Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders

• Published in: Brain research bulletin 2008-07, Vol.76 (5), p.469-473
• Main Authors: Cleary, C, Linde, J.A.S, Hiscock, K.M, Hadas, I, Belmaker, R.H, Agam, G, Flaisher-Grinberg, S, Einat, H
• Format: Article
• Language: English
• Subjects: Affective disorders; Animal models; Animals; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Autophagy; Behavior, Animal - drug effects; Depression; Dose-Response Relationship, Drug; Forced swim test; Male; Mice; Mice, Inbred C57BL; Models, Animal; Mood Disorders - drug therapy; Mood Disorders - physiopathology; Motor Activity - drug effects; mTOR; Neurology; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Sirolimus - pharmacology; Sirolimus - therapeutic use; Tail suspension test; TOR Serine-Threonine Kinases
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2008.03.005

Abstract Lithium, the prototypic mood stabilizer, was recently demonstrated to enhance autophagy in cells. Recent hypotheses regarding the source of therapeutic effects of lithium as well as other mood stabilizers and antidepressants suggest that they may stem from increased neuroprotection, cellular plasticity and resilience. Hence it is clearly a possibility that enhanced autophagy may be involved in the therapeutic action by contributing to increased cellular resilience. A well-documented mechanism to induce autophagy is by inhibition of mTOR, a negative modulator of autophagy and rapamycin (sirolimus) is a commonly used inhibitor of mTOR. Accordingly, the present study was designed to evaluate the effects of rapamycin in animal models of antidepressant activity. A dose-response experiment in the mice forced swim test was performed and followed by additional testing of mice and rats in an open field, the forced swim test and the tail suspension test. Results show that sub-chronic, but not acute, administration of rapamycin doses of 10 mg/kg and above, have an antidepressant-like effect in both mice and rats and in both the forced swim and the tail suspension tests with no effects on the amount or distribution of activity in the open field. Whereas it is tempting to conclude that the antidepressant-like effects are related to mTOR inhibition, they may also be the consequences of interactions with other intracellular pathways. Additional studies are now planned to further explore the behavioral range of rapamycin's effects as well as the biological mechanisms underlying these effects.