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

Br J Pharmacol. 1992 Sep;107(1):233-9. doi: 10.1111/j.1476-5381.1992.tb14492.x.

Abstract

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 micrograms 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 micrograms kg-1, i.p.) and (S)-zacopride (10-100 micrograms 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 micrograms kg-1, i.p.), (S)-zacopride (10-100 micrograms kg-1, i.p.) dose-dependently reversed the (R)-zacopride (10 micrograms kg-1, i.p.) induced reduction in extracellular levels of 5-HT in the rat frontal cortex. The highest dose of (S)-zacopride (100 micrograms 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.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Benzamides / pharmacology*
  • Bridged Bicyclo Compounds / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic*
  • Buspirone / pharmacology
  • Diazepam / pharmacology
  • Dose-Response Relationship, Drug
  • Frontal Lobe / drug effects*
  • Frontal Lobe / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • Male
  • Ondansetron / pharmacology
  • Rats
  • Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology*
  • Stereoisomerism

Substances

  • Benzamides
  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Serotonin Antagonists
  • Serotonin
  • Ondansetron
  • Hydroxyindoleacetic Acid
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • zacopride
  • Diazepam
  • Buspirone