Validating novel targets for pharmacological interventions in schizophrenia.

摘要

An unexpected hint from a rat model of psychosis led scientists to propose a new strategy to treat schizophrenia. In 1998, Bita Moghaddam and Barbara W. Adams (1) observed that activation of group II metabotropic glutamate receptors (mGluRs) by LY354740 (an Eli Lilly agonist of mGluR2/mGluR3) in rats injected with phencyclidine attenuated the disruptive effects of phencyclidine on working memory, stereotypy, locomotion, and cortical glutamate efflux. This behavioral reversal occurred in spite of sustained dopamine hyperactivity. The finding opened a new approach to research on the potential treatments of psychiatric disorders that has extended the range of possible therapeutic targets beyond the dopamine hypothesis of schizophrenia. Almost a decade later, this discovery was followed by a clinical report (2) showing that agonists of group II mGluRs (LY404039 administered as the prodrug LY2140023) improved positive symptoms in patients with schizophrenia, with effects similar in magnitude to those of standard olanzapine treatment.