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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 340-347 |
| Number of pages | 8 |
| Journal | Neuropsychopharmacology |
| Volume | 26 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2002 |
| Externally published | Yes |
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Keywords
- 5-hydroxytryptophan
- d-fenfluramine
- Microdialysis
- p-chlorophenylalanine
- Prepulse inhibition
- Serotonin
- Startle reflex
ASJC Scopus subject areas
- Pharmacology
Cite this
Depletion of 5-HT disrupts prepulse inhibition in rats : Dependence on the magnitude of depletion, and reversal by a 5-HT precursor. / Prinssen, Eric P M; Assié, Marie Bernadette; Koek, Wouter; Kleven, Mark S.
In: Neuropsychopharmacology, Vol. 26, No. 3, 2002, p. 340-347.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Depletion of 5-HT disrupts prepulse inhibition in rats
T2 - Dependence on the magnitude of depletion, and reversal by a 5-HT precursor
AU - Prinssen, Eric P M
AU - Assié, Marie Bernadette
AU - Koek, Wouter
AU - Kleven, Mark S.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - 5-hydroxytryptophan
KW - d-fenfluramine
KW - Microdialysis
KW - p-chlorophenylalanine
KW - Prepulse inhibition
KW - Serotonin
KW - Startle reflex
UR - http://www.scopus.com/inward/record.url?scp=0036179970&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036179970&partnerID=8YFLogxK
U2 - 10.1016/S0893-133X(01)00348-7
DO - 10.1016/S0893-133X(01)00348-7
M3 - Article
C2 - 11850148
AN - SCOPUS:0036179970
VL - 26
SP - 340
EP - 347
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 3
ER -