This is an application for competing renewal of a grant that was funded for five years (1994-1999) and was devoted to an investigation of neurotoxic damage induced in the adult rodent brain by phencyclidine (PCP) and related drugs that block NMDA (N-methyl-D-aspartate) glutamate (Glu) receptors. During the grant period, the applicants developed significant new insight into the mechanism of this adult brain damage syndrome and into the potential relevance of this mechanism to human neuropsychiatric disorders. In the course of this work, it was discovered that the immature brain is not vulnerable to damage by this mechanism, but that NMDA antagonists, including PCP and ketamine (both of which are drugs of abuse), can induce an extensive pattern of permanent damage in the developing rat brain by an entirely different mechanism. As a tool for studying this mechanism we have primarily used MK801, a powerful NMDA antagonist that binds with high affinity to the PCP recognition site in the NMDA receptor ion channel. Our interpretation of the mechanism, based primarily on MK801 studies, is that immature neurons during a specific stage in development (the synaptogenesis stage, also known as the brain 'growth spurt' stage) are intrinsically dependent on NMDA receptor stimulation for survival, and they are programmed to commit suicide (die by apoptosis) if deprived of this receptor input for several consecutive hours during this critical period. The objectives of this renewal application are to further characterize the ability of several drugs of abuse to trigger apoptotic neurodegeneration in the developing mammalian brain, and evaluate the potential relevance of this neurodegenerative phenomenon to human neurodevelopmental disorders.
