Trends in Neurosciences
Is brain estradiol a hormone or a neurotransmitter?
Section snippets
Introduction: neurotransmitters versus hormones
Chemical communication between cells is fundamental to neural function. Categorizing chemical messengers present in the brain is necessary when trying to organize the seemingly endless complexity of the CNS. One categorical distinction established nearly 100 years ago is that between hormones and neurotransmitters [1], but the validity of this distinction continues to be challenged. Our focus here is on the steroid hormone 17β-estradiol (E2) and its identity as a chemical messenger. Hormones
Fast actions of estrogens on cell function
It has been known for many years that estrogens such as E2 mediate some of their effects via nuclear receptors that act as transcription factors to modulate gene transcription, and that they also mediate other, more rapid effects in the brain that do not involve genomic mechanisms (or do so only indirectly) 3, 4, 5. For example, estrogens can change the electrophysiological activity of various populations of neurons with latencies of a few seconds [6], or reduce within minutes Ca2+ currents in
Control of aromatase transcription in the brain by steroids
It was discovered in the early 1970s that estrogens are synthesized in the brain by aromatization of androgens such as testosterone [11]. Estrogens locally produced in the preoptic area have a key role in the activation of sexual behavior in various vertebrate species [12]. Preoptic aromatase activity is, in contrast to aromatase expressed in ovarian or adipose tissues, regulated by genomic actions of sex steroids 13, 14. Testosterone treatment of castrated birds 15, 16 and mammals [17]
Cellular localization of aromatase and its physiological significance
Aromatase-expressing cells are distributed in a relatively small number of discrete brain regions primarily in the diencephalon. However, fibers originating from these cells are much more widespread and can be detected in a relatively large number of brain areas 30, 31. Within cells, a significant fraction of aromatase activity appears to be located in presynaptic boutons. This enzymatic activity is enriched in synaptosomes prepared from zebra finch or rat brain 32, 33, and dense aromatase
Effects on appetitive and consummatory aspects of male sexual behavior
Although rapid effects of estrogens on cell function have been widely identified, few studies have investigated rapid E2 effects on whole-organism responses in behavior and physiology. One study on rats identified effects of estradiol injections on male sexual behavior after latencies of 20–30 min [42]. Rapid membrane actions of E2 were also shown to enhance the genomic effects of this steroid on lordosis behavior (i.e. taking up a sexually receptive position that allows mounting and
What is the cellular basis for these rapid effects on behavior?
During the past decade, E2 has been shown to have short-latency effects on many cellular and biochemical events associated with various neural messenger systems. This topic has been reviewed extensively (e.g. 5, 6, 57, 58) and is beyond the scope of this paper. The mechanisms mediating these cellular actions of estrogens are good candidates to explain the behavioral effects already described. For example, rapid changes in E2 availability in neuronal perikaya could modulate the activity of
Does E2 meet the criteria for a neurotransmitter, and why is that important?
The concept of neurosecretion and associated ideas about the unity of action of the nervous and endocrine systems have been articulated in some form for decades, but assumptions that endocrine and neural signaling are respectively mediated by hormones and neurotransmitters can hinder scientific thinking. Subsequent to the discovery of neurosecretion, it was established that some hormones, in particular testosterone, are actually pro-hormones that must be transformed at target sites into more
Concluding remarks
The recently identified rapid changes in aromatase activity address in part the conceptual gap between the well-documented rapid non-genomic effects of estrogens in the brain and the apparent lack of mechanisms to modify estrogen availability rapidly in specific brain areas [10]. Experiments mimicking the activation or inactivation of aromatase, by acute injection of E2 or an aromatase inhibitor respectively, rapidly affect the expression of sexual behavior or the reaction to noxious stimuli,
Acknowledgements
Research in our laboratory and preparation of this article were supported by grants NIH/NIMH R01 MH50388 to G.F.B. and FRFC 2.4562.05 to J.B. We thank all our collaborators who helped to produce the original data that are the basis of this article, in particular Drs M. Baillien and C.A. Cornil. We thank the following individuals for discussion and comments on the manuscript: Drs Julie Bakker, Claudio Carere, Jean-Pierre Bourguignon, Lucien Bettendorf and Margaret M. McCarthy.
References (75)
Rapid membrane effects of steroid hormones: an emerging concept in neuroendocrinology
Trends Neurosci.
(1990)- et al.
Rapid membrane effects of estrogen in the central nervous system
- et al.
Nongenomic effects of estrogen: why all the uncertainty?
Steroids
(2006) The formation of estrogens by central neuroendocrine tissues
Recent Prog. Horm. Res.
(1975)Preoptic aromatase modulates male sexual behavior: slow and fast mechanisms of action
Physiol. Behav.
(2004)The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters
J. Steroid Biochem. Mol. Biol.
(2003)- et al.
Testosterone-induced brain aromatase is sexually dimorphic
Brain Res.
(1986) Phosphorylation processes mediate rapid changes of brain aromatase activity
J. Steroid Biochem. Mol. Biol.
(2001)Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level
J. Steroid Biochem. Mol. Biol.
(2003)Electrophysiological and neurochemical characterization of neurons of the medial preoptic area in Japanese quail (Coturnix japonica)
Brain Res.
(2004)