Neurosteroids and σ₁ Receptors, Biochemical and Behavioral Relevance

The σ₁ receptor is a 223 amino acid protein sharing no homology with other mammalian protein. It is an intracellular protein present on the endoplasmic reticulum membrane, which can translocates to other organelles and plasma membranes after activation. Activation of the σ₁ receptor results in modulation of calcium mobilization from inositol trisphosphate receptor-gated intracellular pools and, at the plasma membrane, in modulation of several neurotransmitter responses. Behaviorally, σ₁ receptors are involved in learning and memory, response to stress and depression, psychostimulant-induced sensitization, vulnerability to addiction and pain perception. Numerous synthetic compounds bind to σ₁ receptor, playing the role of activator/agonist or blocker/antagonist, and these include benzomorphans, neuroleptics, antidepressants, cocaine, peptides related to neuropeptide Y or calcitonin gene-related peptide. It is also the case of neuro(active)steroids, i. e., circulating neuroactive steroids and neurosteroids synthesized de novo by the brain, which appear as the most important endogenous modulators of σ₁ receptor. Pregnenolone and dehydroepiandrosterone act as σ₁ receptor agonists and progesterone is a potent antagonist. The present paper will review the molecular and biochemical features concerning the σ₁ receptor and focus on the recent studies examining the impact of the neuro(active)steroid/σ₁ receptor interaction on the antidepressant activity of σ₁ receptor agonists in the context of neurodegenerative diseases.

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