Glutamate: Another Avenue for Schizophrenia Treatment?

Most new medications for schizophrenia have been “me too” drugs based on serotonin- and dopamine-receptor antagonism. Because glutamate signaling may be disturbed in schizophrenia, this study examined a completely different approach. The study focus was LY2140023, a prodrug hydrolyzed to LY404039, a selective agonist for metabotropic glutamate receptors 2 and 3 (mGlu2/3) with no affinity for other receptors. The study was developed and supported by the manufacturer of the compound.

First, LY404039 was given to mice treated with phencyclidine hydrochloride (PCP), a possible model of human schizophrenia. LY404039 inhibited the resulting hyperlocomotion in wild-type mice but not in transgenic mice with knocked-out mGlu2/3 receptors.

Then, in a d…