Systemic uptake inhibition decreases serotonin release via somatodendritic autoreceptor activation.
In vivo microdialysis was used to examine the effects of peripheral uptake inhibition on extracellular serotonin (5-HT). Previous results from this lab indicated that systemic fluoxetine caused a decrease in 5-HT when terminal uptake was inhibited by local infusion of the uptake blocker. We hypothesized that the decrease in 5-HT levels in the terminal region was due to an increase in 5-HT in the vicinity of the inhibitory somatodendritic autoreceptors in the dorsal raphe nucleus (DRN). To test this prediction, rats were implanted with probes in both the basal diencephalon (a nerve terminal region) and the DRN (the cell body region). Fluoxetine (10 mg/kg i.p.) increased extracellular 5-HT, in a depolarization-dependent manner, by approximately 140% in both areas. In a separate experiment, fluoxetine was infused into the diencephalon overnight to block nerve terminal uptake sites. This pretreatment caused an eight- to 10-fold increase in 5-HT levels. Subsequent systemic fluoxetine, sertraline, or paroxetine, produced a 50% decrease in extracellular 5-HT in the diencephalon, presumably due to activation of the 5-HT1A somatodendritic autoreceptors. Consistent with this hypothesis, systemic administration of the 5-HT1 antagonists spiperone, penbutolol, or WAY100135 reversed the fluoxetine-induced decrease in 5-HT to approximately 85% of the pre-fluoxetine baseline levels. Likewise, pretreatment with penbutolol, but not selective beta-adrenergic antagonists, blocked the fluoxetine-induced decrease in release. These findings suggest that the ability of acute systemic 5-HT uptake inhibition to elevate nerve terminal 5-HT is limited by autoreceptor activation following elevation of 5-HT in the DRN.
Rutter
J J
JJ
Department of Physiology and Biophysics, Hahnemann University, Philadelphia, Pennsylvania 19102, USA.
Gundlah
C
C
Auerbach
S B
SB
D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004027:Diencephalon / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D006897:Hydroxyindoleacetic Acid; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors