P1‐049: The social recognition test of memory in the rat: A reliable primary in‐vivo cognition assay for guiding drug discovery/development decision‐making relevant to neuropsychiatric diseases

Background: The social recognition test in rats has become increasingly popular for the pharmaceutical industry as a tool to evaluate compounds for pro-cognitive activity. Thismemory test probes short-term recognition/working memory and provides a relatively high-throughput method to investigate novel target mechanisms relevant to cognitive impairment associated with neuopsychiatric disorders such as Alzheimer’s disease (AD), schizophrenia and Parkinson’s disease (PD). This simple test can be configured in a number of formats to develop a rationale for the target mechanism on temporally induced forgetting or reversing pharmacologically-induced impairments (e.g. scopolamine, MK-801 or reserpine) or aged-dependent deficits. Importantly the test uses spontaneous naturalistic behaviour of an adult rat when exposed to a juvenile conspecific on two occasions to access cognition, where the output measured (recognition index/ratio of investigator duration between the two sessions) involves an assessment of social exploration, strongly influenced by an olfactory component. As numerousmechanisms of diverse target classes have been evaluated in this simple cognition assay, the level of pharmacological validation has greatly improved justifying its utility as a screening tool for drug discovery/development decision-making. Furthermore site of actionand lesion studies have identified the frontal cortex as a key anatomic substrate engaged in the social recognition memory task, providing a relatively simple method to examine novel target mechanisms on modulating frontal cognitive function with respect to social encounters. We provide evidence for a reliable deficit in spontaneous recognition towards the familiar juvenile rat following a temporal delay (120 mins) which is reversed by the cholinesterase inhibitor (donepezil) providing a useful benchmark for prosecuting and validating NCE’s relevant to cognitive function, particularly with respect to AD and PD indications. Furthermore robust pharmacologically-induced deficits are presented (e.g. scopolamine andMK-801) following a short delay (30 mins) offering the opportunity of assessing the effects of novel targets onmodulating cholinergic orglutamatergic tone, respectively. Finallywe present data on an aged-related social memory impairment following a short delay (30 mins), relative to young adult rats, providing a relevant paradigm to detect symptomatic and/or disease-modifying effects of novel mechanisms for neuropsychiatric disorders. Methods: Male adult rats (Wistar-Han, from Elevage Janvier, France) were assessed in a social recognition memory test to recall prior exposure to a conspecific juvenile (3-4 weeks of age). Adult rats (350 450g) were housed individually and all testing was carried out in their home cage. An unfamiliar juvenile was introduced and overall investigation (sniffing, grooming, licking and closely following behaviours) was recorded for a 5 min period (contact 1 1⁄4 C1). The juvenile rat was then removed to its home cage. After 120 mins, the same juvenile was reintroduced and overall investigation duration (RID) was again recorded during a second 5 min period (contact 21⁄4 C2). Donepezil (1 or 3 mg/kg i.p.) or vehicle was administered i.p. to the adult rat, immediately after the first exposure period (C1 i.e. 120 mins before C2). To control for non-specific effects, a separate experiment was carried out in which a new unfamiliar/different juvenile was introduced to the adult rats during C2. To evaluate the effect of pharmacologically-induced social recognition impairment, scopolamine (0.25 mg/kg sc) or MK-801 (0.1 mg/kg i.p.) was administered 30 mins prior to C1 relative to vehicle i.p. Following a 30 min delay adult rats were re-exposed to the juvenile conspecific (C2). To establish an aged-dependent effect on social recognition performance, male Wistar (Han) rats of 20 22 months of age (Elevage Janvier, France) were compared to young adult rats (5-6 months of age) using a 30 minUTE temporal delay. All data was evaluated statistically using an ANOVA followed by appropriate post-hoc tests. Results:A temporal delay of 120mins between CI and C2 induced a robust impairment in spontaneous recognition in adult rats towards a familiar juvenile rat when compared to a shorter delay (30 mins). Importantly the cholinesterase inhibitor donepezil (1 and 3 mg/kg i.p.) improved social recognition memory performance of the adult rat using this temporal delay when administered immediately after CI. This was not apparent when a different juvenile was presented to the adult rat on C2, suggesting that the recognition impairment and reversal of the deficit by donepezil is a function of re-exposure to the familiar juvenile. Scopolamine (0.25 mg/kg sc or ip) orMK-801 (0.1 mg/ kg i.p.) administered 30 mins prior to CI induced a significant recognition deficit during C2 following a 30 min delay, suggesting cholinergic and glutamatergic blockade disrupts social working memory. Aged rats (>20 months of age) demonstrated a significant social recognition memory deficit following a short (30 mins) delay as compared to young adult rats (5-6 months of age) confirming the natural occurring decline in social cognitive function as a function of age. Conclusions: The social recognition test in the rat provides a relevant short-term working memory test to evaluate the pro-cognitive activity of numerous target mechanisms aligned to cognitive impairment associated with neuropsychiatry disorders, such as Alzheimer’s disease, schizophrenia, Parkinson’s disease. Importantly this test can be used in a number of configurations to evaluate the effects of novel target mechanisms on natural forgetting cognitive processes i.e. consolidation, as well under the experimental conditions involving pharmacological manipulations such as scopolamine and MK-801. Importantly the selection of the format of the test using pharmacologically-induced impairments can help provide mechanistic insight for NCE’s related to cholinergic or glutamatergic processes to support the subsequent progression to alternative tests probing different cognitive domains and anatomical substrates relevant to neuropsychiatric disorders. The aged-dependent deficits in social recognition memory offers the potential for determining the symptomatic and/or disease modifying properties of a NCE, providing a more disease-relevant assessment for drug discovery/development decision-making.