Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in 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.
References (63)
- et al.
The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm
Behavioural Brain Research
(2006) - et al.
Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia
Neuropsychopharmacology
(2000) - et al.
Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance
Trends in Pharmacological Sciences
(2005) - et al.
Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients
Brain Research, Molecular Brain Research
(2000) - et al.
Frontal cortical α7 and α4β2 nicotinic acetylcholine receptors in working and reference memory
Neuropharmacology
(2007) - et al.
Correlation between left frontal phospholipids and Wisconsin Card Sort Test performance in schizophrenia
Schizophrenia Research
(1995) - et al.
Evidence in post-mortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia
Biological Psychiatry
(1995) - et al.
Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the NOR task in the rat
Behavioural Brain Research
(2007) - et al.
Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria
Biological Psychiatry
(2004) - et al.
SSR180711 phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711
Biological Psychiatry
(2008)
TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms of schizophrenia
Biochemical Pharmacology
Impaired inhibition of conditioned responses produced by subchronic administration of phencyclidine to rats
Neuropsychopharmacology
Behavioural rigidity and rule-learning deficits following isolation-rearing in the rat: neurochemical correlates
Behavioural Brain Research
Nicotine use in schizophrenia: the self medication hypotheses
Neuroscience and Biobehavioural Reviews
A cog in cognition: how the α7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits
Pharmacology & Therapeutics
Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia
Schizophrenia Research
Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat
Behavioural Brain Research
Deficits in attentional set-shifting in rats following sub-chronic phencyclidine (PCP) administration, effect of gender
European Neuropsychopharmacology
A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats
Behavioural Brain Research
D1-like receptor activation improves PCP-induced cognitive deficits in animal models: implications for mechanisms of improved cognitive function in schizophrenia
European Neuropsychopharmacology
Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism.
Pharmacology and Therapeutics.
α7 nicotinic acetylcholine receptor activation ameliorates scopolamine-induced behavioural changes in a modified continuous Y-maze task in mice
European Journal of Pharmacology
Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia
Neuropsychopharmacology
Brain-derived neurotrophic factor downregulation in rat brain following sub-chronic phencyclidine administration
European Neuropsychopharmacology
Influence of gender on working and spatial memory in the novel object recognition task in the rat
Behavioural Brain Research
α7 nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment
Neuropharmacology
Design, synthesis, structure–activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists
Bioorganic and Medicinal Chemistry
Neuronal responses related to long-term recognition memory processes in prefrontal cortex
Neuron
The atypical antipsychotic ziprasidone, but not haloperidol, improves phencyclidine-induced cognitive deficits in a reversal learning task in the rat
Journal of Psychopharmacology
Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alteration in parvalbumin-immunoreactive expression in the rat
Journal of Psychopharmacology
Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia
Neuroscientist
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