Effect of clozapine on ketamine-induced deficits in attentional set shift task in mice

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.

Repeated Clozapine Increases the Level of Serotonin 5-HT1AR Heterodimerization with 5-HT2A or Dopamine D2 Receptors in the Mouse Cortex

“…Mice were housed 5 per cage with mild food deprivation (2.9 g of food pellets per day) and ad libitum access to water. Food deprivation and housing schedule were based on our previous behavioral experiments (Szlachta et al, 2017 ). However, mice used in biochemical studies were not included in behavior experiments (they constituted a separate group of animals).…”

“…were administered twice (second administration was 24 h after the first one) and mice were decapitated 1 h after the second injection. This experimental paradigm resulted from the scheme of our previous behavioral studies (Szlachta et al, 2017 ). For the sub-chronic paradigm, drugs (KET or SAL) were repeatedly administered (i.p.)…”

“…Therefore, in the present study, we investigated whether CLZ, administered to mice acutely or repeatedly in two doses, affected the formation of heterodimers of dopamine D 2 –5-HT 1A receptors as well as 5-HT 1A –5-HT 2A receptors. For development the cognitive deficit we used ketamine (KET) as tool substance, according to our previous publication which showed that CLZ dose-dependently reversed KET-induced cognitive deficits (Szlachta et al, 2017 ). The method of choice to study endogenous G-protein–coupled receptor (GPCR) interaction in the native tissue is the in situ proximity ligation assay (PLA; Trifilieff et al, 2011 ; Perreault et al, 2016 ; Borroto-Escuela et al, 2017b ; Szafran-Pilch et al, 2017 ).…”

NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update

“…and sub-chronic (0.3 mg/kg, i.p. for 7 days) clozapine while the higher dose, of 1 mg/kg, impaired performance in ketamine-treated mice (Szlachta et al, 2017). Administration of ketamine has also been used to induce neurodevelopmental disturbances of relevance to schizophrenia in mice.…”

“…receptor partial agonist AAPD 1 mg/kg sc-lurasidone in female Long-Evans scPCP treated rats 2016) SB-699551, 5-HT 5A receptor antagonist 1 and 3 mg/kg in male Sprague-Dawley acute ketamine treated rats (Nikiforuk et al, 2016a) 0.3, 1 and 3 mg/kg in male Sprague-Dawley acute ketamine treated rats (Nikiforuk et al, 2016a) Clozapine, D 4 antagonist 0.1 mg/kg clozapine in female Lister Hooded scPCP treated rats (Miyauchi et al, 2017) 0.3 mg/kg clozapine in male C57Bl/6J acute ketamine treated mice (Szlachta et al, 2017); 0.3 mg/kg sc-clozapine in male C57Bl/6J sc-ketamine treated mice (Szlachta et al, 2017); • Evaluation of novel treatments in more than one animal model is recommended…”