The demise of old certitudes and the birth of novel opportunities in neuropsychopharmacology Editorial overview Joseph T Coyle Current Opinion in Pharmacology 2004, 4:1–3 This overview comes from a themed issue on Neurosciences Edited by Joseph Coyle 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.12.001 Joseph T Coyle Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA e-mail: joseph_coyle@hms.harvard.edu Joseph T Coyle is the Eben S Draper Professor of Psychiatry and Neuroscience at Harvard Medical School. His research has been directed at the understanding of the neurobiology of severe neuropsychiatric disorders, with a particular interest in the role of glutamatergic neurotransmission in their pathophysiology. Abbreviations LTP long-term potentiation mGluR metabotropic glutamate receptor NMDA N-methyl-D-aspartate It has been an honor and pleasure to be invited to organize this issue of Current Opinion in Pharmacology. This responsibility prompted some reflec- tion on how the field has evolved over the 35 years in which I have been involved. When I commenced pharmacological research in 1968, CNS drug discovery was primarily based on serendipity, linked to attempts to tether behavioral effects of drugs to alterations in chemical neurotransmission. Neurons were believed to use only one neurotransmitter, and the mature nervous system was thought to be ‘hard-wired’, with neurogenesis ceasing soon after birth. Psychiatric disorders were thought to be ‘functional’ without any brain pathology, and treatments other than palliative ones for neurodegenerative disorders were viewed with considerable pessimism. Except for rare conditions, genetics was thought to be irrelevant to the etiology of most neuropsychiatric disorders. The serial destruction of these scientific certitudes over the past 35 years has brought the field to a molecular era of neuropsychotropic drug discovery where genetic risk factors are used to identify molecular targets for drug development. Ultimately, as the genetics of neuropsychiatric disorders and pharmacogenetics advance, one can envision a future with highly selective drug treatments tailored to an individual’s particular genetic subtype of disorder and the drug metabolism status. Thus, these reflections have dictated the selection of topics for this issue. I have tried to include, together with the more traditional neuropharmacological issues, research areas that stretch the concept of pharmacology to therapeutic interventions involving genes and even cells. Glutamate is the primary excitatory neurotransmitter in the brain and is utilized by over 40% of synapses. Although, initially, the focus of interest in glutamate was in excitotoxicity, the ubiquitous distribution of glutamatergic neurons in brain implies that glutamatergic dysfunction probably occurs in many CNS disorders. Glutamatergic neurotransmimssion has been impli- cated in learning and memory through the process of long-term potentiation (LTP). LTP is a use-dependent enhancement of excitatory neurotransmis- sion and typically requires the activation of voltage-dependent N-methyl-D- aspartate (NMDA) receptors as a result of robust stimulation of AMPA receptors. Lynch describes a new group of agents that are allosteric positive www.sciencedirect.com Current Opinion in Pharmacology 2004, 4:1–3