Effects of 5-HT sub(3) receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat

Serotonergic brainstem projections to hippocampus are thought to preferentially target and increase, via 5-HT sub(3) receptors, the excitability of a distinct subpopulation of interneurons that primarily regulate GABA sub(B)-mediated inhibition in the dendritic region of pyramidal cells. Hippocampal slice work suggests that the between-burst hyperpolarization caused by slow (GABA sub(B)) IPSPs plays a significant role in controlling the strength of LTP induced with theta burst stimulation. According to the above observations it was assumed that blockade of hippocampal 5-HT sub(3) receptors should reduce the hyperpolarization and thereby enhance both the frequency of the naturally occurring theta rhythm and the induction of LTP; moreover, if LTP-like mechanisms provide the substrate for certain forms of memory, such treatment was expected to facilitate learning. Each of the above predictions was tested and confirmed in the present set of experiments. The effects of ondansetron, a potent and selective antagonist of the 5-HT sub(3) receptor, were examined on (1) frequency of the hippocampal theta rhythm, (2) induction of LTP in field CA1 of freely moving rats, and (3) retention of olfactory and spatial memory in tasks known to depend on an intact hippocampus. When injected intraperitoneally into freely moving rats, the drug reliably and significantly increased the frequency of the hippocampal theta rhythm in a dose-dependent manner. Second, at concentrations that facilitate theta frequency (100 mu g/kg and 500 mu g/kg), an injection of the drug 30 min prior to delivering electrical stimulation bursts significantly increased the magnitude and duration of LTP compared to that obtained in the same animals after vehicle injections. Third, when tested at a dose of 100 mu g/kg, ondansetron was also found to improve retention in an odor matching problem and in a spatial task.