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Relationship: 1496
Title
7α-hydroxypregnenolone synthesis in the brain, decreased leads to Dopamine release in the brain, decreased
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity | adjacent | Low | Low | Brendan Ferreri-Hanberry (send email) | Not under active development | |
Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior | adjacent | Arthur Author (send email) | Not under active development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Cynops pyrrhogaster | Cynops pyrrhogaster | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Male | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
Adult, reproductively mature |
Key Event Relationship Description
7α-hydroxypregnenolone is synthesized in the diencephalon and the rhombencephalon (newt only) and has a paracrine effect on dopaminergic neurons that project into the telencephalon including the striatum.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
7α-hydroxypregnenolone cannot be directly related to dopamine release since it has no known receptor and the cells that synthesize it are not in direct contact with the dopaminergic neurons. However, it was shown that 7α-hydroxypregnenolone release induces dopamine secretion in the brain.
Empirical Evidence
- 7α-hydroxypregnenolone concentration in the brain of salmon prior to upstream migration was decreased using aminoglutethimide (AG) injection (CYP11A inhibitor) and lead to a decreased dopamine concentration in the telencephalon compared to control. This effect was rescued with intracerebroventricular injection of 7α-hydroxypregnenolone. Simultaneous measurements of hypothalamic dopamine concentration showed an absence of variation after AG-injection or AG+7 PREG (Haraguchi et al., 2015)
- Tyrosine hydroxylase (TH) is a marker of dopamine neurons. Immunolabelling of CYP7B and TH revealed that these enzymes are expressed in two different cell populations in the salmon magnocellular preoptic nucleus and that they are in close proximity to each other (Haraguchi et al., 2015).
- 7α-hydroxypregnenolone (1 ng) was injected in non-breeding male newt and several monoamines concentration were measured using HPLC-electrochemical detection. 7α-hydroxypregnenolone increased dopamine concentration in the rostral brain region including striatum. No change was observed in the concentration of any other monoamine (Matsunaga et al., 2004).
- Newt brain incubated in vitro with 7α-hydroxypregnenolone (0, 10−8, 10−7, or 10−6 M) induced a dose-dependent increase of dopamine concentration after 10 minutes (Matsunaga et al., 2004).
Uncertainties and Inconsistencies
Since the neurosteroid receptor has yet to be identified, no direct interaction between 7α-hydroxypregnenolone and dopaminergic neuron has been demonstrated. It is thus possible that an intermediate event takes place in between to indirectly connect the neurosteroid to dopamine release.
Known modulating factors
Quantitative Understanding of the Linkage
One study specifically performed a dose-reponse experiment for 7α-hydroxypregnenolone in relation to dopamine concentration.
- Newt brain incubated with 7α-hydroxypregnenolone (0, 10−8, 10−7, or 10−6 M) induced a dose-dependent increase of dopamine concentration after 10 minutes (Matsunaga et al., 2004).
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
Haraguchi, S., Yamamoto, Y., Suzuki, Y., Hyung Chang, J., Koyama, T., Sato, M., Mita, M., Ueda, H., and Tsutsui, K. (2015). 7alpha-Hydroxypregnenolone, a key neuronal modulator of locomotion, stimulates upstream migration by means of the dopaminergic system in salmon. Sci Rep 5, 12546.
Matsunaga, M., Ukena, K., Baulieu, E.E., and Tsutsui, K. (2004). 7alpha-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system. Proc Natl Acad Sci U S A 101, 17282-17287.