Neuroactive neurosteroids as endogenous effecters for the sigma, (sigma(1)) receptor: Pharmacological evidence and therapeutic opportunities

Neuroactive neurosteroids, including progesterone, allopregnanolone, pregne nolone and dehydroepiandrosterone, represent steroid hormones synthesized d e novo in the brain and acting locally on nervous cells. Neurosteroids modu late several neurotransmitter systems such as gamma-aminobutyric acid type A (GABA(A)), N-methyl-D-aspartate (NMDA) and acetylcholine receptors. As ph ysiologic consequences, they are involved in neuronal plasticity, learning and memory processes, aggression and epilepsy, and they modulate the respon ses to stress, anxiety and depression. The sigma(1)-receptor protein was re cently purified and its cDNA was cloned in several species. The amino-acid sequences are structurally unrelated to known mammalian proteins, but share d homology with a fungal sterol C-8-C-7 isomerase. The sigma(1)-receptor li gands exert a potent neuromodulation on excitatory neurotransmitter systems , including the glutamate and cholinergic systems. Consequently, selective sigma(1) agonists show neuroprotective properties and beneficial effects in memory processes, stress and depression. The evidence of a direct interact ion between neurosteroids and ol receptors was first suggested by the abili ty of several steroids to inhibit the binding of sigma(1)-receptor radiolig ands in vitro and in vivo. A crossed pharmacology between neurosteroids and sigma(1)-receptor ligands was described in several physiological tests and behavioral responses. This review will detail the recent evidence for a co mmon mechanism of action between neurosteroids and sigma(1)-receptor ligand s and focus on the potential therapeutic interests of such interaction in t he physiopathology of learning and memory impairments, stress, depression a nd neuroprotection.