Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.
Selective serotonin reuptake inhibitors (SSRIs) have been used to treat various psychiatric disorders. Although the cellular mechanisms underlying amelioration of particular symptoms are mostly unknown, recent studies have shown critical importance of the dentate gyrus of the hippocampus in behavioral effects of SSRIs in rodents. Here, we show that serotonin potentiates synaptic transmission between mossy fibers, the sole output of the dentate granule cells, and CA3 pyramidal cells in mouse hippocampal slices. This potentiation is mediated by activation of 5-HT(4) receptors and intracellular cAMP elevation. A chronic treatment of mice with fluoxetine, a widely used SSRI, bidirectionally modulates the 5-HT-induced potentiation: Fluoxetine enhances the potentiation induced by lower concentrations of serotonin, while attenuates that by the higher concentration, which represents stabilization of synaptic 5-HT action. In contrast to the chronic treatment, an acute application of fluoxetine in slices induces a leftward shift in the dose-response curve of the 5-HT-induced potentiation. Thus, acute and chronic fluoxetine treatments have distinct effects on the serotonergic modulation of the mossy fiber synaptic transmission. Exposure of mice to novel environments induces increases in locomotor activity and hippocampal extracellular 5-HT levels. In mice chronically treated with fluoxetine, the novelty-induced hyperactivity is reduced without significant alterations in home cage activity and motor skills. Our results suggest that the chronic fluoxetine treatment can stabilize the serotonergic modulation of the central synaptic transmission, which may contribute to attenuation of hyperactive behaviors.
Department of Pharmacology, Nippon Medical School, Tokyo 113-8602, Japan. kkatsu-tky@umin.ac.jp
Katsunori
K
Kobayashi
Yumiko
Y
Ikeda
Eisuke
E
Haneda
Hidenori
H
Suzuki
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis / Q000379:methods; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology*; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects*
D004298:Dopamine; D005473:Fluoxetine; D010852:Picrotoxin; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors