Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

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Abstract

Rationale

Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia.

Aim

To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987.

Methods

Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance.

Results

Sub-chronic PCP produced significant deficits in both cognitive tasks (P < 0.01–0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P < 0.01) and 20 mg/kg (P < 0.001), and in novel object recognition at 10 mg/kg on day 1 (P < 0.01) and on day 15 (P < 0.001).

Conclusions

These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.

Introduction

Acetylcholine (ACh) is known to play an important role in various domains of cognition, particularly attention, learning, and memory (Friedman, 2004). Indeed, cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to the cognitive deficits observed in various neuropsychiatric disorders, including schizophrenia (Burghaus et al., 2000, Friedman, 2004). It is widely known that smoking rates in individuals with schizophrenia are higher than in the general population, perhaps suggesting that individuals may be self-medicating with nicotine (see Kumari and Postma, 2005). Nicotinic acetylcholine receptors (nAChRs) are ionotrophic receptors with a pentameric structure composed of alpha and beta subunits, and are highly expressed in the hippocampus, cortex, striatum, and thalamus (Breese et al., 2000, Freedman et al., 1995). The most prevalent nAChRs in the brain are the α4β2 and α7 subtypes, both of which have been shown to have reduced numbers in post-mortem studies of schizophrenia patients (Breese et al., 2000, Freedman et al., 1995). It has been suggested that these receptor subtypes play a role in cognition (Chan et al., 2007, Gray and Roth, 2007, Schreiber et al., 2002). The role of α7 nACh receptors in cognition, is further supported by evidence showing that α7 nACh receptor agonists and positive allosteric modulators improve performance in various tests of working and recognition memory (Pichat et al., 2007, Chan et al., 2007, Timmerman et al., 2007, Ng et al., 2007, Bitner et al., 2007, Redrobe et al., 2009, Hashimoto et al., 2008, Hauser et al., 2009). For a recent review of the involvement of α7 nACh receptors in cognitive processing of relevance to schizophrenia, see Leiser et al., 2009.

Our laboratory aims to model, in rats, the seven domains of cognition highlighted by the MATRICS initiative as being impaired in schizophrenia patients (Green et al., 2004, Marder and Fenton, 2004). In our hands, this has predominantly involved the implementation of an operant reversal-learning task (Abdul-Monim et al., 2003, Abdul-Monim et al., 2006, Idris et al., 2005, Idris et al., 2009, McLean et al., 2009a, McLean et al., 2009b), the attentional set-shifting task (McLean et al., 2008, McLean et al., 2010) and the ethologically relevant, novel object recognition task (Grayson et al., 2007, Idris et al., 2009, McLean et al., 2009a). We have repeatedly demonstrated that a sub-chronic PCP dosage regimen produces robust deficits in these behavioural tests (for review see Neill et al., 2010); and that these deficits are accompanied by reductions in parvalbumin-immunoreactive neurons in the hippocampus and M1 (motor area 1) region of the frontal cortex (Abdul-Monim et al., 2007) and brain-derived neurotrophic factor (BDNF) levels in several cortical regions (Snigdha et al., 2007).

PNU-282987 is a selective agonist of the human and rat α7 nAChR (Bodnar et al., 2005, Hajόs et al., 2005). It has been shown to activate the α7-5-HT3 chimera with an EC50 value of 128 nM, and to evoke rapidly desensitizing currents in cultured rat hippocampal neurons. The compound does not interact with α4β2 channels, does not antagonise α3β4 or α1β1γδ nAChRs and only antagonises 5-HT3 receptors at the higher concentrations, with an EC50 value of 4541 nM (Bodnar et al., 2005). The compound was shown to reverse an amphetamine-induced gating deficit in PPI in rats at 1 and 3 mg/kg i.v., and to improve a scopolamine-induced deficit in a continuous Y-maze task in mice at 10 mg/kg i.p. (Redrobe et al., 2009).

The aim of this study was to investigate the role of α7 nACh receptors to improve cognitive function of relevance to schizophrenia by using the selective α7 nAChR agonist, PNU-282987. This compound was tested in the reversal learning and novel object recognition tasks in the sub-chronic PCP model of schizophrenia. Active plasma and brain levels were determined. It has been suggested that nicotinic agonists may produce tolerance (become less efficacious following chronic dosing) due to sustained activation and/or desensitisation of the nAChR, and subsequent neuroadaptations (Harris et al., 2004, Quick and Lester, 2002, Smith et al., 2002, White and Levin, 2004). To address this issue of tolerance, PNU-282987 was tested following 15 days once daily treatment in the novel object recognition task.

Section snippets

Subjects and housing conditions

Two cohorts of female hooded-Lister rats (Harlan, UK) housed in groups of four or five were used as subjects. Animals initially weighing 200–220 g were maintained under standard laboratory conditions at a temperature of 21 °C (± 2 °C) and humidity of 40–50%. They were maintained on a 12-h/12-h light/dark cycle (lights on at 0700 h) and experimental procedures were performed during the light phase. Cohort 1 (50 rats) used in the reversal-learning task was gradually food deprived to approximately 90%

Effect of acute PNU-282987 on reversal learning

For percent correct responding, a paired t-test showed a significant impairment in responding in the reversal phase compared to the initial phase in the PCP-treated group (P < 0.001). A one-way ANOVA in the reversal phase showed a significant interaction (F4,47 = 10.69, P < 0.001). Post-hoc analysis revealed that PNU-282987 significantly improved the PCP-induced deficit at 10 mg/kg (P < 0.01) and 20 mg/kg (P < 0.001, Fig. 1). There was no significant effect on total lever pressing in the initial or

Discussion

The current experiments showed that PNU-282987 attenuated the sub-chronic PCP-induced deficit in reversal learning when administered acutely and in novel object recognition following acute and 15-day administration.

Sub-chronic PCP-treated rats demonstrated reduced accuracy in the reversal phase only; performance in the initial phase was unaffected, suggesting that when the rule changes PCP-treated rats do not switch to respond on the new correct lever. This is a robust and long-lasting (up to 6 

Role of the funding source

SL McLean was supported by a joint University of Bradford–GSK postgraduate studentship.

Contributors

S McLean carried out the reversal-learning experiment and wrote the first draft of the manuscript. B Grayson and N Idris carried out the novel object recognition experiments. C Mackie carried out the pharmacokinetic study. A Lesage, D Pemberton, C Mackie and J Neill designed and supervised the studies. S McLean and B Grayson performed the statistical analysis. All authors contributed to and have approved the final manuscript.

Conflict of interest

Drs Pemberton, Lesage and Mackie are employees of Johnson & Johnson Pharmaceutical Research and Development.

Acknowledgements

We thank the Discovery ADME/Tox and Bioanalysis teams at J&JPRD for generating the satellite pharmacokinetic data.

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