Abstract
RationaleClozapine (CLZ) is an effective treatment for schizophrenia, producing improvements in both negative symptoms and cognitive impairments. Cognitive impairments can be modelled in animals by ketamine (KET) and assessed using the attentional set-shift task (ASST).ObjectiveOur first aim was to determine whether CLZ improves cognitive function and reverses KET-induced cognitive impairments using the ASST. Our second aim was to assess dose dependency of these effects.ResultsOur findings demonstrate that acute as well as sub-chronic administration of KET cause cognitive deficits observed as increase in number of trails and errors to reach the criterion in the EDS phase. CLZ 0.3 mg/kg reversed the effects of both acute and sub-chronic KET, with no effects on locomotor activity. However, clozapine’s effect after sub-chronic administration of dose 0.3 mg/kg was not as explicit as in the case of acute treatment. Moreover, administration of 1 mg/kg CLZ to KET-treated mice induced or enhanced deficits in the extra-dimensional shift phase compared to 1 mg/kg CLZ administration to mice not receiving KET. Locomotor activity test showed sedation effects of CLZ 1 mg/kg after acute treatment; therefore, effect of CLZ 1 mg/kg on KET-induced cognitive deficits was not evaluated in the attentional set-shift task (ASST) test.ConclusionsThe present findings support dose-dependent effects of CLZ to reverse KET-induced cognitive deficits. The observed dose dependency may be mediated by activation of different receptors, including monomers and/or heterodimers.
Highlights
Studying the mechanisms of action for antipsychotic drugs requires development of new rodent models
Analyses of locomotor activity after acute treatment revealed a significant interaction between time (5 min intervals for a total of 30 min) and drug treatment (SAL, KET, CLZ 0.3 mg/kg, KET+CLZ 0.3 mg/kg, CLZ 1 mg/kg, KET+CLZ 1 mg/kg) [F(30,168)] = 2.09, p < 0.01
Two-way ANOVA of the sub-chronic treatment data found no interaction between time and drug treatment [F(30,168)] = 0.58, ns, significant main effects occurred for time [F(6,168)] = 10.64, p < 0.0001 and drug treatment [F(5,168)] = 3.84, p < 0.01
Summary
Studying the mechanisms of action for antipsychotic drugs requires development of new rodent models. Acute administration of KET or PCP rapidly increases PFC metabolic activity in parallel with PFC-related psychotic symptoms in healthy individuals (Vollenweider et al 1997) This observation was adapted to an animal model of schizophrenia; acute and/or sub-chronic treatment with KET or PCP, followed by a washout period, induces cognitive impairments in animals (Scheggia et al 2014; Neill et al 2010; Becker et al 2003; Becker and Grecksch 2004; McLean et al 2008; Kos et al 2011; Nikiforuk et al 2013). Attentional set shift tasks are used to assess frontal lobe damage and cognitive flexibility This kind of tasks is based on the use of compound stimuli (i.e. texture and odour stimuli in different modalities). The attentional set shift task version for rodents is one of the main animal tests to evaluate cognitive deficits (Barnett et al 2010)
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