Previous chronic treatment with different antidepressants (fluoxetine, desipramine) completely abolished the effect of stress on glutamate release (Musazzi et al, unpublished data). The molecular underpinnings of this drug effect are currently being investigated. Therefore, based on these combined data, we speculate that modulation of stress-induced release of glutamate may be a component in the therapeutic mechanism of antidepressants in both depression and anxiety.

Postsynaptic glutamate receptors: action of antidepressants JNK inhibitor Converging evidence suggests that the functional interplay between NMDA and AMPA glutamate receptors in cortical and Inhibitors,research,lifescience,medical limbic areas is involved in both the pathophysiology of mood disorders and in antidepressant mechanisms.72-74 The two types of ionotropic glutamate receptors are often colocalized on the same individual dendritic spines. It. has been clearly demonstrated Inhibitors,research,lifescience,medical that the induction of LTP in the hippocampal CA1 region requires activation of NMDA receptors, which leads to calcium influx and activation of downstream signaling. This in turn favors the recruiting of AMPA receptors to the postsynaptic membrane, a change that is thought

to Inhibitors,research,lifescience,medical mediate the expression of LTP.56 Several preclinical studies have shown that chronic treatment with different, antidepressants induces a reduction in the function or expression of the NMDA receptor. Since the early reports on the antidepressant action of amantadine, various antidepressants, including imipramine and citalopram, have been shown to bind to and inactivate the Inhibitors,research,lifescience,medical glycine-binding site of NMDA receptors.94 Likewise, functional antagonists of the NMDA receptor were shown to induce behavioral changes similar to antidepressants in preclinical screening tests. Traditional antidepressants have been shown to produce time- and dose-dependent changes in the radioligand binding properties of rat brain NMDA receptors, but it is not clear if this is due to downregulation of receptors, because changes in mRNA expression of Inhibitors,research,lifescience,medical NMDA subunits have been only shown in mice.95 We have recently investigated this issue and found that

chronic fluoxetine and reboxetine induce in rat hippocampus downregulation of NR1 (the main subunit, of NMDA receptor) only locally at synapses, with no changes Non-specific serine/threonine protein kinase in total expression.96 The same result was found with escitalopram in a genetic animal model of depression.82 Therefore, it. seems that antidepressant-induced changes in NMDA receptors are more likely to be found at synaptic level. On the other hand, several lines of evidence support the view that increasing the function of AMPA receptors may result in antidepressant, action. First, it. has been shown that AMPA receptor activation increases the expression of BDNF (which is a mediator of antidepressant action, see above)97 as well as stimulating neurogenesis.