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West Yorkshire, BD7 lDP 1 The ability of various anxiolytic and potential anxiolytic agents to modify 5-hydroxytryptamine (5-HT) release in the frontal cortex of the rat was assessed by the microdialysis technique. 2 The benzodiazepine receptor agonist, diazepam (2.5 mg kg-', i.p.), the 5-HTA receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.32 mg kg-', s.c.) and the 5-HTIA receptor partial agonist buspirone (4.0mgkg-', i.p.) maximally reduced extracellular levels of 5-HT in the rat frontal cortex by approximately 50-60%, 70-80% and 30-40%, respectively. 3 (R)-zacopride (1.0-100 Lg kg-', i.p.) dose-dependently reduced extracellular levels of 5-HT in the rat frontal cortex (approximately 80% maximal reduction) whereas the other 5-HT3 receptor antagonists ondansetron (10 igkg-', i.p.) and (S)-zacopride (10-100fLgkg-, i.p.) were ineffective. 4 In contrast to (S)-zacopride (100 nM; administered via the microdialysis probe), (R)-zacopride (1.0-100 nM; administered via the microdialysis probe) induced a concentration-dependent reduction in extracellular levels of 5-HT in the rat frontal cortex (approximately 70% maximal reduction). 5 In contrast to ondansetron (100 fg kg-', i.p.), (S)-zacopride (10-100 ig kg-', i.p.) dose-dependently reversed the (R)-zacopride (10 j.g kg-', i.p.) induced reduction in extracellular levels of 5-HT in the rat frontal cortex. The highest dose of (S)-zacopride (100 jig kg-', i.p.) completely prevented the (R)-zacopride response. In addition, (S)-zacopride (100 nM; administered via the microdialysis probe) attenuated the inhibitory action of (R)-zacopride (10 nM; administered via the microdialysis probe) on extracellular levels of 5-HT in the rat frontal cortex. 6 In conclusion, the present study provides further evidence of the ability of diazepam, 8-OH-DPAT and buspirone to reduce the activity of the central 5-hydroxytryptaminergic system in vivo. Furthermore, the results indicate that the ability of (R)-zacopride to reduce the in vivo release of 5-HT in the rat frontal cortex does not correlate with its 5-HT3 receptor antagonism. However, the differential affinity of (R)-and (S)-zacopride for a (S)-zacopride-insensitive (R)-zacopride site in rat cerebral cortex mirrors the relative activity of the two zacopride stereoisomers to modify the in vivo release of 5-HT in the frontal cortex of the rat and their ability to release suppressed behaviour in animal models of anxiety.

Ingestion of yellow star thistle (Centaurea solstitialis L.) by horses produces parkinsonism due to nigro‐pallidal degeneration. The toxin responsible has not been identified so far. A CH2Cl2 extract from the aerial parts of C. solstitialis exhibited significant neurotoxicity against primary neuronal cultures of foetal rat brain. Activity‐guided fractionation yielded the known sesquiterpene lactones solstitialin A (1), 13‐0‐acetylsolstitialin A (3), cynaropicrin (4), and the hitherto unknown 3‐O‐acetylsolstitialin A (2). In the bioassay with rat foetal full cell culture, 3 and 4 were toxic in a concentration‐dependent manner and may be responsible for the ability of the plant to cause neurodegenerative changes in the brain of horses.

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