sirolimus and Mood-Disorders

Macrolides are protein synthesis inhibitors exerting an action on the bacterial ribosome. The ribosomes coded for by the human mitochondrial deoxyribonucleic acid (DNA) are similar to those from bacteria in size and structure. In addition, mitochondria are thought to have originated from a symbiotic relationship between an anaerobic proto-eukaryotic cell that engulfed an aerobic bacterium. Morphological changes of mitochondria have been observed in bipolar disorder and schizophrenia. Manic episodes associated with the use of antimicrobial agents have been described since the discovery of isoniazid. The oxidative stress induced in the neuronal mitochondria is thought to underlie this effect. The inhibition of GSK-3β in the intra-mitochondrial Akt signaling pathway is thought to convey mood stabilizing properties. Rapamycin is a macrolide that, besides its antiepileptic effect, restores the Akt function and inhibits the mTOR pathway which may have an antidepressant effect. Accordingly, it is hypothesized that rapamycin may have mood stabilizing properties.

Topics: DNA, Mitochondrial; Humans; Mitochondria; Models, Biological; Mood Disorders; Neurons; Oxidative Stress; Proto-Oncogene Proteins c-akt; Ribosomes; Sirolimus; TOR Serine-Threonine Kinases

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 10mg/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.

Topics: Animals; Antibiotics, Antineoplastic; Antidepressive Agents; Behavior, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Models, Animal; Mood Disorders; Motor Activity; Protein Kinases; Rats; Rats, Sprague-Dawley; Sirolimus; TOR Serine-Threonine Kinases