Differential regulation of somatodendritic serotonin 5-HT1A receptors by 2-week treatments with the selective agonists alnespirone (S-20499) and 8-hydroxy-2-(Di-n-propylamino)tetralin: microdialysis and autoradiographic studies in rat brain.

Abstract

Single treatment with the serotonin (5-hydroxytryptamine) 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and alnespirone (S-20499) reduces the extracellular 5-HT concentration (5-HText) in the rat midbrain and forebrain. Given the therapeutic potential of selective 5-HT1A agonists in the treatment of affective disorders, we have examined the changes in 5-HT1A receptors induced by 2-week minipump administration of alnespirone (0.3 and 3 mg/kg/day) and 8-OH-DPAT (0.1 and 0.3 mg/kg/day). The treatment with alnespirone did not modify baseline 5-HText but significantly attenuated the ability of 0.3 mg/kg s.c. alnespirone to reduce 5-HText in the dorsal raphe nucleus (DRN) and frontal cortex. In contrast, the ability of 8-OH-DPAT (0.025 and 0.1 mg/kg s.c.) to reduce 5-HText in both areas was unchanged by 8-OH-DPAT pretreatment. Autoradiographic analysis revealed a significant reduction of [3H]8-OH-DPAT and [3H]WAY-100635 [3H-labeled N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexa necarboxamide x 3HCl] binding to somatodendritic 5-HT1A receptors (but not to postsynaptic 5-HT1A receptors) of rats pretreated with alnespirone but not with 8-OH-DPAT. In situ hybridization analysis revealed no change of the density of the mRNA encoding the 5-HT1A receptors in the DRN after either treatment. These data indicate that continuous treatment for 2 weeks with alnespirone, but not with 8-OH-DPAT, causes a functional desensitization of somatodendritic 5-HT1A receptors controlling 5-HT release in the DRN and frontal cortex.

• Authors: J M Casanovas, M T Vilaró, G Mengod, F Artigas
• Journal: Journal of neurochemistry (J Neurochem) Vol. 72 Issue 1 Pg. 262-72 (Jan 1999) ISSN: 0022-3042 [Print] England
• PMID: 9886078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT1
• Serotonin Receptor Agonists
• Spiro Compounds
• Serotonin
• alnespirone
• 8-Hydroxy-2-(di-n-propylamino)tetralin

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Anxiety (metabolism)
• Autoradiography
• Brain Chemistry (drug effects)
• Dendrites (chemistry, drug effects)
• Depression (metabolism)
• Dose-Response Relationship, Drug
• Frontal Lobe (chemistry, metabolism)
• Gene Expression (drug effects)
• In Situ Hybridization
• Male
• Microdialysis
• RNA, Messenger (analysis)
• Radioligand Assay
• Raphe Nuclei (chemistry, metabolism)
• Rats
• Rats, Wistar
• Receptors, Serotonin (analysis, genetics, metabolism)
• Receptors, Serotonin, 5-HT1
• Serotonin (metabolism)
• Serotonin Receptor Agonists (pharmacology)
• Spiro Compounds (pharmacology)