Ketamine-induced changes in rat behaviour: A possible animal model of schizophrenia

Becker, Axel; Peters, Brigitte; Schroeder, Helmut; Mann, Tobias; Huether, Gerald; Grecksch, Gisela

doi:10.1016/s0278-5846(03)00080-0

Cited by 274 publications

(212 citation statements)

References 107 publications

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“…The model parameters determining local feedback strength are an amalgamated representation designed to capture multiple potential mechanisms that underpin synaptic gain. The ketamine-induced increase in these parameters could reflect enhanced local interneuronal input, hyperpolarizing currents (eg, through blockade of HCN1 channels; Chen et al, 2009) or dopaminergic modulation at D2 receptors (Becker et al, 2003), and is consistent with a recent report showing that ketamine can enhance gamma oscillations by slowing the decay kinetics of GABA A receptor-mediated IPSCs (McNally et al, 2011). In our model, enhanced local feedback inhibition would predict impaired coordinated activity amongst coactive pyramidal cells following ketamine-this should be tested directly, but is consistent with reduced correlated activity following knockout of NMDAR from CA1 pyramidal cells (McHugh et al, 1996).…”

Section: Discussionsupporting

confidence: 88%

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Moran

Jones

Blockeel

et al. 2014

Neuropsychopharmacol

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Systemic doses of the psychotomimetic ketamine alter the spectral characteristics of hippocampal and prefrontal cortical network activity. Using dynamic causal modeling (DCM) of cross-spectral densities, we quantify the putative synaptic mechanisms underlying ketamine effects in terms of changes in directed, effective connectivity between dorsal hippocampus and medial prefrontal (dCA1-mPFC) cortex of freely moving rats. We parameterize dose-dependent changes in spectral signatures of dCA1-mPFC local field potential recordings, using neural mass models of glutamatergic and GABAergic circuits. Optimizing DCMs of theta and gamma frequency range responses, model comparisons suggest that both enhanced gamma and depressed theta power result from a reduction in top-down connectivity from mPFC to the hippocampus, mediated by postsynaptic NMDA receptors (NMDARs). This is accompanied by an alteration in the bottom-up pathway from dCA1 to mPFC, which exhibits a distinct asymmetry: here, feed-forward drive at AMPA receptors increases in the presence of decreased NMDAR-mediated inputs. Setting these findings in the context of predictive coding suggests that NMDAR antagonism by ketamine in recurrent hierarchical networks may result in the failure of top-down connections from higher cortical regions to signal predictions to lower regions in the hierarchy, which consequently fail to respond consistently to errors. Given that NMDAR dysfunction has a central role in pathophysiological theories of schizophrenia and that theta and gamma rhythm abnormalities are evident in schizophrenic patients, the approach followed here may furnish a framework for the study of aberrant hierarchical message passing (of prediction errors) in schizophrenia-and the false perceptual inferences that ensue.

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Section: Discussionsupporting

confidence: 88%

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Moran

Jones

Blockeel

et al. 2014

Neuropsychopharmacol

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“…Another test that is being used to characterize animal models of schizophrenia and to evaluate compounds Thus, our data confirm the usefulness of repeated subanesthetic ketamine to induce cognitive impairments relevant to model schizophrenia symptoms in rodents and corroborate the use of this pharmacological approach as a useful animal model to study some aspects of this disease (Becker et al 2003, Neill et al 2010). …”

Section: Immobility Behavior For Modeling Schizophrenias 1663supporting

confidence: 75%

“…This drug is able to induce hyperlocomotion, stereotypy, as well as deficits in attentional and memory processes in rodents (Chan et al 2008, Imre et al 2006, Neves et al 2013, Pietersen et al 2007, Pitsikas et al 2008, Rodvelt et al 2008, Wang et al 2006). Becker et al (2003 and Becker and Grescksch (2004) showed that a sub-anesthetic dose of ketamine (30 mg/kg/day i.p.)…”

Section: Introductionmentioning

confidence: 99%

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Neves

Borsoi

Antonio

et al. 2017

An. Acad. Bras. Ciênc.

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Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine subanesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

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“…An acute low dose of ketamine (7 mg/kg) has been reported to reduce social interaction in adult male rats (Silvestre et al, 1997). Another study by Becker et al, (2003) has reported that two weeks after the final ketamine injection dose (30 mg/kg ip ketamine daily for five consecutive days), the percentage of nonaggressive behaviour (sniffing, following and grooming the partner, social play) was decreased in ketamine-treated rats. These studies suggest that treatment with both acute and sub-chronic doses of ketamine may induce social interaction deficits relevant to negative symptoms of schizophrenia.…”

mentioning

confidence: 99%

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Neill

Barnes

Cook

et al. 2010

Pharmacology & Therapeutics

475

322

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Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro-and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive disturbances of relevance to schizophrenia in rodents and their subsequent reversal by first-and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-choice serial reaction time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel therapies for improved therapy of cognitive deficits and negative symptoms in schizophrenia.

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Ketamine-induced changes in rat behaviour: A possible animal model of schizophrenia

Cited by 274 publications

References 107 publications

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

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