Chapter 4.4 The glutamatergic system as a potential therapeutic target for the treatment of anxiety disorders

Glutamate is the major excitatory neurotransmitter in the adult central nervous system. Its fast actions are mediated by ionotropic receptors (NMDA, AMPA and kainate receptors). In addition, three groups comprised of eight G-protein coupled metabotropic glutamate receptors (mGluR) mediate slower modulatory actions of glutamate on neurotransmitter release and cell excitability. In recent years, there has been an accumulation of evidence that selective targeting of glutamate receptors may be a useful strategy for the treatment of anxiety disorders. Such evidence has been contingent on the availability of predictive animal models, and is largely driven by the development of selective, potent and orally bioavailable tools for distinct glutamate receptors and receptor binding sites in the brain. Moreover, the availability of genetically modified mice is also adding to the armamentarium, researchers have to dissect the role of glutamate in brain circuits relevant to anxiety. Clinical validation of the anxiolytic effects derived from preclinical models is now warranted.