Rapid regulation of brain oestrogen synthesis: the behavioural roles of oestrogens and their fates

Abstract

Besides their well-known genomic actions, oestrogens also exert effects through the activation of receptors associated with the plasma membrane that are too fast to be mediated by transcriptional activation (nongenomic effects). Although the existence of such rapid effects of oestrogens and their involvement in various biological processes are not in doubt, questions remain about the mechanisms responsible for the rapid modulations of oestrogen production that are required to sustain their nongenomic effects. Recent data indicate that the conversion of androgens into oestrogens in the brain by the enzyme aromatase can be rapidly modulated by conformational changes of the enzyme, thus providing a possible mechanism for rapid controls of the effects of oestrogens on male sexual behaviour. In this review, the data supporting this hypothesis are described. Subsequently, a few unanswered questions are discussed, such as the mechanism of oestrogen inactivation or the potential cellular sites of action of brain-derived oestrogens on male sexual behaviour.

Figure 1. Acute effects of oestrogens and of aromatase inhibition on male sexual behaviour in quail and mice

A. Time-response curve of the acute effects of 17β-oestradiol (E2, 500μg/kg) on consummatory behaviour assessed by mount attempt (MA) and cloacal contact movements (CCM) frequency. B. Time-response curve of the acute effects of the aromatase inhibitor, vorozole^™ (30mg/kg), on appetitive (as assessed by the frequency of the rhythmic cloacal sphincter movements [RCSM]) and consummatory sexual behaviour (as assessed by the frequency of mount attempts) expressed as percentage of controls. C. Acute effect of E2 (500μg/subject) and absence of acute effect of the aromatase inhibitor, ATD (1,4,6-androstatriene-3,17-dione, 4mg/subject), on male sexual behaviour in aromatase knock-out mice (ArKO) injected 10 minutes before the test. D. Acute effect of ATD (4mg/subjects) on male sexual behaviour in wild-type mouse injected 10 minutes before the test. E. Acute effect of E2 (500μg/subject) on male sexual behaviour in wild-type mouse chronically treated with ATD (0.5mg/subject) to inhibit the genomic effects of estrogens. Redrawn from [22, 23, 41].

Figure 2. Should oestrogens be considered as neurotransmitters/neuromodulators? – A potential model

Several criteria have been established for a molecule to be considered as a neurotransmitter/neuromodulator. These criteria involve 1) synthesis and storage in presynaptic vesicles, 2) release upon stimulation in the synaptic cleft in concentrations sufficient to activate post-synaptic receptors, 3) specificity for a defined receptor so that action can be blocked by specific antagonists, 4) presence of inactivation mechanisms (e.g., catabolism or reuptake). Recent evidence suggests that oestrogens might fulfil some, if not all, of these criteria. (1) Oestrogens are formed via aromatisation of androgens catalysed by the enzyme aromatase. Aromatase-immunoreactive material and enzymatic activity have been detected in presynaptic terminals, indicating that oestrogens are synthesised and present in synapses [32, 33]. Although estrogens are probably not stored in vesicles, this does not necessarily disqualify them as transmitters. The gaseous transmitter nitric oxide (NO) is similarly not stored in vesicles; its synthesis and release directly depend on neuronal activation [61]. This may also be the case for brain-derived oestrogens. (2) Oestrogen synthesis is rapidly modulated by conformational changes of aromatase [25, 26, 28] themselves triggered by various behavioural as well as chemical stimuli [29, 30]. Given that oestrogens are liposoluble and easily cross the cell membrane, rapid changes in oestrogen production should regulate their bioavailability in the synaptic cleft. (3) Various membrane/cytoplasmic effects of oestrogens have been identified that are supported by a diversity of intracellular cascades through the activation of nuclear receptors associated or not to the membrane of novel G protein coupled membrane oestrogen receptors (receptors characterized by 7 transmembrane domains) [–15]. The intracellular pathways triggered by such non-genomic actions of oestrogens may affect neuronal firing through the modulation of ionic conductance via phosphorylation of ionotropic receptors or the uncoupling of G protein-coupled receptors from their ionic channels or intracellular effectors [1, 16, 47]. Some behavioural effects of oestrogens are rapidly blocked by aromatase inhibition or by antagonists of nuclear receptors [18, 41] indicating that events triggered by oestrogens are rapidly blocked by known antagonists. Together, these data support the specific nature of the actions triggered by brain-derived oestrogens. (4) Finally, mechanisms of rapid inactivation of oestrogens exist [35, 36] but their role in the control of non-genomic actions of oestrogens in the brain has not formerly been tested yet. It is also possible that locally synthesised oestrogens might simply diffuse away from their target sites. For further discussion of these issues, the interested readers should refer to previously published papers critically discussing the definition of neurotransmitters [61] and the potential extension of this definition to neuro-oestrogens [34]. The nuclear receptor is schematically represented only in association with the membrane for simplicity but non-genomic effects can also occur in the cytoplasm.

Figure 3. Potential models of the modulation of synaptic transmission by brain-synthesised oestrogens involved in the acute control of male sexual behaviour

A. Presynaptic control of the release of a neurotransmitter (N) co-expressed in the aromatase-imunoreactive neurone. Oestrogen synthesized in the terminal could act pre-synaptically on its own neurone (the mER is then called an autoreceptor) to control the release of neurotransmitter N which could then act post-synaptically to modulate neuronal excitability. B. Presynaptic control of the release of a neurotransmitter (N) from a neurone on which the aromatase-positive synapse makes axo-axonal contacts. In this case, oestrogens would act on the pre-synaptic terminal of the neurotransmitter N-containing neuron (the mER then being called an heteroreceptor) and modulate the release of neurotransmitter N which could then act post-synaptically to modulate neuronal excitability. C. Post-synaptic control of neuronal excitability. The oestrogens synthesized in the pre-synaptic neurone would be released in the synaptic cleft synthesis and could then activate membrane-associated receptors at the post-synaptic level resulting in the modulation of the neuronal firing rate. D. Retrograde modulation of synaptic transmission through release of post-synaptic oestrogens that could act on the pre-synaptic element to influence the neurotransmitter’s release. In these models, the membrane oestrogen receptor is schematically represented as a G-protein coupled receptor (GPCR) for simplicity. These receptors are diverse and can include a nuclear receptor associated with another GPCR, a novel membrane ER or a known GPCR or ion-gated receptor whose activity would be modulated by oestrogens. In addition, purely cytoplasmic non-genomic effects of oestrogens have also been identified and should be considered as well.