Ondansetron modulates pharmacodynamic effects of ketamine on electrocardiographic signals in rhesus monkeys

Electrocardiographic signal dynamics were examined in rhesus monkeys ( Macaca mulatta) before and after treatment with ketamine and/or ondansetron. Ketamine exerts differential pharmacodynamic effects on behavior in animals stratified according to a measure of central serotonergic turnover. We hypothesized that measures of serotonergic turnover might explain some of the variance in the electrocardiographic (ECG) response to ketamine. Electrocardiographic recordings of animals were obtained at baseline, after administration of either saline or ondansetron (0.125 mg/kg), and after administration of ketamine (15 mg/kg). Electrocardiographic signal dynamics were measured using an algorithm that extracts the Hurst parameter ( H) of the interbeat interval (IBI) time-series. H decreased after ketamine administration, (mean±S.E.M.), 0.33±0.04 vs. 0.12±0.02, P≤0.001, n=10. Cerebrospinal fluid 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations, a measure of serotonergic turnover, predicted the monkeys' response to ketamine, H=0.001 (5-HIAA, pmol/ml)-0.130, R=0.66, P≤0.003, n=18. Ondansetron attenuated the response to ketamine, 0.14±0.02 vs. 0.08±0.02, P≤0.05, n=8, ondansetron vs. saline. These data provide evidence that naturally occurring differences in serotonin function alter the ECG response of the animals to ketamine and that activation of the serotonin type-3 receptor by ketamine is involved.