Differential modulation of extracellular levels of 5‐hydroxytryptamine in the rat frontal cortex by (R)‐ and (S)‐zacopride

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−1, i.p.), the 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT, 0.32 mg kg−1, s.c.) and the 5‐HT1A receptor partial agonist buspirone (4.0 mg kg−1, 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 μg kg−1, 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 μg kg−1, i.p.) and (S)‐zacopride (10–100 μg kg−1, 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 μg kg−1, i.p.), (S)‐zacopride (10–100 μg kg−1, i.p.) dose‐dependently reversed the (R)‐zacopride (10 μg kg−1, i.p.) induced reduction in extracellular levels of 5‐HT in the rat frontal cortex. The highest dose of (S)‐zacopride (100 μg kg−1, 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.