Effects of the Synthetic Neurosteroid 3β-Methoxypregnenolone (MAP4343) on Behavioral and Physiological Alterations Provoked by Chronic Psychosocial Stress in Tree Shrews

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 3 beta-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 3 beta-methoxypregnenolone, we investigated effects of a longer treatment (4-week oral administration; 50 mg/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 3 beta-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 3 beta-methoxypregnenolone. Alpha-tubulin isoforms were measured in hippocampi: we found that 3 beta-methoxypregnenolone reversed the specific decrease in acetylation of a-tubulin induced by psychosocial stress, while it did not modify the psychosocial stress-elicited reduction of tyrosinated alpha-tubulin. Conclusions: Taken together, these data strongly suggest a potent antidepressant-like effect of 3 beta-methoxypregnenolone on translational parameters.