Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia

The anterior cingulate cortex is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Previous studies suggest abnormalities in the glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia patients. In the present study we used quantitative autoradiography to investigate the binding of [ 3 H]MK801, [ 3 H]L-␣ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA),Glutamate is the primary excitatory neurotransmitter in the human brain. Excitatory synaptic activity conveyed by glutamate is mediated by three pharmacologically defined subtypes of ionotropic glutamate receptors: N-methyl-D-aspartate (NMDA), D, L-␣ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate. The NMDA receptor comprises two subunits that are coded by genes designated NR1 and NR2A-D. Non-NMDA glutamate receptor subunits comprise GluR1-4, which are AMPA-preferring, and GluR5-7, KA1 and KA2, which are kainate preferring (Hollmann and Heinemann 1994).Pharmacological and biochemical data have suggested deficiency in glutamatergic transmission in schizo- Although it is usually the NMDA receptor that is implicated in schizophrenia, disturbances of any of the glutamate receptors could result in a condition that produces the appearance of an abnormally functioning NMDA receptor. For example, NMDA receptors are blocked by magnesium at physiological concentrations, and AMPA receptor-mediated depolarization of the membrane extrudes magnesium from the NMDA receptor complex (Reynolds and Miller 1990). Therefore, a pathological change in the function of non-NMDA receptors may affect the NMDA receptor.Given the possibility of glutamate receptor dysfunction in schizophrenia, the expression of ionotropic glutamate receptors has been studied in post-mortem brain of schizophrenia patients and abnormalities in glutamate receptors have been reported in many brain areas (reviewed by Meador-Woodruff and Healy 2000; see also Deakin and Simpson 1997). Some of these reports have not been replicated and have been done primarily in membrane preparations. These studies illustrate that the occurrence and nature of glutamate receptor abnormalities in schizophrenia can differ between brain regions.The anterior cingulate cortex (ACC; Brodmann's area 24) is localized within a gyrus on the media surface of each hemisphere, bordering on the corpus callosum. It receives projections from the amygdala (Vogt and Pandya 1987), thalamus (Vogt et al. 1979) and hippocampus (Vogt et al. 1979;Tamminga et al. 2000), possibly excitatory in nature. Abnormalities in glutamatergic neurotransmission have been reported in the ACC in schizophrenia. Recent studies using post-mortem human ACC indicate a dramatic increase in vertical glutamatergic axons in the superficial layers of ACC in schizophrenia (Benes 2000) and imaging studies suggest impaired activation of ACC in patients with schizophrenia during performance tasks, which could be attributed to a reduced efferent glutamatergic signal from the hippo...

Section: Resultssupporting

confidence: 62%

mentioning

confidence: 99%

Selective Alterations in Ionotropic Glutamate Receptors in the Anterior Cingulate Cortex in Schizophrenia

Zavitsanou

Ward

Huang

2002

“…These ideas are supported by the finding that schizophrenic patients had lower cerebrospinal fluid glutamate concentrations than controls (Kim et al 1980); however, this finding remains controversial (e.g., Perry, 1982 failed to find such an effect). Furthermore, glutamate receptors have been reported to be increased in schizophrenia (an effect presumably secondary to reduced glutamate transmission; Toru et al 1994).…”

Section: Glutamatergic and Gabaergic Dysfunctionmentioning

confidence: 96%

The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

Jentsch

Roth²

1999

1,202

772

Administration of noncompetitive NMDA ր glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animalsBiological psychiatric research has seen the development of many putative animal models of schizophrenia. The etiological bases of these models have varied widely from the administration of purportedly psychotomimetic drugs (Snyder 1988; Javitt and Zukin 1991; Jentsch et al. 1998a), to perinatal insults (Lipska et al. 1993;El-Khodor and Boksa 1997;Moore and Grace 1997; Bertolino et al. 1997), to chronic social isolation or stress (Jones et al. 1990), and beyond. The administration of psychotomimetic drugs to humans and animals represents probably the most widely accepted and utilized class of schizophrenia models. These "pharmacological" models seem to represent methods for the induction of psychopathology in humans and aberrant (potentially related) behavior in animals.At the behavioral level, there seems to be some heterogeneity in the effects of different psychotomimetic drug classes. The psychomotor stimulants, such as amphetamine and cocaine, can clearly induce a form of 20 , NO . 3 paranoid psychosis in human subjects after high-dose or long-term administration, but evidence regarding the ability of these agents to induce "deficit" state symptoms is conflicting (Angrist and Gershon 1970;Everitt et al., 1997); moreover, there is evidence that amphetamine may actually alleviate negative and cognitive symptoms in schizophrenic patients (Angrist et al. 1982;Goldberg et al. 1991; Carter et al. 1997). Psychotomimetic indoleamines, such as lysergic acid diethylamide, can induce profound sensory hallucinations without causing any apparent deficit state in normal subjects (Geyer and Markou 1994) and without precipitating symptomatology in schizophrenic patients (Cohen et al. 1962). In contrast, the noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) ր glutamate receptor, including phencyclidine (PCP) and ketamine, seem to be capable of inducing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans (Snyder 1980; Javitt and Zukin 1991;Tamminga 1998); these drugs also profoundly exacerbate both positive and negative symptoms in schizophrenic patients (Itil et al. 1967;Lahti et al. 1994;Malhotra et al. 1997a).Because of the more comprehensive psychopathology induced by PCP, many researchers have studied the effects of NMDA receptor antagonists in humans and animals to gain insights into the neurobiology of schizophrenia. In this review, the validity of NMDA receptor antagonist-induced models of schizophrenia in humans and animals are considered, and the applicability of acute versus chronic administration of PCP as a more precise model is assessed. The neurobiological substrates of the observed behavior...

“…The results of these investigations have emphasized hypofunction of glutamatergic neurons and/or the N-methyl-D-aspartate (NMDA) glutamate receptor (Tsai et al 1995;Kim et al 1980aKim et al , 1980bSherman et al 1991;Deutsch et al 1989;Javitt and Zukin 1991;Olney 1988a;Olney 1988b;Olney and Farber 1995). An important element of several of these theoretical positions is that NMDA receptor hypofunction (NRH) produced by any mechanism can be psychotogenic.…”

mentioning

confidence: 99%

Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis

Newcomer

Farber

Jevtović-Todorović

et al. 1999

541

350

Considerable research interest has recently been focused on the role of glutamate and related neural circuitry in the neurobiology of schizophrenia. The results of these investigations have emphasized hypofunction of glutamatergic neurons and/or the N-methyl-D-aspartate (NMDA) glutamate receptor (Tsai et al. 1995;Kim et al. 1980aKim et al. , 1980bSherman et al. 1991;Deutsch et al. 1989;Javitt and Zukin 1991;Olney 1988a;Olney 1988b;Olney and Farber 1995). An important element of several of these theoretical positions is that NMDA receptor hypofunction (NRH) produced by any mechanism can be psychotogenic. This has renewed interest in the clinical effects of NMDA glutamate receptor antagonists.Ketamine and phencyclidine (PCP) are non-competitive NMDA glutamate receptor antagonists (Zukin and Zukin 1979;Vincent et al. 1979;Lodge and Anis 1982;Lodge et al. 1987) which can produce a transient state of NRH in the brain. Early investigators characterized a PCP-induced clinical syndrome of schizophrenia-like Received March 18, 1998; revised June 19, 1998; accepted June 29, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 2 NMDA Receptor Hypofunction Induced Memory Decrease 107 symptoms, including hallucinations, delusions, idiosyncratic and illogical thinking, poverty of speech and thought, agitation, disturbances of emotion, affect, withdrawal, decreased motivation, and dissociation (Johnstone et al. 1959;Luby et al. 1959;Rosenbaum et al. 1959;Luby et al. 1962;Corssen and Domino 1966;Bakker and Amini 1961;Davies and Beech 1960;Domino and Luby 1981). This PCP-induced syndrome can be indistinguishable from acute presentations of schizophrenia (Yesavage and Freeman 1978;Erard et al. 1980). Ketamine, a PCP analog still used in human anesthesia, has been reported to cause reactions similar to but not as severe as those caused by PCP, including brief, reversible "positive" and "negative" schizophrenia-like symptoms (Krystal et al. 1994;Malhotra et al. 1996). Both PCP and ketamine can exacerbate psychosis in schizophrenia Luby et al. 1962;Lahti et al. 1995a;Lahti et al. 1995b;Malhotra et al. 1997).Declarative, explicit or secondary memory and learning deficits in patients with schizophrenia occur early in the course of the illness and are quantitatively large compared with deficits in other differentiated elements of cognitive performance, showing stability "on" versus "off" antipsychotic medication and over repeated testing (Gruzelier et al. 1988;Saykin et al. 1991Saykin et al. , 1994Cannon et al. 1994). Clinical and preclinical investigations suggest the hypothesis that changes in NMDA glutamate receptor activity in patients with schizophrenia may be causally related to memory impairments found in this disorder. Relevant to this hypothesis, the activation of post-synaptic NMDA receptors is important for the induction of the activity-dependent synaptic modification called long-term potentiation (LTP) (Bliss and Collingridge 1993;Collingridge and Bliss 1995), and hippocampal LTP has been postulated to underlie cert...