Effects of 5-HT3 receptor antagonism on hippocampal cellular activity in the freely moving rat

Recent physiological studies conducted in the hippocampi of freely moving rats have revealed that systemic injections of the selective serotonin-3 (5-HT3) receptor antagonist ondansetron facilitate induction of long-term potentiation (LTP), increase the frequency of the theta electroencephalogram rhythm, and enhance retention of memory in hippocampally dependent tasks. To gain insight into the cellular mechanisms underlying these observations, in the present study we examined the effects of intraperitoneal injections of ondansetron on the firing rate of CA1 interneurons and pyramidal cells in the dorsal hippocampi of freely moving rats. Mean firing rates of a substantial proportion (17 of 27) of isolated neurons were significantly different before and after ondansetron injection (500 and 1,000 micrograms/kg). Of the interneurons that exhibited an effect, all (11 of 11) significantly decreased their mean firing rate, with an average change of -22.4 +/- 3.9% (mean +/- SE) across cells. Eighty-three percent (5 of 6) of pyramidal cells showing a change in mean firing rate displayed a significant increase in activity, with an average change of 56.3 +/- 25.6% across cells. Ondansetron (1.0 mg/kg ip) had no detectable effect on spontaneous behavioral activity as measured by line crossings and rearings in an open-field apparatus. The present results show that pharmacological blockade of 5-HT3 receptors causes a reduction in firing activity of a subset of CA1 hippocampal interneurons, with concomitant increases in the firing rate of pyramidal cells. These changes may be directly related to the ondansetron-induced enhancement of LTP induction and memory formation observed in previous studies.