Abstracts

Rationale: Studying drug response in chronic conditions such as epilepsy in animals presents unique challenges. Repeated dosing via injections is logistically difficult for small animals due to their fast metabolism and the impracticality of administering doses at night. To address these issues, an automated drug delivery system using drug-in-food pellets was developed [1]. This approach is economical and allows for multiple daily doses without the need for experimenter intervention. However, this method introduces new challenges, as it is possible that the animals may refuse to consume the food. In this study, we investigate the consumption preferences of rats to characterize the palatability of drug-in-food pellets for conducting chronic testing of antiseizure therapies.


Methods: Sprague-Dawley rats were treated with a repeated low-dose kainate paradigm to induce status epilepticus leading to chronic epilepsy, with n=4 per group. A control group, hand-fed ad-libitum, was used to characterize standard consumption rate of the chocolate-flavored pellets, which are the base ingredient for all non-medicated (control food) and medicated pellets. Hand-fed groups were weighed and recorded prior to feeding and were given two daily meals consisting of 20g/kg of food by placing pellets manually in the cage by an experimenter. For groups administered food by the automated feeding system, the feeders were programmed to deliver 20 half-gram pellets per 1kg of body weight, per meal. In cohort 1, rats were administered high and low concentrations of four drugs (doses in mg/kg/day: CBZ 300 and 600, CLB 10 and 20, VPA 600 and 1200, and LEV 300 and 600) were hand-fed twice daily for 12 days, with the remaining pellets weighed at each collection. A second cohort was used to study consumption of CBZ (300 mg/kg/day) under 3 different patterns: rats fed medicated food via feeders with and without pre-exposure to non-medicated pellets delivered via feeders, and pre-exposure to non-medicated pellets hand-fed. The feeders dispensed pellets four times daily, pellets not consumed were weighed twice daily.


Results: Control animals consumed 15.6±6.4 g/kg during the day time and 39.3±6.8 g/kg during the night time. In the first cohort, both CBZ groups demonstrated insufficient consumption throughout the study. The rest of the drugs showed sufficient consumption by the end of the study, suggesting adaptation to food taste. To address the insufficient consumption, CBZ was tested in a second cohort and demonstrated that the group utilizing pre-exposure and feeders resulted in quicker adaptation to CBZ food.


Conclusions: Consumption of drug-in-food pellets is a complex relationship that requires testing and characterizing each drug to account for different taste profiles. Combining pre-exposure to non-medicated chocolate pellets and utilizing the feeders increased consumption in a meaningful way, suggesting a conditioned response to the activation of the feeders.

[1] Thomson KE, White HS. A novel open-source drug-delivery system that allows for first-of-kind simulation of nonadherence to pharmacological interventions in animal disease models. J Neurosci Methods. 2014 Dec 30;238:105-11.


Funding: NINDS/NIH Contract#75N95022C00007