Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions.

Schizophrenia affects up to 1% of the population worldwide. The dopamine hypothesis has been the leading neurochemical explanation, proposing that excess dopamine in striatal regions and deficits in prefrontal regions cause symptoms. About 15 years ago, an alternative model emerged based on the observation that drugs like PCP and ketamine, which block NMDA-type glutamate receptors, induce psychotic and cognitive symptoms similar to schizophrenia. Since then, evidence has accumulated supporting NMDA receptor hypofunction in schizophrenia. NMDA antagonists produce negative and cognitive symptoms as well as positive ones, unlike dopaminergic agents. Treatment studies with NMDA modulators such as glycine, d-serine, and glycine transport inhibitors have shown encouraging but controversial results. Genetic and neurochemical studies point to causes of NMDA dysfunction.

Study at a glance

Abstract

Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. As of yet, neurochemical mechanisms underlying schizophrenia remain unknown. To date, the most widely considered neurochemical hypothesis of schizophrenia is the dopamine hypothesis, which postulates that symptoms of schizophrenia may result from excess dopaminergic neurotransmission particularly in striatal brain regions, along with dopaminergic deficits in prefrontal brain regions. Alternative neurochemical models of schizophrenia, however, have been proposed involving glutamatergic mechanisms in general and N-methyl-D-aspartate (NMDA) receptors in particular. A potential role for glutamatergic mechanisms in schizophrenia was first proposed approximately 15 years ago based on the observation that the psychotomimetic agents phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at NMDA-type glutamate receptors. Since that time, significant additional evidence has accumulated supporting a role for NMDA hypofunction in the pathophysiology of schizophrenia. Clinical challenge studies with PCP and ketamine have confirmed the close resemblance between NMDA antagonist-induced symptoms and neurocognitive deficits and those observed in schizophrenia, and suggest that NMDA dysfunction may lead to secondary dopaminergic dysregulation in striatal and prefrontal brain regions. As compared to dopaminergic agents, NMDA antagonists induce negative and cognitive symptoms of schizophrenia, as well as positive symptoms. Treatment studies with NMDA modulators, such as glycine, d-serine, and glycine transport inhibitors (GTIs), have yielded encouraging findings, although results remain controversial. Finally, genetic linkage and in vivo neurochemical studies in schizophrenia highlight potential etiological mechanisms giving rise to glutamatergic/NMDA dysfunction in schizophrenia.