Upstream event7α-hydroxypregnenolone synthesis in the brain, decreased
Dopamine release in the brain, decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity||adjacent||Low||Low|
|Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior||adjacent|
|Cynops pyrrhogaster||Cynops pyrrhogaster||NCBI|
Life Stage Applicability
|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 Supporting this KER
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.
- 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.
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).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.