title: Difference in the in vivo influence of serotonin1A autoreceptors on serotonin release in prefrontal cortex and dorsal hippocampus of the same rat treated with fluoxetine.
abstract: Recent studies have demonstrated that antagonism of somatodendritic serotonin1A (5-HT1A) autoreceptors can potentiate the increase of extracellular 5-HT concentrations induced by selective serotonin reuptake inhibitors including fluoxetine. The present study was conducted to uncover any functional difference between the 5-HT1A autoreceptors located on the cell bodies of 5-HT neurons in the dorsal (DRN) and median (MRN) raphe nuclei. The investigational approach used in the present study was to detect extracellular 5-HT concentrations in two terminal areas, prefrontal cortex (Pfc) and dorsal hippocampus (Dhp), which are mainly innervated by the 5-HT neurons located in the DRN and MRN respectively. To avoid possible variation between individual animals a dual-probe microdialysis procedure was applied to determine 5-HT concentrations in both brain areas of the same rat. Fluoxetine (10 mg/kg, s.c.) alone produced a smaller increase in the extracellular 5-HT concentration in the Pfc than Dhp of the same rat (maximal 5-HT concentrations were 183% and 223% of the baseline values in Pfc and Dhp respectively). However, an antagonist of 5-HT1A receptors, WAY100635, subsequently injected (s.c.) at 1 mg/kg brought the 5-HT concentrations to similar levels in the Pfc (332%) and Dhp (308%). Since the 5-HT concentrations immediately before the injection of WAY100635 were lower in the Pfc (102%) than Dhp (186%), WAY100635 induced a larger 5-HT net increase in the Pfc (332%-102%=230%) than Dhp (308%-186%=122%). On the other hand, WAY100635 alone did not significantly change the extracellular 5-HT concentrations in both areas. Furthermore, extracellular concentrations of dopamine (DA) and two DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in both areas were not altered by the administrations of fluoxetine and WAY100635. In conclusion, the present study demonstrated that the antagonist of 5-HT1A receptors, WAY100635, produced a more robust potentiation in the fluoxetine-induced 5-HT increases in the Pfc than Dhp. Since Pfc and Dhp are predominately innervated by 5-HT neurons located in the DRN and MRN respectively, this result may indicate a functional difference between the 5-HT1A autoreceptors located on the cell bodies of 5-HT neurons in the DRN and MRN.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: X M
authors.initials: XM
authors.lastname: Li
authors.forename: K W
authors.initials: KW
authors.lastname: Perry
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D017660:Autoreceptors; D004298:Dopamine; D005473:Fluoxetine; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide