L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Epigenetic mechanisms are involved in the pathophysiology of depressive disordersand are unique potential targets for therapeutic intervention. The acetylatingagent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as anantidepressant by the epigenetic regulation of type 2 metabotropic glutamate(mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect inFlinders Sensitive Line rats and in mice exposed to chronic unpredictable stress,which, respectively, model genetic and environmentally induced depression. Inboth models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing thetranscription of Grm2 gene encoding for the mGlu2 receptor in hippocampus andprefrontal cortex. Importantly, LAC reduced the immobility time in the forcedswim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine.Moreover, there was no tolerance to the action of LAC, and the antidepressanteffect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibitionprevented the increase in mGlu2 expression induced by LAC, whereas the use of ahistone deacetylase inhibitor supported the epigenetic control of mGlu2expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonistLY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetichypothesis of depressive disorders in humans, paving the way for more efficientantidepressants with faster onset of action.