Figure 10.

Novel mechanisms for rapidly acting medications to treat stress-related disorders. a, The novel antidepressant candidate acetyl-L-carnitine (LAC) may act inside and outside the nucleus to exert fast antidepressant responses: it has been shown that LAC corrects mGlu2 deficits in vulnerable animal models by increasing acetylation of either the histone H3K27 bound to Grm2 promoter gene or the NFkB-p65 member (Nasca et al 2013) b, The use of the light-dark test as a screening method allows identification of clusters of animals with a different baseline susceptibility along with differences in mineralocorticoid receptor (MR) levels in hippocampus. The susceptible mice that are characterized by higher baseline MR levels show reduced hippocampal mGlu2 expression associated with exacerbation of anxious and of depressive-like behaviors after acute and chronic stress, respectively. Conversely, individuals with lower baseline MR levels cope better with stress and show adaptation in mGlu2 receptor expression in hippocampus. The epigenetic allostasis model points to the developmental origins of these individual differences, suggesting that unknown epigenetic influences early in life may lead to alterations in MR hippocampal levels (Nasca et al 2014)