Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system – implications for the 3Rs and preclinical drug discovery

Abstract

Background: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias. Aim: To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an N-methyl-D-aspartate (NMDA) receptor antagonist commonly utilised to model aspects of schizophrenia. Methods: Rats housed in groups of three were implanted with radio frequency identification (RFID) tags. Each homecage was placed over a RFID reader baseplate for the automated monitoring of the social and locomotor activity of each individual rat. For all rats, we acquired homecage data for 24 h following administration of both saline and PCP (2.5 mg/kg). Results: PCP resulted in significantly increased distance travelled from 15 to 60 min post injection. Furthermore, PCP significantly enhanced time spent isolated from cage mates and this asociality occured from 60 to 105 min post treatment. Conclusions: Unlike conventional assays, in-cage monitoring captures the temporal duration of drug effects on multiple behaviours in the same group of animals. This approach could benefit psychiatric preclinical drug discovery through improved welfare and increased between-laboratory replicability.

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

“…Impaired social functioning is a key feature of autism, but there are limitations in capturing the complexity and multidimensional nature of this domain in rodent models 8 , in part because standard paradigms involve elements of stress responsivity, as behaviour is monitored in a novel environment often between unfamiliar animals, over a limited time frame. We therefore monitored behaviours in group-housed mice in a home cage environment over 5 days 33 . Measures of locomotor activity and anxiety were monitored in parallel.…”

“…In this study, we assess the behaviour of 16p11.2 DEL mice in an ethological context, using an automated home cage monitoring system which permits group housed animals to be assessed simultaneously for social and locomotor behaviours, and where the impact of acute stress can be separated from baseline behavioural responses [30][31][32][33] . In addition, we assess the ability of NAC, as compared to the 5-HT 1B/1D/1F agonist eletriptan, to ameliorate the behavioural impact of the 16p11.2 deletion.…”

Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction

“…We tested to see whether ethological behaviours are disrupted in Mtnr1b KO mice. We choose to explore these behaviours in group-housed mice in a home-cage environment as (1) ethologically relevant behaviours can be measured simultaneously in the same mice, (2) the temporal aspects of behaviour can be monitored over several days and (3) mice are subject to less stress than in tests, such as the EPM and three-chamber test, where single animals are taken out of their home cage and placed in a novel environment ( Bains et al, 2016 ; Mitchell et al, 2020a )…”

“…We tested to see whether ethological behaviours are disrupted in Mtnr1b KO mice. We choose to explore these behaviours in group-housed mice in a home-cage environment as (1) ethologically relevant behaviours can be measured simultaneously in the same mice, (2) the temporal aspects of behaviour can be monitored over several days and (3) mice are subject to less stress than in tests, such as the EPM and three-chamber test, where single animals are taken out of their home cage and placed in a novel environment (Bains et al, 2016;Mitchell et al, 2020a) In relation to locomotor activity, the anticipated circadian variation in patterns of activity was observed, with male and female mice of both genotypes showing more activity in the dark phase as compared to the light phase. Of interest is the marked increase in locomotor activity immediately prior to the onset of the dark phase, which then subsides during the course of the dark period.…”

The Promise of Automated Home-Cage Monitoring in Improving Translational Utility of Psychiatric Research in Rodents

“…This unique combination allows researchers to automatically assess proximity between cage-mates and to visually monitor social behavior during specific times. Although convincing data about the utility of the Actual-HCA to detect social deficits in rodents is still tenuous ( Mitchell et al, 2020b ), it was successfully used to characterize social behavior in rats administered Phencyclidine ( Mitchell et al, 2020a ). The Actual-HCA provided important information about sedative and latent effects of treatment with chlorpromazine, clonidine and amphetamine that were not detected using traditional manual scoring ( Tse et al, 2018 ).…”