Depletion of 5-HT disrupts prepulse inhibition in rats: dependence on the magnitude of depletion, and reversal by a 5-HT precursor.
The 5-HT(1A) agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3(rd) PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy-L-tryptophan reinstated PPI during retest. These data, together with recently published studies, provide strong evidence that pharmacologically-induced depletion of 5-HT disrupts PPI.
Prinssen
Eric P M
EP
Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, F-81106 Castres Cédex, France. eric.prinssen@pierre-fabre.com
Assié
Marie-Bernadette
MB
Koek
Wouter
W
Kleven
Mark S
MS
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D004338:Drug Combinations; D010134:Fenclonine / Q000494:pharmacology*; D005277:Fenfluramine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D006916:5-Hydroxytryptophan; D004338:Drug Combinations; D010134:Fenclonine; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors