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Effects of Quetiapine and Sertindole on Subchronic Ketamine-Induced Deficits in Attentional Set-Shifting in Rats

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Effects of Quetiapine and Sertindole on Subchronic Ketamine-Induced Deficits in Attentional Set-Shifting in Rats Psychopharmacology (2012) 220:65–74 DOI 10.1007/s00213-011-2487-x ORIGINAL INVESTIGATION Effects of quetiapine and sertindole on subchronic ketamine-induced deficits in attentional set-shifting in rats Agnieszka Nikiforuk & Piotr Popik Received: 7 June 2011 /Accepted: 10 August 2011 /Published online: 15 September 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract administration of ketamine induces cognitive inflexibility Rationale Prefrontal cortical dysfunctions, including an after a washout period. This cognitive deficit likely reflects impaired ability to shift perceptual attentional set, are core clinically relevant aspects of cognitive dysfunction encoun- features of schizophrenia. Nevertheless, the effectiveness of tered in schizophrenic patients. The beneficial effects of second-generation antipsychotic drugs in treating specific quetiapine on set-shifting may have therapeutic implica- prefrontal dysfunctions remains equivocal. tions for the treatment of schizophrenia and other disorders Objectives To model schizophrenia-like cognitive inflexi- associated with frontal-dependent cognitive impairments. bility in rats, we evaluated the effects of repeated administration of ketamine, the noncompetitive antagonist Keywords Cognitive flexibility. Attentional set-shifting . of the N-methyl-D-aspartate receptor, after a washout period Ketamine . Quetiapine . Sertindole . Schizophrenia . Animal of 14 days in the attentional set-shifting task (ASST). Next, models . Prefrontal cortex we investigated whether the atypical antipsychotics quetia- pine and sertindole would alleviate the ketamine-induced set-shifting impairment. Introduction Methods Ketamine (30 mg/kg) was administered intra- peritoneally to rats once daily for 5 or 10 consecutive days Deficits of prefrontal cortical function are prominent to assess its efficacy in producing cognitive impairment. features of schizophrenia. These neurocognitive dysfunc- The ASST was performed 14 days following the final drug tions include reduced flexibility in modifying behavior in administration. Quetiapine (0.63, 1.25 or 2.5 mg/kg) or response to the altering relevance of stimuli. This aspect of sertindole (2.5 mg/kg) was administered per os 120 min executive function is commonly assessed in humans using before testing. the Wisconsin Card Sorting Test (WCST) (Grant and Berg Results The results of the present study demonstrate that 1948) and its modified version, the Intradimensional/ ketamine treatment for 10 but not 5 days significantly and Extradimensional Shift (ID/ED) task, developed by Roberts specifically impaired rats’ performance in the extra- et al. (1988). In fact, a poor WCST and/or ID/ED dimensional shift (EDs) stage of the ASST. This cognitive performance, which is an impairment reminiscent of that inflexibility was reversed by acute administration of observed in patients with frontal lobe damage (Pantelis et sertindole or quetiapine. Quetiapine also promoted set- al. 1999), is the key cognitive symptom of schizophrenia shifting in cognitively unimpaired control animals. (Elliott et al. 1998). Conclusion The data presented here show that subchronic Cognitive flexibility may also be assessed in the rodent version of the ID/ED task, i.e., in the attentional set-shifting : A. Nikiforuk (*) P. Popik task (ASST) (Birrell and Brown 2000). In this paradigm, Behavioral Neuroscience and Drug Development, rats must select a bowl containing a food reward based on Institute of Pharmacology, Polish Academy of Sciences, the ability to discriminate the odors and the media covering 12 Smetna Street, 31-343 Kraków, Poland the bait. The ASST requires rats to initially learn a rule and e-mail: [email protected] form an attentional “set” within the same stimulus 66 Psychopharmacology (2012) 220:65–74 dimensions. At the extra-dimensional shift (EDs), animals rats' ASST performance assessed after 2 weeks of drug must switch their attention to a new, previously irrelevant withdrawal. This protocol has been effective for inducing stimulus dimension and, for example, discriminate between behavioral changes mimicking the positive and negative the odors and no longer between the media covering the symptoms of schizophrenia, as revealed by potentiating bait. The EDs phase, regarded as an index of cognitive dizocilpine-induced hyperlocomotion and by the decrease flexibility, is impaired by lesions of the medial prefrontal in social behavior, respectively (Becker et al. 2003). cortex (mPFC) (Birrell and Brown 2000). Hence, the ASST Likewise, cognitive deficits were observed in tasks assess- measures specific frontal-dependent cognitive functions in a ing spatial working memory (Enomoto and Floresco 2009) way homologous to human tests and therefore represents a and reversal learning (Floresco et al. 2009). Additionally, useful translational approach from animal models to the second-generation antipsychotic drugs (i.e., clozapine and clinic (Keeler and Robbins 2011). risperidone) but not typical neuroleptics such as haloperidol Noncompetitive antagonists of the N-methyl-D-aspartate ameliorated ketamine-induced impairment of social inter- receptor (NMDAR), such as ketamine and phencyclidine action, suggesting predictive validity of this subchronic (PCP), produce a behavioral syndrome in healthy humans treatment paradigm (Becker and Grecksch 2004). In line that closely resembles the symptoms of schizophrenia with persistent behavioral abnormalities, this ketamine (Lahti et al. 1999). Therefore, NMDAR-based models are dosing schedule also induced dysfunction in GABAergic commonly used to mimic a schizophrenia-like state in interneurons (Keilhoff et al. 2004). Therefore, repeated laboratory animals. Interestingly, ketamine administration to ketamine administration represents a validated model in healthy volunteers produced inflexible responding in the preclinical schizophrenia research. WCST, as revealed by an increase in perseverative errors Although atypical antipsychotic medications appear to (Krystal et al. 1994). In line with clinical findings, our demonstrate a promising effect on cognitive functioning in previous study demonstrated that acute administration of schizophrenia patients (Harvey and Keefe 2001), several ketamine to rats also impaired their cognitive flexibility specific dysfunctions including cognitive inflexibility are during the EDs phase of the ASST (Nikiforuk et al. 2010). not normalized by these treatments (Goldberg et al. 2007). However, although acute administration of NMDAR Accordingly, atypical antipsychotics including clozapine, antagonists evokes a broad range of schizophrenia-like olanzapine and risperidone were largely ineffective in symptoms, experimental data suggest that repeated dosing normalizing set-shifting deficits in preclinical schizophrenia protocols might represent a more appropriate preclinical models (Rodefer et al. 2008; Goetghebeur and Dias 2009; approach for modeling neurochemical changes relevant to the but see also McLean et al. 2008). To date, only sertindole pathophysiology of this disorder. Specifically, the repetitive has consistently been shown to reverse cognitive inflexi- administration of NMDAR antagonists reduced the expression bility (Broberg et al. 2009; Goetghebeur and Dias 2009; of glutamic acid decarboxylase 67 (GAD67) and the calcium- Kos et al. 2011; Nikiforuk et al. 2010; Rodefer et al. 2008). binding protein, parvalbumin, in cortical aminobutyric acid- Clinical data indicate that among the newer atypical drugs, ergic (GABAergic) interneurons (Abdul-Monim et al. 2007). quetiapine may possess a distinctive cognitive-enhancing This GABAergic impairment has been regarded as the most action (Riedel et al. 2010). The pro-cognitive efficacy of consistently demonstrated pathological disturbance in schizo- quetiapine has been demonstrated in several cognitive phrenia (Lewis and Gonzalez-Burgos 2008). Repeated PCP domains known to be affected in schizophrenia, including treatment also evoked a metabolic abnormality, i.e., reduced executive functions (Kopala et al. 2006; Purdon et al. 2001; glucose utilization in the rat PFC, that resembled the Vo ru ga nt i e t a l. 2007). Therefore, the second goal of the hypofrontality commonly observed in schizophrenic patients present study was to evaluate the effects of quetiapine on the (Dawson et al. 2010). Additionally, repeated NMDAR ASST performance of ketamine-treated and control rats; antagonist administration leads to dysfunction of cortical sertindole was used as a positive control. dopaminergic transmission in both nonhuman primates and rodents (Jentsch et al. 1997; Jentsch et al. 1998). Because these enduring neurochemical and metabolic alternations in Materials and methods the PFC are thought to underlie cognitive impairments (Dawson et al. 2010; Abdul-Monim et al. 2007; Jentsch et Animals al. 1997), NMDAR antagonist-based preclinical models may represent a useful tool for assessing the pro-cognitive efficacy Male Sprague–Dawley rats (Charles River, Germany) of antipsychotic drugs. weighing 250–280 g on arrival were used in this study. The first aim of the present study was to investigate the They were initially group-housed (5 rats/cage) in a impact of subchronic (5 or 10 consecutive days) adminis- temperature- (21±1°C) and humidity-controlled (40–50%) tration of the subanesthetic dose (30 mg/kg) of ketamine on colony room under a 12/12-h light/dark cycle (lights on at Psychopharmacology (2012) 220:65–74 67 0600 hours). Rats were allowed
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