the macaque retina. Following this is a discussion on how ischaemia may enhance neurotransmitter release or disrupt its uptake, thus causing an increase in extracellular concentration of these neurotransmitters and subsequent neuronal damage. The mechanisms involved in glutamate neurotoxicity are reviewed, because excess glutamate is the likely cause of retinal ischaemic damage. Finally, the mechanisms behind four possible modes of treatment of neurotransmitter toxicity and their advantages and disadvantages are discussed. Hopefully, further research in this area will lead to the development of a rational therapy for retinal, as well as cerebral ischaemia.

Amino Acids

Compartmentalization of monoaminergic synaptic vesicles in the storage and release of neurotransmitter.

Monoaminergic nerves are characterized by the presence of a population of small synaptic vesicles (40-60 nm in diameter) containing a few large vesicles (80-90 nm in diameter). Thus, although both types of vesicles contain monoamines, the small vesicles must be considered as the organoid responsible for the storage and release of the neurotransmitter, whereas the large ones possibly are involved in the modulation of the process. The small vesicles are electron-lucent or have an osmiophilic electron-dense core that is always linked to the vesicle membrane. Considering morphological and histochemical evidence under different experimental conditions, we proposed the existence of two compartments in the small vesicles: the core and the matrix, corresponding respectively to the electron-dense core and the electron-lucent space between the core and the vesicle membrane in osmium tetroxide fixations. The sizes of both compartments are inversely related, i.e., the smaller the core, the larger the matrix and vice versa. The core even disappears, giving way to a small electron-lucent vesicle made exclusively by the matrix. Thus, the matrix is a constant component of the vesicle, whereas the core is a transient one. Each compartment has a different pool of amine: a loosely bound, easily releasable pool in the matrix and a tightly bound, more resistant pool in the core. These two pools subserve, respectively, a tonic or phasic release of the neurotransmitter, correlated with a tonic or phasic stimulation of the receptor. The core may be considered as a storage or reserve pool. Experimental evidence from our laboratory supports the concept that different mechanisms are operative in both compartments in the release of the neurotransmitter. For instance, a Ca2(+)-independent release would be primarily concerned with the neurotransmitter contained in the matrix, and a Ca2(+)-dependent efflux would be primarily related with the neurotransmitter stored in the core. However, it still must be established that a simple relationship exists between each kind of stimulus and each vesicle compartment, rather than both compartments being integrated in a dynamic functional unit.

Animals

The pre- and postnatal influence of hormones and neurotransmitters on sexual differentiation of the mammalian hypothalamus.

A number of brain structures and a great number of brain functions have been shown to be sexually dimorphic. It has also been shown that development and differentiation of these structures and functions proceeds during a critical pre- and postnatal period of increased susceptibility, and is controlled by gonadal steroids and neurotransmitter substances. The brain of male and female mammals seems to be still undifferentiated before the period of increased susceptibility to gonadal steroids and neurotransmitters starts. Feminization of brain structure and functions, e.g., establishment of the cyclic LH-surge mechanism and the expression of lordosis behavior, seems to depend on the moderate interaction of estrogens with the developing nervous system. Defeminization and masculinization of brain functions seem to be established during interaction of the developing nervous system with androgens, which have to be converted, at least in part, into estrogens. Structural differentiation of the male brain, e.g., the sexually dimorphic nucleus of the preoptic area (SDN-POA), seems to be exclusively estrogen-dependent, during differentiation of male brain functions, however, estrogens may be supportive, rather than directive, to the primary action of androgens. The molecular mechanisms of sexual differentiation of the brain are not yet fully understood. It seems, however, that the priming action of gonadal steroids during the period of increased susceptibility is either mediated by neurotransmitters, or neurotransmitters modulate the priming action of gonadal steroids. In particular, the adrenergic, the serotoninergic, the cholinergic, and possibly the dopaminergic system were shown to have strong influences on sexual differentiation of brain structure and functions. In contrast to the great number of available studies on the influence of gonadal steroids on sexual differentiation of the brain, there are rather few studies available concerning the influence of neurotransmitter systems. The available results are partly contradictory, so that an interpretation must be done with caution and will leave plenty of room for speculation. Postnatal application of compounds which stimulate or inhibit adrenergic activity mainly affected the neural control of gonadotropin secretion, and had only minor influences on differentiation of behavior patterns. It seems, however, that adrenergic participation in the differentiation of the center for cyclic gonadotropin release is very complex and stimulatory and inhibitory components may operate simultaneously. Activation or inhibition of beta-adrenergic receptors during postnatal development was shown to impair the responsiveness of the center for cyclic gonadotropin release to gonadal steroids, and impairs the expression of ejaculatory behavior in male rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals