The sigma1 protein as a target for the non-genomic effects of neuro(active)steroids: molecular, physiological, and behavioral aspects.

Steroids synthesized in the periphery or de novo in the brain, so called 'neurosteroids', 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 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor and therefore act as inhibitory steroids, while pregnenolone sulphate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are negative modulators of the GABA(A) 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 (sigma) receptors. Recent studies particularly demonstrated that the sigma1 receptor contributes effectively to their pharmacological actions. The present article will review the data demonstrating that the sigma1 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 sigma1-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 sigma1 drugs.

Sigma-1 receptor as regulator of neuronal intracellular Ca2+: clinical and therapeutic relevance.

Preserving brain function and cognitive faculties during aging and psychiatric diseases (e.g. psychotic, anxiety and affective disorders, dementia) is essential for the self-reliance and quality of life of patients. Cognitive loss involves not only memory, but also motor function. The decrease of catecholaminergic and excitatory neurotransmissions, as well as of protein phosphorylation, have currently been identified as prominent biological markers of the above-mentioned diseases. Such deleterious biological events are well known to occur downstream of a progressive decline of intracellular Ca2+ signalling. This latter constitutes a key target for the neuronal plasticity that has also been reported during aging and psychiatric disorders. Most of the medicines used in psychiatry are active on the sigma-1 receptor. This membrane bound receptor is widely distributed in memory-associated cortical and motor-related brainstem areas, prompting the hypothesis that it might contribute to the pathophysiology of these behavioural brain diseases. The sigma-1 receptor is characterized by a unique mode of action by regulating both Ca2+ entry at the plasma membrane level (i.e. via potassium channels, voltage-sensitive Ca2+ channels) and Ca2+ mobilization from endoplasmic stores [i.e. via Ins(1,4,5)P3 receptors]. This review presents recent data supporting the notion that drugs acting via the endoplasmic reticulum-coupled sigma-1 receptor might reverse these deleterious events by restoring both extra- and intra-cellular Ca(2+)-dependent neuronal responses.

Behavioural disturbances following Japanese B encephalitis.

Clinically, Japanese B encephalitis (JBE) is often overlooked as its occurrence in Western countries is rare. However, its neurological, cognitive and psychiatric sequelae constitute a major public health problem in the Far East where JBE is endemic. European and American subjects may however experience the JBE when returning from a Far East journey. In such cases, misdiagnosis is frequent because of the unawareness of psychiatrists and physicians. The present review, therefore, documents the behavioural and cognitive sequelae of JBE. This reactivates the debate concerning the vaccination against the virus all the more that the literature enlightens the importance of the vaccination for those who undertake frequent and extensive tourist excursions to the Orient but still discusses it for occasional travellers. Following is a case-report of a young western European post-graduate student who has contracted JBE by experiencing an acute febrile delirium during an unusual short stay in South East Asia. Pyramidal syndrome, Parkinsonism and amnesia were the prominent acute deficits. Whereas these faded in great part during convalescence, emotional and behavioural instability associated with affective involvement, obsessive-compulsive symptoms and cognitive impairments appeared. A partial recovery was however obtained with neuroleptics, lithium and following electro-convulsive therapy. Organic personality syndrome was persistent and thereafter constituted the main sequelae syndrome. Hypersomnia and several enuretic episodes persisted.