Endocrine Abstracts

Neuroactive steroids synthesized in the brain, referred to as neurosteroids, have gained particular attention as they appear to be involved in the modulation of various neuroendocrine, behavioral and pathophysiological processes. Thus, the distribution of steroidogenic enzymes and the identification of the biochemical pathways leading to neurosteroid formation have now been almost completely elucidated in various groups of vertebrates. In contrast however, the neuronal mechanisms controlling the activity of neurosteroid-producing cells in the brain have received little attention. Therefore, we have investigated the effects of neurotransmitters and neuropeptides on the biosynthesis of neurosteroids, using the frog brain as an experimental model. We have first observed that steroid-synthesizing neurons express several subunits of the GABA_A/central-type benzodiazepine receptor (CBR) complex, and we have found that GABA, acting through GABA_A receptors, inhibits the synthesis of neurosteroids. We have shown that glial cells containing the octadecaneuropeptide (ODN; endogenous ligand of CBR)-like immunoreactivity make contact with neurosteroid-producing neurons, and that ODN stimulates steroid biosynthesis in hypothalamic neurons in a dose-dependent manner through activation of CBR. Steroid-producing neurons are also innervated by vasotocin (VT)-containing fibers, and they are gathered in hypothalamic regions which actively express the V1a receptor subtype and mesotocin (MT) receptor (MTR). We have found that VT and MT, acting on V1a and MTR respectively, are potent stimulators of neurosteroidogenesis. Finally, we have shown that steroidogenic neurons are innervated by NPY and GnRH fibers, and that the nuclei where these neurons are located are enriched with NPY Y₁ and Y₅ receptors, and GnRHR1/3 receptors. We have observed that NPY, acting through Y₁ receptors, inhibits neurosteroid biosynthesis, while GnRH stimulates the production of neurosteroids probably via GnRHR1/3 receptors. Taken together, these data suggest that some of the activities exerted by neurotransmitters and neuropeptides in the brain may be mediated via the regulation of neurosteroid production.

Supported by INSERM (U413), the Regional Platform for Cell Imaging, a France-Québec exchange program (INSERM-FRSQ), a France-Korean exchange program (STAR) and the Conseil Régional de Haute-Normandie.