Neurostéroïdes : aspects comportementaux et implications physiologiques

Neurosteroids: pharmacology and physiological implications in behavior

INSERM U488 « Stéroïdes et Système Nerveux », 80, rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex. E-mail : yakwa@kb.inserm.fr

Résumé

Les neurostéroïdes sont produits dans le système nerveux et agissent localement. Les principaux neurostéroïdes actifs au niveau du système nerveux central incluent le sulfate de prégnénolone (S-PREG), le sulfate de déhydroépiandrostérone (S-DHEA) et le dérivé réduit de la progestérone, l’alloprégnanolone. Ces neurostéroïdes neuroactifs modulent la transmission nerveuse en interagissant, de façon allostérique, avec des récepteurs de neurotransmetteurs, dont le récepteur de type A de l’acide γ-amino-butyrique. De la sorte, ils influencent un certain nombre de comportements. Des études pharmacologiques révèlent qu’ils contrôlent le sommeil et l’anxiété chez le rat. Leurs effets physiologiques sont encore largement à préciser. Cependant les concentrations endogènes de S-PREG dans le cerveau se révèlent être importantes dans l’inhibition du comportement agressif chez la souris et dans la préservation de la mémoire chez le rat âgé.

Abstract

The term “neurosteroids” applies to those steroids that are both formed in the nervous system from sterol precursors, and accumulate in the nervous system, at least in part, independently of peripheral steroidogenic glands secretion. Neurosteroids that are active on the central nervous system include, mainly, pregnenolone (PREG), dehydroepiandrosterone (DHEA) and their sulfate esters (PREG-S and DHEA-S), as well as the reduced metabolite of progesterone, 3α,5α-ΤΗ PROG also called allopregnanolone. These neuroactive neurosteroids alter neuronal excitability by modulating the activity of several neurotransmitter receptors and thus can influence behavior. PREG-S decreases the sleeping time in rats anesthetized with a barbiturate, which is consistent with its antagonist action on the GABA_A receptor (GABA_A-R). Allopregnanolone is anxiolytic in rats tested in a conflict paradigm, through an interaction at a site specific for the benzodiazepine (BZ) receptor inverse agonist RO15-4513 and/or at the picrotoxinin site on GABA_A-R. The contribution of the amygdala, a key region involved in the control of anxiety, is also demonstrated for the anxiolytic action of allopregnanolone. An anti-agressive effect of DHEA can be observed in castrated male mice who become agressive in the presence of lactating females. This inhibition of agressiveness by DHEA is associated to a selective decrease in the brain of PREG-S, which may, in turn, trigger an increase of endogenous GABAergic tone. Finally, cognitive performances of aged rats tested in the Morris water maze and the Y-maze can be correlated with individual concentrations of PREG-S in the hippocampus, i.e poor performance in both tasks with low levels of PREG-S. Remarkably, the memory deficits are significantly improved, albeit transiently, by an intra-hippocampal injection of PREG-S in impaired aged rats. Promnesiant PREG-S may then reinforce some neurotransmitter systems that can decline with age. This brief review provides evidence of the pharmacology and physiological correlates of neurosteroids involved in behavioral phenomena. However, neurobiological mechanisms of behavioral effects of neurosteroids await further investigation.