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.
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.
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Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Perry
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Wong
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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*
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