Glutamate and anxiety.

Although glutamate is a simple molecule, its actions in the limbic system and areas concerning anxiety are complex and widespread. These actions are mediated through different combinations of ionotropic and metabotropic glutamate receptors. Preclinical studies have shown that compounds active at NMDA, AMPA/kaïnate and metabotropic receptors might have anxiolytic properties. The major research effort so far has been directed towards the development of compounds which modulate the function of NMDA receptors. In general, the utility of NMDA and AMPA/kaïnate antagonists is greatly hampered by adverse effects. For the treatment of clinical anxiety disorder a more delicate regulation of the glutaminergic system is required. It is encouraging that different ways to fine-tune the glutaminergic system are emerging, e.g., modulators of the glycine site and compounds acting at the AMPA receptor. Metabotropic glutamate receptor agonists and antagonists are in particular promising in this respect. It can be expected that selective modulators of glutamate activity will be of great clinical significance for the treatment of anxiety disorders.