Deficits of [ 3 H]D -aspartate binding to glutamate uptake sites in striatal and accumbens tissue in patients with schizophrenia M. Iraide Aparicio-Legarza, Andrew J. Cutts, Ben Davis, Gavin P. Reynolds* Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK Received 10 June 1997; received in revised form 24 July 1997; accepted 24 July 1997 Abstract The hypothesis involving glutamate in the neuropathology of schizophrenia has attracted great interest. Several studies report dysfunc- tions in glutamatergic systems, including alterations in kainate and N-methyl-D-aspartate (NMDA) receptors in various areas, as well as changes in the number of glutamate uptake sites. We have studied this further using [ 3 H]D-aspartate binding to glutamate uptake sites as a measure of the integrity of presynaptic glutamate systems in several areas (caudate nucleus, putamen, nucleus accumbens, frontal cortex and temporal cortex) of brain tissue taken at autopsy from schizophrenic patients and controls. A significant decrease in the number of glutamate uptake sites was apparent in caudate nucleus, putamen and nucleus accumbens in the schizophrenia group, indicating an impaired glutamatergic innervation of these subcortical regions. However, no significant changes were found in the two cortical regions studied.  1997 Elsevier Science Ireland Ltd. Keywords: Schizophrenia; Glutamate uptake sites; [ 3 H]D-aspartate binding; Postmortem human tissue; Antipsychotic drugs Glutamate is the most abundant amino acid in brain, where it plays an important role, not only in the synthesis of peptides and proteins, but as a well-established major excitatory neurotransmitter in the central nervous system (CNS). It has been suggested that reduced glutamate neuro- transmission may be involved in the pathophysiology of schizophrenia. This hypothesis is based on several observa- tions. Phencyclidine (PCP) is a drug which can induce a schizophrenia-like psychosis including both positive and negative symptoms [17] and exerts its action by blocking the ion channel linked to the N-methyl-D-aspartate (NMDA) glutamate receptor subtype [11]. This is supported by the observation that other non-competitive NMDA antagonists such as MK-801 and ketamine elicit PCP-like psychoses, whereas PCP derivatives that block dopamine (DA) reup- take but do not bind to the NMDA receptor fail to reproduce the PCP-induced effects [14]. Furthermore, it may be that there is a reduced glutamate release in the brain of schizo- phrenics. Although the reported decrease of glutamate con- centration in cerebrospinal fluid of schizophrenic patients [13] has not been supported by further studies [20], it has been observed that there is a significantly reduced glutamate release induced by veratridine, kainate and NMDA in synaptosomal preparations from brains of schizophrenic patients [21]. A further line of evidence relates to the close relationship between dopamine and glutamate systems [2]; dopamine has long been implicated in schizophrenia since antipsychotic drugs are considered to exert their action via dopamine D 2 receptor antagonism. Finally, numerous recent reports show alterations in glutamate receptor bind- ing in postmortem assays [10], with [ 3 H]kainate binding being increased in frontal cortex [6,19], MK-801 binding in-creased in putamen [15] and in temporal cortex [22], whereas [ 3 H]AMPA binding shows no changes [8,12,16]. Such increases in the number of glutamate receptors have been interpreted as compensatory and due to a glutamater- gic hypofunction [6,15]. This is supported by experiments by Ulas et al. [23] demonstrating that an increase in the number of NMDA and kainate receptors in ipsilateral hip- pocampus occurs after unilateral lesions of the entorhinal cortex in the rat. However, it is important to assess the function of the presynaptic glutamatergic system in schizo- phrenia using more specific and direct markers. Several Neuroscience Letters 232 (1997) 13–16 0304-3940/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(97)00563-6 * Corresponding author. Tel.: +44 114 2224662; fax: +44 114 2765413; email: g.p.reynolds@sheffield.ac.uk