Mazindol attenuates ketamine-induced cognitive deficit in the attentional set shifting task in rats

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Abstract

Cognitive impairments associated with schizophrenia await an effective treatment. In order to model schizophrenia-like cognitive deficits in rats, we evaluated the effects of ketamine, a dissociative anesthetic NMDA/glutamate receptor channel blocker in the attentional set-shifting task (ASST). Acute administration of ketamine (10 but not 3 mg/kg) selectively impaired solving of the extradimensional (ED) set-shifting component. Next, we investigated whether the co-administration of mazindol, a dopamine and norepinephrine reuptake inhibitor would protect rats from ketamine-induced deficits. Mazindol dose-dependently and selectively alleviated ketamine-induced ED deficit with a minimal effective dose of 0.5 mg/kg. The ED component improvement was noted primarily in ketamine — but not in vehicle co-treated rats, in which the drug facilitated ED shift solving at the dose as high as 5 mg/kg. A “positive control”, sertindole (2.5 mg/kg) also ameliorated ketamine-induced ED deficit. Microdialysis of the prefrontal cortex in a separate group of animals revealed that 2–3 h after the administration of 5 mg/kg of mazindol and ketamine (i.e., at the time of ED component solving), the extracellular concentrations of dopamine were enhanced by ~ 300% as compared to the baseline and were intermediate between the mazindol- and ketamine-treated reference groups. However, at that time the levels of norepinephrine, serotonin and glutamate appeared unaffected. We conclude that ketamine may be useful in mimicking deficits specifically related to cognitive inflexibility observed in schizophrenia, and suggest that these anomalies could be ameliorated by mazindol. The beneficial effects of mazindol on ASST performance may have therapeutic implications for the treatment of schizophrenia.

Introduction

Schizophrenia is characterized by “positive” symptoms such as hallucinations, delusions, and disorganized thought, the “negative” symptoms such as lack of motivation, blunted affect, anhedonia, self-neglect and social withdrawal; and cognitive impairments including deficits in set shifting, attention, and working memory. Specifically, schizophrenic patients develop neuropsychological dysfunctions including reduced flexibility in modifying behavior in response to altering relevance of stimuli. This aspect of executive function, controlled by the prefrontal cortex (PFC), is commonly assessed in humans using Wisconsin Card Sorting Test (WCST) (Grant and Berg, 1948) and its modified version developed by Roberts et al. (1988). In fact, a poor WCST performance is the behavioral key symptom of schizophrenia (Elliott et al., 1998) an impairment reminiscent of that observed in patients with frontal lobe damage (Pantelis et al., 1999). Although atypical antipsychotic medications appear to demonstrate a promising effect on cognitive functioning (Harvey and Keefe, 2001), several specific dysfunctions including cognitive inflexibility are not normalized by these treatments (Goldberg et al., 2007).

Birrell and Brown (2000) have developed the rodent model of attentional set-shifting task (ASST), an equivalent of WCST used in humans. In this paradigm, the rats have to select a bowl containing food reward, based on the ability to discriminate the odors and the media covering the bait. The ASST requires rats to initially learn a rule and form an attentional set within the same stimulus dimensions. In the extra-dimensional (ED) shift, the crucial part of the test, the subjects have to switch their attention to a new, previously irrelevant stimulus dimension (e.g. from the odors to the media covering the bait). The ED component is impaired by lesions of the medial frontal cortex (Birrell and Brown, 2000) as well as by the administration of psychotomimetic dissociative anesthetic phencyclidine (PCP) (Egerton et al., 2005); see Discussion section.

The noncompetitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has been used clinically as a dissociative anesthetic since the 1960s (Martin and Lodge, 1985). Like PCP (Luby, 1959), ketamine produces schizophrenia-like states in healthy humans (Krystal et al., 1994), and, therefore, it has been commonly used to model some symptoms of schizophrenia in animals (e.g., Verma and Moghaddam, 1996, Becker et al., 2003). Interestingly, the ketamine-induced cognitive impairments include attentional-set shifting deficits as measured by the WCST (Krystal et al., 2000), but ketamine-induced disturbances in attentional flexibility have not been reported in rodents. Thus, the first goal of the present study was to identify whether ketamine, an easily available (as opposed to PCP) dissociative anesthetic, would produce attentional-set shifting deficits also in rats. To mimic human experiment conditions, we administered ketamine systemically in an acute dose.

The second goal of the present study was to determine whether ketamine-induced deficits could be alleviated by broadly available dopamine-mimetic medication. We investigated mazindol, a dopamine (DA) and norepinephrine (NE) reuptake inhibitor (Javitch et al., 1984) due to the accumulating evidence indicating an involvement of dopaminergic pathways in cognitive processes governed by the prefrontal cortex. Specifically, data from a number of human studies and animal models have suggested that DA neurotransmission in PFC might regulate attentional flexibility. For instance, a deficit in attentional-set shifting was observed in healthy humans after administration of the DA D2 receptor antagonist sulpiride (Mehta et al., 1999), and DA depletion impaired fronto-striatal functional connectivity during the set-shifting task (Nagano-Saito et al., 2008). In line with human studies, 6-hydroxydopamine (6-OHDA) lesion in the PFC of common marmoset impaired the ability to acquire an attentional-set (Crofts et al., 2001) and an enhanced DA release in the rat medial PFC under set-shifting condition was correlated with the rapidity, with which animals shifted between discrimination rules (Stefani and Moghaddam, 2006). Using maze-based set-shifting paradigm in rats, Floresco et al. (2006) have demonstrated that the effects of DA receptors agonists and antagonists on attentional flexibility depend on their subtype-selectivity.

As we found that the ketamine-induced impairment of a specific component of the ASST was prevented by mazindol, the third goal of the present study was to characterize the effects of both compounds on the PFC extracellular concentrations of dopamine, serotonin, norepinephrine and their metabolites as well as the levels of glutamate. We hypothesized that the beneficial effects of mazindol on ketamine-induced cognitive deficit were due to the increased extracellular concentrations of dopamine.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, Germany) weighting 250–280 g on the arrival were used in this study. They were initially group-housed (five rats/cage) in a temperature (21 ± 1 °C) and humidity (40–50%) controlled colony room under 12/12-h light/dark cycle (lights on at 06:00 h). Rats were allowed to acclimatize for at least 7 days before the start of the experimental procedure. For one week prior to the testing the rats were individually housed and mildly food deprived (15 g of food pellets

Experiment 1

As illustrated in Fig. 1, all groups of rats required significantly more trials to reach the criterion on the ED than the ID stage of the task, demonstrating that they had formed an attentional set towards the relevant dimension before ED discrimination stage. Additionally, initial relevant dimension on which animals were trained prior to ED stage (e.g., the odor or the medium) had no influence on their performance. Ketamine administrated at a dose of 10 mg/kg (but not 3 mg/kg) significantly and

Discussion

The present study provides a link between preclinical and human data by showing ketamine-induced cognitive deficits at the ED stage of attentional set-shifting task in the rat. Second, we demonstrated that acute, systemic administration of the DA and NE reuptake inhibitor mazindol at relatively low doses (0.5–1.25 mg/kg) selectively protected rats from the ketamine-induced impairment of ED set shifting. Microdialysis of the prefrontal cortex suggested that the beneficial effects of mazindol on

Role of the funding source

This work was supported by the Statutory Funds of the Institute of Pharmacology, Polish Academy of Sciences and the Grant for Scientific Network of the Ministry of Science and Higher Education.

Contributors

PP and AN designed the study. AN collected the data, undertook the statistical analyses and wrote the first draft of the manuscript. PP wrote the final draft of the manuscript. KG performed the microdialysis study. All authors contributed to, and have approved the final manuscript.

Conflict of interest

The authors have no conflicts of interest to report, nor any involvement to disclose, financial or otherwise, that may bias the conduct, interpretation or presentation of this work.

Acknowledgements

This work was supported by the Statutory Funds of the Institute of Pharmacology, Polish Academy of Sciences and the Grant for Scientific Network of the Ministry of Science and Higher Education. The authors wish to thank H. Lundbeck A/S, Denmark for the generous gift of sertindole.

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