Interestingly, recent, clinical studies found a rapid and sustained antidepressant effect, (up to 1 week) of a single infusion of the noncompetitive NMDA antagonist ketamine.100,101 In a preclinical study Macng et al102 showed that in rats the antidepressant effect (measured in the forced swim test) may last, for 2 weeks. They also showed

that AMPA receptor throughput is required for the antidepressant effect of ketamine, and suggested that enhancement of AMPA to NMDA troughput in Inhibitors,research,lifescience,medical critical circuits is the mechanism of rapid antidepressant effect.102 The use of ketamine for a rapid antidepressant, effect has been proposed as a strategy for treatment-resistant Dorsomorphin IC50 depression.74 Intriguingly, acute administration of ketamine increases glutamate release, probably by disinhibiting NMDA receptor-containing GABAergic neurons and in turn enhancing the firing rate of glutamatergic neurons. But, as addressed above, the prevalent effect of traditional antidepressants in limbic Inhibitors,research,lifescience,medical and cortical areas seems to be a reduction in glutamate release (particularly if measured as a response to stress; Musazzi et al, unpublished data); how could this riddle be solved? Early observations and our preliminary results may suggest that also traditional antidepressants acutely increase the presynaptic Inhibitors,research,lifescience,medical release of glutamate and that reduction

of glutamate release is an adaptive change which takes time to develop.70,103 Therefore, in this hypothesis, at. the beginning Inhibitors,research,lifescience,medical of treatment traditional antidepressants might, transiently increase presynaptic glutamate release in critical circuits (a feature perhaps linked to worsening of symptomatology, eg, anxiety); in the course Inhibitors,research,lifescience,medical of treatment, release of glutamate in limbic/cortical areas, such as hippocampus and prefrontal cortex, will be reduced along with a synaptic reduction of NMDA receptor levels. This combined effect, would produce a dampening

of glutamate transmission and an enhancement of AMPA- vs NMDA-mediated transmission. More work is required to understand if this is the mode of action of traditional antidepressants, and if quicker redistribution of AMPA vs NMDA-mediated transmission may speed up the onset of antidepressant action. Finally, metabotropic glutamate receptors (mGlu) are Entinostat also crucial for the regulation of glutamatergic neurotransmission as well as for other neurotransmitters that arc involved in mood disorders and depression. Limited clinical proof of concept for mGlu receptor ligands in the treatment of affective disorders has been achieved. In sellckchem particular, group II receptor agonists (mGlu2/3) and group I receptor antagonists (mGlu5) have shown activity in animal and/or human conditions of fear, anxiety, or stress.