The effect of a 5-HT2A inverse agonist on animal models of obsessive-compulsive disorder: marble burying tasks

Compulsive persistent, non-functional behavior is a staple characteristics of obsessive-compulsive disorder (OCD) in humans. It is commonly studied in rodents through defensive burying of harmless objects. Multiple serotonergic drugs have affected marble burying in rodents. The inclusion of other kinds of interaction with marbles has been suggested as an additional model for compulsive behavior not motivated by anxiety or reward. This study hypothesized that marble interactions, like marble burying will persist or increase over days despite not being motivated by anxiety. It was also hypothesized that pimavanserin, an FDA-approved 5-HT2A serotonin receptor inverse agonist, will decrease the amount of marble interaction over four consecutive days. There was a 20 minute baseline observation with all rats injected with isotonic saline. An experimental group of Lewis rats received 1 mg/kg intraperitoneally of pimavanserin in isotonic saline, daily for four subsequent days. Control rats were injected daily with isotonic saline alone. On each day, there were injections, habituation to the test room and a 20 minute observation with the rat in a tub containing 16 marbles on rodent litter. The baseline scores were subtracted from each rat’s subsequent test score. These change scores were than averaged over all four test days. There was very little deliberate marble burying. In fact review of video recordings show that most “buried” marbles had simple simply been accidently stepped upon by the rats. The control rats persisted in other marble interactions over time, despite showing no aversion to the marbles. This suggests compulsive-like behavior. There was an increase from baseline of marble interactions in the placebo group but a slight decrease in the pimavanerin group. This difference was statistically significant. There were no significant effects on activity level or bouts of inactivity to explain this difference. Thus pimavanserin may serve to decrease compulsive behaviors, and reducing 5HT2A receptor activation might be a novel strategy for managing obsessive-compulsive behaviors.