Mode of Action and Functional Significance of 7?-Hydroxypregnenolone Stimulating Locomotor Activity

Abstract

Previous studies over the past two decades have demonstrated that the brain and other nervous systems possess key steroidogenic enzymes and produces pregnenolone and other various neurosteroids in vertebrates in general. Recently, 7α-hydroxypregnenolone, a novel bioactive neurosteroid, was identified in the brain of newts and quail. Importantly, this novel neurosteroid is produced from pregnenolone through the enzymatic activity of cytochrome P4507α and acts on brain tissue as a neuronal modulator to stimulate locomotor activity in these vertebrates. Subsequently, the mode of action of 7α-hydroxypregnenolone was demonstrated. 7α-Hydroxypregnenolone stimulates locomotor activity through activation of the dopaminergic system. To understand the functional significance of 7α-hydroxypregnenolone in the regulation of locomotor activity, diurnal, and seasonal changes in 7α-hydroxypregnenolone synthesis were further characterized. Melatonin derived from the pineal gland and eyes regulates 7α-hydroxypregnenolone synthesis in the brain, thus inducing diurnal locomotor changes. Prolactin, an adenohypophyseal hormone, regulates 7α-hydroxypregnenolone synthesis in the brain, and also induces seasonal locomotor changes. In addition, 7α-hydroxypregnenolone mediates corticosterone action to modulate locomotor activity under stress. This review summarizes the current knowledge regarding the mode of action and functional significance of 7α-hydroxypregnenolone, a newly identified bioactive neurosteroid stimulating locomotor activity.

New Biosynthesis and Biological Actions of Avian Neurosteroids

“…52 It thus appears that 7α-hydroxypregnenolone acts as a novel bioactive neurosteroid to stimulate locomotor activity in male quail (See reviews by Tsutsui et al77–81). A similar stimulatory effect of 7α-hydroxypregnenolone on locomotor activity has been shown in male newts 40,82…”

“…A similar stimulatory effect of 7α-hydroxypregnenolone on locomotor activity has been shown in male newts. 40,82 From sex differences in 7α-hydroxypregnenolone synthesis, concentration, and locomotor activity in quail, 52 it is considered that this neurosteroid plays an essential role in the control of locomotor activity in males. 52 Consistent with this notion, it has been shown that the cytochrome P450 inhibitor ketoconazole decreases locomotor activity in male quail.…”

“…83,84 Importantly, the telencephalic region is enriched with dopamine D 1 and D 2 receptors in birds. 85,86 Accordingly, 7α-hydroxypregnenolone actively synthesized in the diencephalon may act on dopamine neurons localized in the VTA and SN to stimulate dopamine release from their termini in the striatum and increase locomotor activity in male quail as in male newts (See reviews by Tsutsui et al [77][78][79][80][81] and Haraguchi et al 82 ) (See Fig. 3A).…”

“…A similar stimulatory effect of 7α-hydroxypregnenolone on locomotor activity has been shown in male newts. 40 , 82 …”

Neurosteroid Biosynthesis in the Brain of Amphibians

“…The observation that 7α-OH-Δ 5 P biosynthesis in the newt brain is stimulated by melatonin (Tsutsui et al, 2010a ) and prolactin (Haraguchi et al, 2010 ) strongly suggests that these two factors are responsible, respectively, for the diurnal and seasonal variations in 7α-OH-Δ 5 P formation. The functional significance of 7α-OH-Δ 5 P in the control of locomotor activity is discussed in a companion paper (Haraguchi et al, 2011 ).…”