Abstract
The 5-HT1A 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 3rd 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.
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Acknowledgements
The authors thank Christelle Marc for technical assistance with the behavioral experiments, ValƩrie Rigal for technical assistance with the microdialysis experiments, and Joƫl Besnard and Christelle Marc for assistance with data management. Citalopram was kindly donated by Lundbeck (Copenhagen, Denmark).
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Prinssen, E., AssiĆ©, MB., Koek, W. et al. Depletion of 5-HT Disrupts Prepulse Inhibition in Rats: Dependence on the Magnitude of Depletion, and Reversal by a 5-HT Precursor. Neuropsychopharmacol 26, 340ā347 (2002). https://doi.org/10.1016/S0893-133X(01)00348-7
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DOI: https://doi.org/10.1016/S0893-133X(01)00348-7
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