The effect on melatonin on ketamine induced mTOR phosphorylation

Many people affected by chronic depression fail to respond to currently prescribed antidepressants, and even in the most successful treatment cases these drugs are plagued by a three week latency to therapeutic benefit (Duman et al., Neuropharmacology 2012:62;35-41). Ketamine, an NMDA antagonist used as an anesthetic and a drug of abuse, has been shown to exert a rapid antidepressant effect at sub-anesthetic doses in a clinical trial (Berman et al., Biol Psychiatry 2000;47:351-354) and to decrease immobility in mice subjected to the forced swimming test (Li et al. Science 2010;329:959-964). The effect of ketamine in mice relies on the activation the mammalian target of rapamycin (mTOR) in the prefrontal cortex (Li et al. Science 2010;329:959-964).  The overall goal of this project is to determine whether the effect of ketamine on mTOR activation is altered by melatonin, a hormone whose receptors are being investigated as targets of novel antidepressants (Hickie and Rogers, Lancet 2011;378:621-631). In this study, we treated C3H/HeN mice with vehicle, melatonin (10 mg/kg, i.p.) or ketamine (0.3, 1, 3, and 10 mg/kg, i.p.). The mice were sacrificed 30 minutes later for brain harvesting and dissection, and mTOR activation in the prefrontal cortex was analyzed by Western blot. We found that treatment with 10 mg/kg ketamine enhanced mTOR activation. Additional studies will determine the effect of melatonin on the induction of mTOR signaling by ketamine. This analysis will help us understand the potential of melatonin to safely modulate the antidepressant-like effect of ketamine.