Summary
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.
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References
Andrade R, Nicoll RA (1987) Pharmacologically distinct actions of serotonin on single pyramidal neurons of the rat hippocampus recorded in vitro. J Physiol 394:99–124
Assaf SY, Miller JJ (1978a) The role of a raphe serotonin system in the control fo septal unit activity and hippocampal desynchronization. Neuroscience 3:539–550
Assaf SY, Miller JJ (1978b) Neuronal transmission in the DG: role of inhibitory mechanisms. Brain Res 151:587–592
Azmitia EC, Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179:641–668
Barrioneuevo G, Harty TP, Bradler JE, Berger TW (1987) Nonlinear response characteristics of the perforant path-dentate system in the in-vitro rabbit hippocampus. Neuroscience Suppl 22:144
Beck SG, Goldfarb J (1985) Serotonin produces a reversible concentration dependent decrease of population spikes in rat hippocampal slices. Life Sci 36:557–563
Buzsaki G, Czech G (1981) Commissural and PP interaction in the rat hippocampus. Exp Brain Res 43:429–438
Buzsaki G (1986) Hippocampal sharp waves: their origin and significance. Brain Res 398:242–252
Colino A, Halliwell JV (1987) Differential modulation of three separate K-conductances in hippocampal CA1 neurons by serotonin. Nature 328:73–77
Costa E, Rinaldi F (1958) Biochemical and electroencephalographic changes in the brain of rabbits injected with 5-hydroxytryptophan (influence of chlorpromazine premedication). Am J Physiol 194:214–220
Crunelli V, Segal M (1985) An electrophysiological study of neurons in the rat median raphe and their projections to septum and hippocampus. Neuroscience 15:47–60
Douglas RM, McNaughton BL, Goddard GV (1983) Commissural Inhibition and facilitation of granule cell discharge in fascia dentata. J Comp Neurol 219:285–294
Fuxe K, Farnebo LO, Hamberger B, Ogren SO (1975) On the in vivo and in vitro action of fenfluramine and its derivatives on central monoamines neurons, especially 5-hydroxytryptamine neurons and their relation to the anorectic activity of fenfluramine. Postgrad Med J 51 (Suppl 1):35–45
Invernizzi R, Berettera C, Garattini S, Samanin R (1986) Isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat. Eur J Pharmacol 120:9–15
Jahnsen H (1980) The action of 5-hydroxytryptamine on neuronal membranes and synaptic transmission in area CA1 of the hippocampus in vitro. Brain Res 197:83–94
Jaim-Etcheverry G, Zieher ML (1980) DSP-4:a novel compound with neurotoxic effects on noradrenergic neurons of adult and developing rats. Brain Res 188:513–523
Klancnik JM, Phillips AG, Miller JJ (1987) Dentate granule cell PS amplitude is increased by systemic administration of the 5-HT1a receptor agonist 8-OH-DPAT. Neuroscience Suppl 22:1053p
Koe BL, Weissman A (1986) P-chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–510
Miller FP, Cox RH, Snodgrass WR, Maickel RP (1970) Comparative effects of p-chlorophenylalanine, p-chloroamphetamine and p-chloro-N-methylamphetamine on rat brain norepinephrine, serotonin and 5-hydroxyindole-3-acetic acid. Biochem Pharmacol 19:435–442
Mizumori SJY, McNaughton BL, Barnes CA (1989) A comparison of supramammillary and medial septal influences on hippocampal field potentials and single unit activity. J Neurophysiol 61(1):5–31
Peroutka SJ, Mauk MD, Kocsis JD (1987) Modulation of neuronal activity in the hippocampus by 6-hydroxytryptamine and 5-hydroxytryptamine1A selective drugs. Neuropharmacology 26:139–146
Richter-Levin G, Segal M (1988) Serotonin releasers modulate reactivity of the rat hippocampus to afferent stimulation. Neurosci Lett 94:173–176
Richter-Levin G, Segal M (1990) Grafting of midbrain neurons into the hippocampus restores serotonergic modulation of hippocampal activity in the rat. Brain Res (in press)
Ropert N (1988) Inhibitory action of serotonin in CA1 hippocampal neurons in vitro. Neuroscience 26:69–81
Rowan MJ, Andwyl R (1985) The effect of prolonged treatment with tricyclic antidepressants on the actions of 5-hydroxytryptamine in the hippocampal slice of the rat. Neuropharmacology 24:131–137
Sanders-Bush E, Massari VJ (1977) Action of drugs that deplete serotonin. Fed Proc (USA) 36:2149–2153
Schuster CR, Lewis M, Seiden LS (1986) Fenfluramine: neurotoxicity. Psychopharm Bull 22:148–151
Segal M (1975) Physiological and pharmacological evidence for a serotonergic projection to the hippocampus. Brain Res 94:115–131
Segal M (1980) The action of serotonin in the rat hippocampal slice preparation. J Physiol (Lond) 303:423–439
Segal M (1990) Serotonin attenuates slow IPSP's in hippocampal neurons. Neuroscience (in press)
Srebro B, Azmitia EC, Winson J (1982) Effect of 5-HT depletion of the hippocampus on neuronal transmission from through DG. Brain Res 235:142–147
Trulson ME, Jacobs BL (1976) Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur J Pharmacol 36:149–154
Winson J (1980) Influence of raphe nuclei on neuronal transmission from through DG. J Neurophysiol 44:937–950
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Richter-Levin, G., Segal, M. Effects of serotonin releasers on dentate granule cell excitability in the rat. Exp Brain Res 82, 199–207 (1990). https://doi.org/10.1007/BF00230852
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DOI: https://doi.org/10.1007/BF00230852