Imaging the glutamatergic system in vivo – relevance to schizophrenia

Abstract

Schizophrenia is a devastating psychiatric illness. Its pathophysiology is not fully clarified. Animal data, in vitro and indirect in vivo imaging support glutamatergic N-methyl-D-aspartate (NMDA) receptor hypofunction in the disorder. A lack of suitable ligands has obstructed direct evaluation of the NMDA receptor hypofunction hypothesis of schizophrenia. Many research groups are working towards developing appropriate single-photon emission tomography and positron emission tomography ligands for the NMDA receptor. This paper briefly presents evidence for links between glutamatergic system dysfunction and schizophrenia. It reviews the radioligands to evaluate glutamatergic receptors in vivo and discusses issues in developing novel ligands for the glutamatergic system.

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

“…Therefore, the SAP97 reduction in the prefrontal cortex is likely to contribute to the impaired expression of the AMPA receptor protein and resultant glutamatergic dysfunction in this brain region. These findings lend support to the hypothesis and previous reports of hypofunction of the prefrontal cortex in schizophrenic patients, which presumably involves impaired excitatory neurotransmission (Duncan et al 1999;Bressan and Pilowsky 2000).…”

“…Interestingly, a major psychotomimetic drug, phencyclidine, acutely alters SAP97 gene expression, suggesting a potential link between psychotic symptoms and the PDZ protein SAP97 (Linden et al 2001). Accordingly, the impaired protein expression of SAP97 and GluR1 in the prefrontal cortex might be associated with the hypofunction of the prefrontal cortex in schizophrenic patients revealed by the above neurochemical studies as well as by neuroimaging studies (Weinberger et al 1986;Selemon et al 1995;Andreasen et al 1997;Duncan et al 1999;Bressan and Pilowsky 2000).…”

A Randomized, Placebo-Controlled Study of Memantine as Adjunctive Treatment in Patients with Schizophrenia

“…The rationale for using memantine as an adjunctive therapy for patients with schizophrenia comes from the fact that the glutamatergic system, and specifically hypofunctioning of NMDA receptors, has been implicated in the pathophysiology of schizophrenia, and is thought to mediate several psychopathological components of the disease including psychotic, negative, and cognitive symptoms (Javitt and Zukin, 1991;Bressan and Pilowsky, 2000;Carlsson et al, 2000;Egerton et al, 2005;Yang and Chen, 2005).…”

Glutamate and psychiatric disorders

“…There is clearly need to explore new treatment approaches in schizophrenia, as even the best therapeutic responses obtained with existing typical or atypical antipsychotic drugs are often delayed and not fully restorative (Tamminga, 1998 Bressan & Pilowsky, 2000). Since glycine-related compounds act indirectly as obligatory co-agonists increasing the frequency of the NMDA-gated channel openings, medications that act at the glycine site have subsequently been tested.…”