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, 110 (12), 4804-9

L-acetylcarnitine Causes Rapid Antidepressant Effects Through the Epigenetic Induction of mGlu2 Receptors

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L-acetylcarnitine Causes Rapid Antidepressant Effects Through the Epigenetic Induction of mGlu2 Receptors

Carla Nasca et al. Proc Natl Acad Sci U S A.

Abstract

Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim 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 antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC 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 LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Rapid and long-lasting antidepressant activity of LAC in FSL rats.(A) Immobility time in FST in FSL and FRL rats treated i.p. with saline, LAC, or CLO. n = 8. P < 0.05 vs. the respective values at t0 (*), the corresponding values in saline-treated rats (#), or in rats treated with CLO (§). F = 82.1 (time) and 4.7 (treatments). (B) Immobility time in FST in FSL rats treated with LAC for 21 d and with saline or LY341495 on the following day (t22). n = 6. P < 0.05 vs. t0 values (*) or vs. t22 values of FSL rats injected with saline (#). F = 45.5. (C) LAC effect on sucrose preference test in FSL and FRL rats. n = 7. *P < 0.05 vs. the respective values at t0 and the corresponding values of saline-treated rats. F = 46.6 (time) and 8.4 (treatments).
Fig. 2.
Fig. 2.
LAC treatment corrects abnormalities in BDNF and glutamate release in FSL rats. (A) BDNF levels in prefrontal cortex and hippocampus of FRL and FSL rats treated with saline or LAC for 21 d. n = 6. P < 0.05 vs. all other values (*) or vs. FRL rats treated with LAC (#). F = 25.4 and 13.6 for hippocampus and prefrontal cortex, respectively. (B) Levels of acetylated H3K27 bound to BDNF promoter gene in prefrontal cortex and hippocampus of FRL and FSL rats treated with saline or LAC for 21 d, n = 4. P < 0.05 vs. all other values (*) or vs. FSL rats treated with saline (#). F = 31.78 and 8.099 for hippocampus and prefrontal cortex, respectively. (C) Serum BDNF levels in FRL and FSL rats treated with saline or LAC for 21 d. n = 6. *P < 0.05 vs. FSL rats treated with saline. F = 8.9. (D) LAC effect on depolarization-evoked glutamate and GABA release in superfused hippocampal synaptosomes, n = 6. *P < 0.05 vs. all other values.
Fig. 3.
Fig. 3.
Epigenetic regulation of mGlu2 receptors by LAC in FSL rats. (A) mGlu2 receptors expression in prefrontal cortex and hippocampus of FRL and FSL rats treated with saline or LAC for 3 or 21 d. n = 4 (3 d) or 6 (21 d). *P < 0.05 vs. all other values. F = 8.54 and 13.9 at 3 d, 12.9 and 12.4 at 21 d, for prefrontal cortex and hippocampus, respectively. (B) mRNA levels of mGlu2 and mGlu3 receptors in prefrontal cortex and hippocampus of FRL and FSL rats treated with saline or LAC. n = 6. P < 0.05 vs. the respective values of FRL rats (*) and vs. FSL rats treated with saline (#). F = 91.6. (C) Increased acetylation of p65/NF-κB in prefrontal cortex and hippocampus of FSL rats, n = 6. *P < 0.05 vs. the respective values of FSL rats treated with saline. (D) mGlu2 receptors expression in prefrontal cortex and hippocampus of FRL and FSL rats treated with sodium salicylate and/or LAC, n = 4. *P < 0.05 vs. the corresponding values obtained in FRL rats. F = 1.58E-002 and 9.22 for prefrontal cortex and hippocampus, respectively. (E) Levels of acetylated H3K27 bound to the Grm2 promoter gene in prefrontal cortex and hippocampus of FRL and FSL rats treated with saline or LAC. n = 6. *P < 0.05 vs. all other values. F = 8.7 and 8.3 for prefrontal cortex and hippocampus, respectively. (F) mGlu2 receptors expression in prefrontal cortex of FRL and FSL rats treated with saline or MS-275 for 21 d. n = 4. *P < 0.05 vs. all other values. F = 10.16.
Fig. 4.
Fig. 4.
Antidepressant activity of LAC in mice exposed to CUS. (A) LAC effect on immobility time of CUS mice and unstressed mice. n = 6. P < 0.05 vs. the corresponding t0 values (*) and vs. the respective values of stressed mice treated with saline (#). F = 8.4 and 5.4 for time and treatments, respectively. (B) Sucrose preference test in CUS mice and unstressed mice. n = 6. *P < 0.05 vs. both the corresponding t0 values and the respective values of stressed mice treated with saline. F = 32.2 and 2.28 for time and treatments, respectively. (C) Immobility time in FST in CUS mice treated with LAC for 21 d and with an acute i.p. injection of saline or LY341495 on the following day (t22). n = 6. P < 0.05 vs. t0 values (*) or vs. t22 values of stressed mice injected with saline (#). F = 0.72. (D) Immobility time in wild-type and mGlu2−/− mice treated with saline or LAC for 14 d. n = 6. *P < 0.05 vs. both the corresponding t0 values and the respective values of stressed mice treated with saline. F = 46.7 and 10.8 for time and treatments, respectively.

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