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

Electrocardiographic signal dynamics were examined in rhesus monkeys (Macac a mulatta) before and after treatment with ketamine and/or ondansetron. Ket amine exerts differential pharmacodynamic effects on behavior in animals st ratified according to a measure of central serotonergic turnover. We hypoth esized that measures of serotonergic turnover might explain some of the var iance in the electrocardiographic (ECG) response to ketamine. Electrocardio graphic recordings of animals were obtained at baseline, after administrati on 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 in terval (IBI) time-series. H decreased after ketamine administration, (mean +/- S.E.M,), 0.33 +/- 0.03 vs. 0.12 +/- 0.02, P less than or equal to 0.001 , n = 10. Cerebrospinal fluid 5-hydroxyindole-3-acetic acid (5-HIAA) concen trations, a measure of serotonergic turnover, predicted the monkeys' respon se to ketamine, H = 0.001 (5-HIAA, pmol/ml)-0.130, R = 0.66, P less than or equal to 0.003, n = 18. Ondansetron attenuated the response to ketamine, 0 .14 +/- 0.02 vs. 0.08 +/- 0.02, P less than or equal to 0.05, n = 8, ondans etron vs, saline. These data provide evidence that naturally occurring diff erences in serotonin function alter the ECG response of the animals to keta mine and that activation of the serotonin type-3 receptor by ketamine is in volved. (C) 2000 Elsevier Science B.V. All rights reserved.