Differential Regulation of Somatodendritic Serotonin 5‐HT 1A Receptors by 2‐Week Treatments with the Selective Agonists Alnespirone(S‐20499) and8‐Hydroxy‐2‐(Di‐ n ‐Propylamino)tetralin

: Single treatment with the serotonin (5‐hydroxytryptamine)5‐HT 1A receptor agonists8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (8‐OH‐DPAT) and alnespirone(S‐20499) reduces the extracellular 5‐HT concentration (5‐HT ext ) inthe rat midbrain and forebrain. Given the therapeutic potential of selective5‐HT 1A agonists in the treatment of affective disorders, we haveexamined the changes in 5‐HT 1A receptors induced by 2‐week minipumpadministration of alnespirone (0.3 and 3 mg/kg/day) and 8‐OH‐DPAT (0.1 and 0.3mg/kg/day). The treatment with alnespirone did not modify baseline5‐HT ext but significantly attenuated the ability of 0.3 mg/kg s.c.alnespirone to reduce 5‐HT ext in the dorsal raphe nucleus (DRN) andfrontal cortex. In contrast, the ability of 8‐OH‐DPAT (0.025 and 0.1 mg/kgs.c.) to reduce 5‐HT ext in both areas was unchanged by 8‐OH‐DPATpretreatment. Autoradiographic analysis revealed a significant reduction of[ 3 H]8‐OH‐DPAT and [ 3 H]WAY‐100635 { 3 H‐labeled N ‐[2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl]‐ N ‐(2‐pyridyl)cyclohexanecarboxamide· 3HCl} binding to somatodendritic 5‐HT 1A receptors (but notto postsynaptic 5‐HT 1A receptors) of rats pretreated withalnespirone but not with 8‐OH‐DPAT. In situ hybridization analysis revealed nochange of the density of the mRNA encoding the 5‐HT 1A receptors inthe DRN after either treatment. These data indicate that continuous treatmentfor 2 weeks with alnespirone, but not with 8‐OH‐DPAT, causes a functionaldesensitization of somatodendritic 5‐HT 1A receptors controlling 5‐HT release in the DRN and frontal cortex.