Depression is thought to involve epigenetic mechanisms which are potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate receptors (mGlu2). It causes a rapid and long-lasting antidepressant effect in rodent models of depression. L-Acetylcarnitine reduced the immobility time in the forced swim test and increased sucrose preference after as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. There was no tolerance to the action of L-acetylcarnitine, and the antidepressant effect was still seen 2 wk after drug withdrawal. Increased mGlu2 receptor expression was observed in the hippocampus and prefrontal cortex after L-acetylcarnitine treatment. By contrast, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by L-acetylcarnitine, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Supporting a role of mGlu2 receptors, L-acetylcarnitine had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked L-acetylcarnitine action. The authors suggest that the rapid and long-lasting antidepressant action of L-acetylcarnitine may be a unique approach to study of the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Mattrisciano F, Battaglia G, Mathé AA, Pittaluga A, Lionetto L, Simmaco M, and Nicoletti F: L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. PNAS 110(12): 4804-4809 (2013).
