J Pharmacol Sci 100, 93 – 118 (2006) Journal of Pharmacological Sciences ©2006 The Japanese Pharmacological Society Critical Review The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects François P. Monnet1 and Tangui Maurice2,* 1Unité 705 de l’Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 7157 du Centre National de la Recherche Scientifique, Université de Paris V et VII, Hôpital Lariboisière-Fernand Widal, 2, rue Ambroise Paré, 75475 Paris cedex 10, France 2Unité 710 de l’Institut National de la Santé et de la Recherche Médicale, Ecole Pratique des Hautes Etudes, Université de Montpellier II, cc 105, place Eugène Bataillon, 34095 Montpellier cedex 5, France Received December 15, 2005 Abstract. Steroids synthesized in the periphery or de novo in the brain, so called ‘neuro- steroids’, exert both genomic and nongenomic actions on neurotransmission systems. Through rapid modulatory effects on neurotransmitter receptors, they influence inhibitory and excitatory neurotransmission. In particular, progesterone derivatives like 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) are positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor and therefore act as inhibitory steroids, while pregnenolone sulphate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are negative modulators of the GABAA receptor and positive modulators of the N-methyl-D-aspartate (NMDA) receptor, therefore acting as excitatory neurosteroids. Some steroids also interact with atypical proteins, the sigma (σ) receptors. Recent studies particularly demonstrated that the σ1 receptor contributes effectively to their pharmaco- logical actions. The present article will review the data demonstrating that the σ1 receptor binds neurosteroids in physiological conditions. The physiological relevance of this interaction will be analyzed and the impact on physiopathological outcomes in memory and drug addiction will be illustrated. We will particularly highlight, first, the importance of the σ1-receptor activation by PREGS and DHEAS which may contribute to their modulatory effect on calcium homeostasis and, second, the importance of the steroid tonus in the pharmacological development of selective σ1 drugs. Keywords: neuro(active)steroid, sigma1 receptor, neurotransmission, neuronal plasticity, learning and memory 1. Neurosteroids and σ receptors ......................................................94 3. Physiological aspects of σ receptor and neurosteroid functions ... 101 1.1. Neuro(active)steroids biosyntheses 3.1. Does σ binding protein interfere with (neuro)steroid synthesis? 1.2. Neurosteroids play a role in the excitatory/inhibitory balance 3.2. Neurosteroids and σ drugs share modulatory functions at both in the brain pre- and post-synaptic levels 1.3. The σ receptor, an atypical neuromodulatory system 3.2.1. Do neurosteroids and σ drugs exhibit similar effects 1.4. The σ1 receptor acts as an intracellular amplifier of signal on neuronal firing? transduction system involved in the formation 3.2.2. Neurosteroids and σ drugs affect neuronal excitability and recomposition of membrane lipid microdomains induced by the NMDA receptor 2. Neurosteroids and σ drugs apparently share the same binding sites 3.2.3. Neurosteroids and σ drugs may have a similar impact ...............................................................................................98 on neurotransmitter release 2.1. Steroids and neurosteroids bind both σ1 and σ2 sites 4. Behavioral effects of σ-receptor ligands and neurosteroids....... 105 in the central nervous system 4.1. Neurosteroids and σ drugs affect learning and memory 2.2. Steroids and neurosteroids bind both σ1 and σ2 sites processes in peripheral tissues 4.1.1. Pro-mnesic effects of neurosteroids and σ drugs 2.3. Do neurosteroids also bind atypical σ-receptor subtypes? 4.1.2. Anti-amnesic effects in cholinergic models of amnesia 4.1.3. Anti-amnesic effects in NMDA-receptor-dependent amnesia *Corresponding author. [email protected] 4.1.4. Anti-amnesic effects of neurosteroids and σ drugs Published online in J-STAGE: February 11, 2006 during aging DOI: 10.1254/jphs.CR0050032 4.2. Neurosteroids and σ drugs may influence abused drug intake 4.3. Cross-influences between neurosteroids and σ receptor Invited article 5. Conclusions................................................................................ 111 93 94 FP Monnet and T Maurice 1. Neurosteroids and σ receptors P450 side-chain cleavage (P450scc) enzyme, a conver- sion that constitutes the rate-limiting step in steroido- The first description of a biological activity for genesis (3). PREG could then be metabolized into steroids, the anesthetic properties of progesterone, dates progesterone by a 3β-hydroxysteroid dehydrogenase from the 1941 report by Selye (1). The subsequent (3βHSD). PREG could also be converted into 17α- characterization of central effects exerted by steroid hydroxypregnenolone by a cytochrome P450c17, which hormones, and their syntheses in the nervous system leads to dehydroepiandrosterone (DHEA) and andros- defining the concept of neurosteroids, dates from 25 tenedione by the scission of the c17,20 bond. These years ago. Neuroactive steroids include both steroids two pathways lead to the formation of pregnanes and from the periphery, which are transported through the androstanes steroids, respectively, and the most highly blood-brain-barrier and act within the brain, and locally expressed steroids in the brain are PREG, DHEA, their synthesized neurosteroids. Their physiological actions, sulphate esters (PREGS and DHEAS), progesterone, demonstrated from embryogenesis through adult life, and 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) involve genomic actions, mediated by steroid receptors among the tetrahydroprogesterone isomers. The expres- translocating into the nucleus, and non-genomic neuro- sion, distribution, and ontogeny of most of the modulatory actions affecting directly several ion chan- steroidogenic enzymes and synthesized steroids have nels, neurotransmitter receptors, and second messenger been determined in the brain (3) and similarities with systems. The syntheses and effects of these neuro the peripheral synthetic pathway were identified. Most (active)steroids and their physiopathological conse- of the enzymes, including P450scc, P450c17, 3βHSD, quences have been extensively reviewed (2 – 13). In and 5α-reductase, which convert PREG into progester- particular, the mechanisms by which they act as allos- one, are co-expressed in limbic structures such as the teric modulators of the γ-aminobutyric acid type A hippocampus, caudate putamen, hypothalamic nuclei, (GABAA) receptor and N-methyl-D-aspartate (NMDA) cortex, olfactory bulb, and cerebellum (3). type of glutamate receptor is now extensively docu- Various physiological and pathological conditions are mented. They also affect acetylcholine systems through associated with changes in neurosteroid levels. Neuro- direct and indirect actions. More atypical is their re- steroid syntheses significantly vary during acute and ported interaction with the sigma1 (σ1) receptors (14 – chronic stress, pregnancy, neural development, and 17). In the present review article, we will detail the normal and pathological aging. In humans, plasma levels molecular, physiological, and behavioral data support- of DHEAS decline with age (22, 23). In rodents, ing the concepts that not only certain neurosteroids significant decreases of PREGS levels in aged Sprague interact at physiological concentration with σ1 receptors Dawley rat brain were reported to correlate with and may represent their endogenous ligands but also that impaired memory functions (24). Aged C57BL/6 mice the neurosteroid/σ1 receptor interaction may present or senescence-accelerated (SAM) mice also show major physiopathological consequences. We will parti- important decreases in the brain levels of PREG and cularly illustrate their involvement in memory processes PREGS (PREG/S), DHEA and DHEAS (DHEA/S), and vulnerability to drug addiction. or progesterone (25, 26). Moreover, brain structural abnormalities related to Alzheimer’s disease, like both 1.1. Neuro(active)steroids biosyntheses β-amyloid deposits and neurofibrillary tangles, which Steroids are synthesised in adrenal glands and gonads result from the aggregation of pathologic τ proteins, and exert their hormonal effects in peripheral organs and affect brain neurosteroid levels. Brown et al. (27) the brain. The identification of pools of steroids whose reported that β1–42-amyloid protein increased DHEA levels were higher in the brain than in plasma, indepen- levels in a human glia-derived cell line, after a 24 h dently of peripheral sources led to the concept of ‘neuro- application, a synthesis interpreted as a neuroprotective steroids’ (18 – 20). These neurosteroids are synthesized response to the β-amyloid-induced toxicity. Neuro- locally in the mitochondria of glial cells, such as oligo- steroid levels were measured in two in vivo models of dendrocytes and astrocytes, and neurons. Fifteen days β-amyloid toxicity, the intracerebroventricular injection after removing the sources of circulating steroids by of aggregated β25–35-amyloid peptide in mice and the adrenalectomy and gonadectomy (AdX/CX) in rodents, chronic infusion during a 2-week period of β1–40-amyloid no difference in the brain neurosteroid levels could be protein in rats. Decreased