The phencyclidine-glutamate model of schizophrenia.

The long-standing assumption that schizophrenia stems from chronic dopamine hyperactivity is questioned by a review of evidence. Direct examinations of schizophrenic brains have not found elevated dopamine levels, altered dopamine-related enzymes, or increased dopamine receptor concentrations or affinity, meaning no direct observations link psychosis to increased dopamine activity. The anesthetic drug phencyclidine (PCP), which induces psychosis-like states, acts as a glutamate antagonist, and glutamatergic abnormalities have been detected in schizophrenic brains. This evidence suggests that glutamate hypofunction may be involved in psychotic pathology, and a functional link exists between glutamate and dopamine systems. The review concludes that dysfunctional glutamatergic pathways are involved in psychotic pathology.

Study at a glance

Abstract

For the past 20 years, it has been widely assumed that schizophrenia results from chronic dopamine (DA) hyperactivity. However large amounts of evidence exist that call into question this assumption. After examining the brains of schizophrenic patients, studies failed to find evidence of elevated levels of DA, alterations in DA-producing or degrading enzymes or both, or increased DA-receptor concentrations or affinity; thus, there are no direct observations linking psychosis to increases in DA activity. Therefore, it seems that mechanisms unrelated to altered dopaminergic functioning may be involved in the underlying pathology of schizophrenia. The anesthetic drug phencyclidine (PCP) is capable of inducing psychosis-like states through nondopaminergic mechanisms. PCP acts as a glutamate antagonist; glutamatergic abnormalities have been detected in the brains of schizophrenics. This evidence suggest that glutamate hypofunction may be involved in the pathology of psychosis. Additionally, a functional link exists between glutamate and DA neural systems. Based on these facts, as well as an extensive review of the literature, it is concluded that dysfunctional glutamatergic pathways are involved in psychotic pathology.