Identification, biosynthesis, and function of 7alpha-hydroxypregnenolone, a new key neurosteroid controlling locomotor activity, in nonmammalian vertebrates.

It is now clearly established that steroids can be synthesized de novo by the brain and the peripheral nervous systems. Such steroids are called neurosteroids, and de novo neurosteroidogenesis from cholesterol is a conserved property of vertebrate brains. Our studies over the past decade have demonstrated that the brain expresses several kinds of steroidogenic enzymes and produces a variety of neurosteroids in submammalian species. However, the biosynthetic pathway of neurosteroids in nonmammalian vertebrates as well as in mammals may be still incompletely mapped out. We recently found that the brain of newts and quail actively produces 7alpha-hydroxypregnenolone, a novel bioactive neurosteroid, from pregnenolone. Interestingly, 7alpha-hydroxypregnenolone stimulates locomotor activity by means of the dopaminergic system. Subsequently, we demonstrated that melatonin regulates synthesis of 7alpha-hydroxypregnenolone, a key factor for induction of locomotor activity, thus inducing diurnal locomotor changes.