Involvement of Glutamate Transporters in Neuropathology of Phencyclidine Abuse

Abuse of phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate receptor antagonist, induces schizophrenia-like psychosis in humans. In addition, emotional and cognitive behavioral impairments, or glutamatergic-based dysfunction, have been noted following subchronic PCP administration to adult and perinatal rodents. Such impairments have also been noted following a combination of immune activation by polyriboinosinic-polyribocytidylic acid (Poly I:C) administered to neonatal rodents and by subchronic PCP administration to adolescent rodents. These impairments are associated with increased glial cell expression of the glial glutamate and aspartate transporter. Facilitation of glutamatergic neurotransmission by intracerebral microinjection of glutamate transporter inhibitor ameliorated the behavioral impairments in mice that had received subchronic PCP or a combination of Poly I:C and PCP. Given the clinical similarity between PCP psychosis and schizophrenia, and the findings described here, this approach may provide a useful animal model for studying the neuropathology of PCP psychosis or schizophrenia, and the usefulness of glutamate transporter inhibitors as potential therapeutic targets.