Partial agonism at the α7 nicotinic acetylcholine receptor improves attention, impulsive action and vigilance in low attentive rats.

Inattention is a disabling symptom in conditions such as schizophrenia and attention deficit/hyperactivity disorder. Nicotine can improve attention and vigilance, but is unsuitable for clinical use due to abuse liability. Genetic knockout of the α7 nicotinic acetylcholine receptor (nAChR) induces attention deficits therefore selective agonism may improve attention, without the abuse liability associated with nicotine. The α7 nAChR partial agonist encenicline (formerly EVP-6124) enhances memory in rodents and humans. Here we investigate, for the first time, efficacy of encenicline to improve attention and vigilance in animals behaviourally grouped for low attentive traits in the 5 choice-continuous performance task (5C-CPT). Female Lister Hooded rats were trained to perform the 5C-CPT with a variable stimulus duration (SD). Animals were then grouped based on performance into upper and lower quartiles of d' (vigilance) and accuracy (selective attention), producing high-attentive (HA) and low-attentive (LA) groups. LA animals showed an increase in selective attention and vigilance at 0.3mg/kg encenicline, a reduction in impulsive action (probability of false alarms) and increase in vigilance following 1mg/kg at 0.75sSD. At 1mg/kg, HA animals had reduced selective attention at 0.75sSD and reduced vigilance at 0.75 and 1.25sSD. Improvement of attention, vigilance and impulsive action in LA animals demonstrates that encenicline has pro-attentive properties dependent on baseline levels of performance. Our work suggests that α7 nAChR partial agonism may improve attention particularly in conditions with low attention.

Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents.

The novel object recognition test (NOR) test is a two trial cognitive paradigm that assesses recognition memory. Recognition memory is disturbed in a range of human disorders and NOR is widely used in rodents for investigating deficits in a variety of animal models of human conditions where cognition is impaired. It possesses several advantages over more complex tasks that involve lengthy training procedures and/or food or water deprivation. It is quick to administer, non-rewarded, provides data quickly, cost effective and most importantly, ethologically relevant as it relies on the animal's natural preference for novelty. A PubMed search revealed over 900 publications in rats and mice using this task over the past 3 years with 34 reviews in the past 10 years, demonstrating its increasing popularity with neuroscientists. Although it is widely used in many disparate areas of research, no articles have systematically examined this to date, which is the subject of our review. We reveal that NOR may be used to study recognition memory deficits that occur in Alzheimer's disease and schizophrenia, where research is extensive, in Parkinson's disease and Autism Spectrum Disorders (ASD) where we observed markedly reduced numbers of publications. In addition, we review the use of NOR to study cognitive deficits induced by traumatic brain injury and cancer chemotherapy, not disorders per se, but situations in which cognitive deficits dramatically reduce the quality of life for those affected, see Fig. 1 for a summary. Our review reveals that, in all these animal models, the NOR test is extremely useful for identification of the cognitive deficits observed, their neural basis, and for testing the efficacy of novel therapeutic agents. Our conclusion is that NOR is of considerable value for cognitive researchers of all disciplines and we anticipate that its use will continue to increase due to its versatility and several other advantages, as detailed in this review.

The involvement of distraction in memory deficits induced by NMDAR antagonism: relevance to cognitive deficits in schizophrenia.

Recognition memory, impaired in neuropsychiatric conditions and currently untreated, may be assessed by the novel object recognition (NOR) task with robust impairments induced by sub-chronic treatment with the N-methyl-d-aspartate receptor antagonist phencyclidine (PCP). The aim of the present study was to investigate how sub-chronic PCP produces its effects in this task. Forty adult female rats received vehicle or PCP (2mg/kg i.p. twice daily for 7 days followed by 7 days washout). Rats completed a 3-min acquisition trial followed by differential inter-trial-interval (ITI) conditions (1 min in the home cage, 10s in the home cage, 1 min in the NOR test box in the presence of an unfamiliar object or 1 min in the NOR test box completely undisturbed) followed by a 3-min retention trial. Control rats spent significantly more time exploring the novel compared with the familiar object in retention. This effect was abolished in the sub-chronic PCP treated animals following all ITI conditions except in rats left completely undisturbed in the NOR test box for a 1 min ITI. The combined influence of sub-chronic PCP treatment and the effect of distraction provides further support for the validity of the NOR test in mimicking cognitive deficits of relevance to schizophrenia.