The sigma1 receptor is critically involved in the rewarding effect of cocaine, as measured using the conditioned place preference (CPP) procedure in mice. Neuroactive steroids exert rapid neuromodulatory effects in the brain by interacting with GABA(A), NMDA, and sigma1 receptors. At the sigma1 receptor level, 3beta-hydroxy-5-androsten-17-one [dehydroepiandrosterone (DHEA)] and 3beta-hydroxy-5-pregnen-20-one (pregnenolone) act as agonists, whereas 4-pregnene-3,20-dione (progesterone) is an efficient antagonist. The present study sought to investigate the action of neuroactive steroids in acquisition of cocaine-induced CPP in C57BL/6 mice. None of these steroids induced CPP alone. However, pretreatment with DHEA or pregnenolone (5-20 mg/kg, s.c.) during conditioning with cocaine (10 mg/kg, i.p.) increased the conditioned score. On the contrary, pretreatment with either progesterone (10 or 20 mg/kg, s.c.) or finasteride (25 mg/kg, twice a day), a 5alpha-reductase inhibitor, blocked acquisition of cocaine (20 mg/kg)-induced CPP. A crossed pharmacology was observed between steroids and sigma1 ligands. The sigma1 antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine blocked cocaine-induced CPP and its potentiation by DHEA or pregnenolone. Progesterone blocked cocaine-induced CPP and its potentiation by the sigma1 agonist igmesine. These results showed that neuroactive steroids play a role in cocaine-induced appetence, through their interaction with the sigma1 receptor. Therefore, neuroendocrine control of cocaine addiction may not involve solely glucocorticoids. The importance of neuroactive steroids as factors of individual vulnerability to drug addiction should, thus, be considered.

Vimentin belongs to the family of intermediate filament (IF) proteins. During the nervous system development in mammals, it is transiently expressed in precursor cells of neuronal and glial lineages, and then it is progressively replaced by other types of IF proteins. Surprisingly, mice knock-out for vimentin develop and reproduce without any apparent defects (Colucci-Guyon et al. Cell 79:679-694, 1994). In adult rodents, Bergmann glia (BG) of the cerebellum continue to express vimentin together with glial fibrillary acidic protein (GFAP). A careful analysis of cerebellar morphology and ultrastructure in mutants showed poorly developed and highly abnormal BG, whereas the migration of granular neurons proceeded normally. Moreover, many Purkinje cells (PC) appeared stunted with a loss of spiny branchlets, and some of them were necrotic. Finally, impaired motor coordination was evidenced by behavioral tests. These observations demonstrate a role for vimentin in contributing to the normal development and morphology of BG and reveal a hitherto unreported functional relationship between BG and PC.

Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importinβ1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired. Abbreviations : ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementiaC9ALS-FTD, C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal dementiaCS, citrate synthaseER, endoplasmic reticulumGSS, glutathione synthetaseHRE, hexanucleotide repeat expansionHSPA5/BiP, heat shock protein 5LAMP1, lysosomal-associated membrane protein 1MAM, mitochondria-associated endoplasmic reticulum membraneMAP1LC3/LC3, microtubule-associated protein 1 light chain 3NP, nuclear poreNSC34, mouse motor neuron-like hybrid cell lineNUPs, nucleoporinsPOM121, nuclear pore membrane protein 121SIGMAR1/Sigma-1R, sigma non-opioid intracellular receptor 1TFEB, transcription factor EBTMEM97/Sigma-2R, transmembrane protein 97