Ketamine activates psychosis and alters limbic blood flow in schizophrenia

Lahti, Adrienne C.; Holcomb, Henry H.; Medoff, Deborah R.; Tamminga, Carol A.

doi:10.1097/00001756-199504190-00011

Cited by 412 publications

(251 citation statements)

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“…In addition, NMDA receptor binding in the hippocampus is transiently decreased (at 3 h) and subsequently increased (for approximately 2 days) after single-dose PCP administration (Gao and Tamminga 1996). Interestingly, the transient metabolic and glutamatergic effects of PCP are most closely temporally associated with symptom production in ketamine-treated schizophrenic subjects (Lahti et al 1994) and are consistent with increased limbic blood flow in patients (Lahti et al 1995). Of course, it is the early effects that are most closely linked with the ketamine-induced psychosis and cognitive impairments, because these effects are largely short-lived (on the order of hours; Krystal et al 1994).…”

Section: Glutamatergic and Gabaergic Dysfunctionmentioning

confidence: 91%

“…Recent studies of regional cerebral blood flow after ketamine or PCP administration may provide clues as to the neural circuits affected by NMDA receptor antagonist administration in humans. Acute ketamine exposure markedly increases frontal cortical blood flow, especially in the anterior cingulate and frontomedial cortical regions of normal humans or schizophrenic patients (Lahti et al 1995;Breier et al 1997a;Vollenweider et al 1997). In sharp contrast, long-term abuse of PCP by humans has been associated with reduced frontal lobe blood flow and glucose utilization (Hertzman et al 1990;Wu et al 1991).…”

Section: Do Acute and Long-term Pcp Exposure Have Similar Consequences?mentioning

confidence: 99%

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

Jentsch

Roth²

1999

Neuropsychopharmacology

1,207

772

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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...

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Section: Glutamatergic and Gabaergic Dysfunctionmentioning

confidence: 91%

Section: Do Acute and Long-term Pcp Exposure Have Similar Consequences?mentioning

confidence: 99%

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

Jentsch

Roth²

1999

Neuropsychopharmacology

1,207

772

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“…Ketamine is a non-competitive antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor (Jantzen, 1994;Lahti et al, 1995) which causes an initial decrease in striatal tissue O 2 and regional cerebral blood flow (rCBF), followed, on recovery, by an increase in both variables to levels above basal, which is accompanied by a period of intense motor activity predominated by stereotypic head movements (Lowry, J.P., unpublished observations). A typical example of the effect of a subanaesthetic ketamine injection (50 mg/kg) on the Pt/PPD/GOx and O 2 (CPE) signals recorded simultaneously in the striatum of a freely-moving rat is shown in Fig.…”

Section: Effect Of Oxygen On Biosensor Response In 6i6omentioning

confidence: 99%

An amperometric glucose-oxidase/poly(o-phenylenediamine) biosensor for monitoring brain extracellular glucose: in vivo characterisation in the striatum of freely-moving rats

Lowry

Miele

O’Neill

et al. 1998

Journal of Neuroscience Methods

100

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Amperometric glucose biosensors based on the immobilization of glucose oxidase (GOx) on Pt electrodes with electropolymerized o-phenylenediamine (PPD) were implanted in the right striatum of freely-moving rats. Carbon paste electrodes for the simultaneous monitoring of ascorbic acid (AA) and/or tissue O 2 were implanted in the left striatum. A detailed in vivo characterization of the Pt/PPD/GOx signal was carried out using various pharmacological manipulations. Confirmation that the biosensor responded to changing glucose levels in brain extracellular fluid (ECF) was obtained by intraperitoneal (i.p.) injection of insulin that caused a decrease in the Pt/PPD/GOx current, and local administion of glucose (1 mM) via an adjacent microdialysis probe that resulted in an increase in the biosensor current. An insulin induced increase in tissue O 2 in the brain was also observed. Interference studies involved administering AA and subanaesthetic doses of ketamine i.p. Both resulted in increased extracellular AA levels with ketamine also causing an increase in O 2 . No significant change in the Pt/PPD/GOx current was observed in either case indicating that changes in O 2 and AA, the principal endogenous interferents, have minimal effect on the response of these first generation biosensors. Stability tests over a successive 5-day period revealed no significant change in sensitivity. These in vivo results suggest reliable glucose monitoring in brain ECF.

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“…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). …”

mentioning

confidence: 99%

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

Newcomer

Farber

Jevtović-Todorović

et al. 1999

Neuropsychopharmacology

546

350

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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...

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Ketamine activates psychosis and alters limbic blood flow in schizophrenia

Cited by 412 publications

References 0 publications

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

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

An amperometric glucose-oxidase/poly(o-phenylenediamine) biosensor for monitoring brain extracellular glucose: in vivo characterisation in the striatum of freely-moving rats

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

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