Tangui Maurice1, Van-Ly Phan1, Alexandre Urani1,
Hiroyuki Kamei2, Yukihiro Noda2 and Toshitaka Nabeshima2
1INSERM U. 336, Behavioral Neuropharmacology Group, ENSCM, 8,
rue de l'Ecole Normale, 34296 Montpellier Cedex 5, France
2Department of Neuropsychopharmacology and Hospital Pharmacy,
Nagoya University School of Medicine, Tsuruma-cho, Nagoya 466 - 8560, Japan
Abstract: Neuroactive neurosteroids, including progesterone,
allopregnanolone, pregnenolone and dehydroepiandrosterone, represent steroid
hormones synthesized de novo in the brain and acting locally on nervous
cells. Neurosteroids modulate several neurotransmitter systems such as ƒÁ-aminobutyric
acid type A (GABAA), N-methyl-d-aspartate (NMDA) and acetylcholine
receptors. As physiologic consequences, they are involved in neuronal plasticity,
learning and memory processes, aggression and epilepsy, and they modulate
the responses to stress, anxiety and depression. The ƒÐ1-receptor
protein was recently purified and its cDNA was cloned in several species.
The amino-acid sequences are structurally unrelated to known mammalian proteins,
but shared homology with a fungal sterol C8-C7 isomerase.
The ƒÐ1-receptor ligands exert a potent neuromodulation on excitatory
neurotransmitter systems, including the glutamate and cholinergic systems.
Consequently, selective ƒÐ1 agonists show neuroprotective properties
and beneficial effects in memory processes, stress and depression. The evidence
of a direct interaction between neurosteroids and ƒÐ1 receptors
was first suggested by the ability of several steroids to inhibit the binding
of ƒÐ1receptor radioligands in vitro and in vivo. A crossed pharmacology
between neurosteroids and ƒÐ1-receptor ligands was described
in several physiological tests and behavioral responses. This review will
detail the recent evidence for a common mechanism of action between neurosteroids
and ƒÐ1-receptor ligands and focus on the potential therapeutic
interests of such interaction in the physiopathology of learning and memory
impairments, stress, depression and neuroprotection.
Keywords: Neurosteroid, Sigma1 receptor, Neuromodulation,
Memory, Stress, Depression,
Pathological aging