INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Int J Geriatr Psychiatry 2003; 18: S33–S40. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/gps.933 Glutamate and the glutamate receptor system: a target for drug action Stefan Bleich*, Konstanze Ro ¨mer, Jens Wiltfang and Johannes Kornhuber Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Germany SUMMARY Glutamate is the most important excitatory neurotransmitter in the central nervous system. In the process, glutamate fulfills numerous physiological functions, but also plays an important role in the pathophysiology of different neurological and psychiatric diseases, especially when an imbalance in glutamatergic neurotransmission occurs. Under certain conditions, glutamate has a toxic action resulting from an activation of specific glutamate receptors, which leads to acute or chronic death of nerve cells. Such mechanisms are currently under discussion in acute neuronal death within the context of hypoxia, ischaemia and traumas, as well as in chronic neurodegenerative or neurometabolic diseases, idiopathic parkinsonian syn- drome, Alzheimer’s dementia and Huntington’s disease. It is hoped that glutamate antagonists will lead to novel therapies for these diseases, whereby the further development of glutamate antagonists for blocking disease-specific subtypes of glu- tamate receptors may be of major importance in the future. Copyright # 2003 John Wiley & Sons, Ltd. key words — glutamate; glutamate receptors; excitotoxicity; glutamate antagonists; neuroprotective treatment GLUTAMATE RECEPTORS The excitatory amino acid glutamate is the most important excitatory transmitter in the central nervous system. Glutamate is involved in developmental, adult synaptic plasticity, neurogenesis, and neurode- generation (Danbolt, 2001). Although glutamate is a crucial mediator of physiological communication between neuronal cells, under certain conditions acti- vation of glutamate receptors kills neurones which is called excitotoxicity (Rothman and Olney, 1987). Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central ner- vous system ischemia, trauma, and other neurological disorders. In general, synaptic overactivity leads to the excessive release of glutamate. Glutamate stimu- lates glutamate receptors, which are divided into dif- ferent subtypes and subgroups on the basis of their ligands, the subsequent signal induction mechanisms and their molecular homology. The glutamate recep- tors are membrane based and are divided into two main groups. Metabotropic receptors change intracel- lular processes via signal transduction mechanisms and in this way intervene in a wide variety of different cellular functions. Ionotropic receptors cause ion flows at the cell membrane and changes in membrane potential. The NMDA subtype of glutamate receptors plays a key role in mediating excitotoxic damage, owing to its high Ca 2þ permeability (MacDermott et al., 1986) and evoking the generation of reactive oxygen species. Moreover, primary inhibition of the mitochondrial respiratory chain indirectly induced NMDA receptor stimulation, which is termed second- ary excitotoxicity (Greene and Greenamyre, 1995). Each of these groups of receptors (metabotropic or ionotropic) has further molecular diversity, which results in the composition of different subunits or dif- ferent subtypes (Danbolt, 2001; Ozawa et al., 1998). METABOTROPIC GLUTAMATE RECEPTORS The metabotropic glutamate receptors (mGluR) do not have ion channels, but mediate their function via G-proteins (Pin and Duvoisin, 1995), which then in turn trigger further second-messenger systems. As described in Figure 1, the activation of mGluR from group I with the subtypes mGluR1 and 5 leads to an Copyright # 2003 John Wiley & Sons, Ltd. Accepted 19 January 2003 * Correspondence to: Dr S. Bleich, Friedrich-Alexander University of Erlangen-Nuremberg, Department of Psychiatry and Psychother- apy, Schwabachanlage 6-10, 91054 Erlangen, Germany. Tel: þ49 9131 8534143. Fax: þ49 9131 8534105. E-mail: stefan.bleich@psych.imed.uni-erlangen.de