Effects of serotonin releasers on dentate granule cell excitability in the rat

Serotonin modulating effects on hippocampal electrical activity were studied using serotonin releasing drugs (e.g. d-fenfluramine, FFA, and p-chloroamphetamine, PCA). FFA and PCA enhanced the reactivity of the dentate gyrus to stimulation of the perforant path (PP) in the anesthetized rat. The population spike (PS) but not the population EPSP (EPSP) was enhanced by FFA indicating that the drug effect is not exerted at the PP synapse, but at some postsynaptic site between the synapse and the spike generation mechanism. A depth profile of the response to PP stimulation indicated that the largest effect of FFA was present just below the granular cell layer. There were no systematic effects of FFA on the EPSP at any depth tested. The effect of FFA was much reduced in rats depleted of serotonin by p-chlorophenylalanine (PCPA) and restored when serotonin stores were repleted by the serotonin precursor 5-hydroxytryptophane (5-HTP). d-FFA was at least twice as effective as 1-FFA in enhancing responses in the dentate gyrus (DG). In noradrenaline (NA) depleted rats the increase in PS size was as in control rats. The effects of FFA were blocked by the 5-HT1a antagonist spiperone but not by the 5-HT2 antagonist mianserin. These results suggest that the effect of FFA is primarily due to release of serotonin from its terminals. At the gross electrographic level, FFA suppressed spontaneous sharp wave activity and reduced the magnitude of hippocampal EEG. Spontaneous extracellular single unit activity, recorded in the DG, was also inhibited by FFA concomitantly with the increase in the PS size. FFA did not affect paired-pulse depression. Transection of the commissural connection to the hippocampus (stimulation of which elicits feed forward inibition) markedly attenuated the effects of FFA. It is suggested that serotonin exerts a dual effect on DG granule cells; it suppresses spontaneous activity while enhancing excitability to afferent stimulation. Possibly, the effects of serotonin are exerted by modulation of commissural feed-forward inhibition.