A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

Abstract

Rationale: The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective: The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods: Adult female hooded-Lister rats received subchronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for seven days, followed by a seven-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for seven days and were then tested in the perceptual set-shifting task. Results: PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions:These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCPinduced cognitive deficit.

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

“…We have consistently demonstrated that a low dose of risperidone improves object recognition memory (Grayson et al, 2007), reversal learning (McLean et al, 2010b) and attentional set shifting (McLean et al, 2008) deficits induced by sub-chronic PCP in female hL rats. It is important to note that the dose we use is not sufficient to block dopamine D2 receptors and is more likely to overcome the PCP deficit through other mechanisms (see Neill et al 2014 for a discussion of this topic).…”

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

“…This deficit was attenuated by seven-day treatment with 20 clozapine and risperidone, but was unaffected by haloperidol (McLean et al, 2008). Rodefer and colleagues combined the attentional set-shifting test with a sub-chronic PCP dosing regimen in male Long-Evans rats (5 mg/kg twice daily, i.p., for 7 days followed by a 10 day drug washout period) and found a selective deficit in the EDS phase (Rodefer et al, 2005).…”

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

“…PCP hydrochloride (Sigma, UK) was dissolved in 0.9% saline. This dosage regime has proved to be very successful in our laboratory in producing robust reversal learning (Abdul-Monim et al, 2006;McLean et al, 2009) object recognition (Grayson et al, 2007) and attentional set-shifting deficits (McLean et al, 2008a), and social behaviour deficits (Snigdha and Neill, 2008a;. In these experiments we have used female rats and we have previously shown that the stage of oestrous cycle does not affect reversal learning performance (McLean et al, 2009).…”

“…In our laboratory, we have shown that PCP selectively impairs performance in reversal learning (Abdul-Monim et al, 2006;McLean et al, 2009), attentional set-shifting (McLean et al, 2008a) and novel object recognition (Grayson et al, 2007), importantly these tests are all of relevance to schizophrenia as highlighted by the MATRICS.ucla.edu initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia), and subsequently the TURNS.ucla.edu program (Treatment Units for Research on Neurocognition and Schizophrenia). Our sub-chronic PCP dosing regime causes reduced density of parvalbumin-immunoreactive neurons in hippocampal regions (Abdul-Monim et al, 2007) and levels of brain-derived neurotrophic factor mRNA (BDNF) in cortical regions (Snigdha et al, 2007) in rats.…”