title: Effects of the Synthetic Neurosteroid: 3β-Methoxypregnenolone (MAP4343) on Behavioral and Physiological Alterations Provoked by Chronic Psychosocial Stress in Tree Shrews.
abstract: BACKGROUND
  Most currently available active antidepressant drugs are selective serotonin/noradrenaline reuptake inhibitors. However, as their clinical efficacy is not immediate, long-term administration is often accompanied by substantial side effects, and numerous patients remain non- or partial responders. We have recently found that the synthetic neurosteroid derivative 3β-methoxypregnenolone, which binds to the microtubule-associated protein-2, can provide a novel therapeutic approach in experimental model of depressive disorders in rats. To further validate the antidepressant-like efficacy of 3β-methoxypregnenolone, we investigated effects of a longer treatment (4-week oral administration; 50mg/kg/d) in a nonrodent species, the tree shrew, exposed to psychosocial stress that elicits close-to-human alterations observed in patients with depressive disorders.
  
  
  METHODS
  During the experimental period, physiological parameters were registered, including core body temperature and electroencephalogram, while animals were videotaped to analyze their avoidance behavior. Morning urine samples were collected for measurements of cortisol and noradrenaline levels.
  
  
  RESULTS
  We found that treatment with 3β-methoxypregnenolone abolished stress-triggered avoidance behavior and prevented hormone hypersecretion, hypothermia, and sleep disturbances, further suggesting its antidepressant-like efficacy. Comparative treatment with fluoxetine also prevented some of the physiological alterations, while the hypersecretion of cortisol and sleep disturbances were not or partially restored by fluoxetine, suggesting a better efficacy of 3β-methoxypregnenolone. Alpha-tubulin isoforms were measured in hippocampi: we found that 3β-methoxypregnenolone reversed the specific decrease in acetylation of α-tubulin induced by psychosocial stress, while it did not modify the psychosocial stress-elicited reduction of tyrosinated α-tubulin.
  
  
  CONCLUSIONS
  Taken together, these data strongly suggest a potent antidepressant-like effect of 3β-methoxypregnenolone on translational parameters.
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs).
authors.forename: Lucie
authors.initials: L
authors.lastname: Parésys
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs).
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs). nicolas.froger@mapreg.com.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Froger
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs).
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Villey
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs).
authors.forename: Etienne-Emile
authors.initials: EE
authors.lastname: Baulieu
authors.affiliation: MAPREG SAS, Le Kremlin-Bicêtre, France (Drs Parésys, Froger, Bianchi, Villey, and Baulieu); German Primate Center, Göttingen, Germany (Drs Hoffmann and Fuchs).
authors.forename: Eberhard
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006854:Hydrocortisone / Q000652:urine; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000652:urine; D011284:Pregnenolone / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D012919:Social Behavior; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology*; D014404:Tubulin / Q000378:metabolism; D014418:Tupaiidae
chemical_list: C510148:3beta-methoxypregnenolone; D000928:Antidepressive Agents; D014404:Tubulin; D011284:Pregnenolone; D006854:Hydrocortisone; D009638:Norepinephrine
keywords: Psychosocial stress; antidepressant; microtubules; neurosteroids; tree shrews