Activation of postsynaptic 5-HT(1A) receptors by fluoxetine despite the loss of firing-dependent serotonergic input: electrophysiological and neurochemical studies.
Systemic doses of fluoxetine slow dorsal raphe cell firing by blocking the reuptake carrier located in the cell body region with the surplus 5-HT thus generated activating inhibitory autoreceptors. The concurrent actions of fluoxetine on postsynaptic receptors in raphe projection areas has not been as thoroughly investigated, although it is presumed that a reduction in cell firing should curtail these targeted effects. The goal of the present studies was to assess the degree of postsynaptic receptor activation obtained with fluoxetine and relate it to cell body autoreceptor activation and the level of extracellular 5-HT obtained at the nerve endings. Changes in firing rates of CA3 hippocampal neurons following systemic administration of fluoxetine were used as a marker of SSRI-dependent changes in postsynaptic 5-HT receptor activation; monitoring of unit activity of neurons in the dorsal raphe nucleus served to gauge the degree of serotonergic input in a parallel series of animals. Estimates of the corresponding changes in terminal 5-HT release in the CA3 region were analyzed by microdialysis. The results indicate that fluoxetine inhibits hippocampal cell firing in a dose-dependent manner (ED(50) = 4.4 mg/kg i.v.) and one sensitive to pretreatment with the 5-HT(1A) antagonist WAY-100,635. Within the same dose range, increases in hippocampal extracellular 5-HT approaching 300% above basal levels were achieved. Both the changes in hippocampal neuronal activity and extracellular 5-HT are evident at doses of fluoxetine in excess of that required to inhibit dorsal raphe cell firing (ED(50) = 1.1 mg/kg i.v.). Taken together, these data suggest that increases in extracellular levels of 5-HT on the order of that observed are sufficient to alter postsynaptic excitability and that this accumulation of synaptic 5-HT and the subsequent activation of postsynaptic 5-HT(1A) receptors are achievable despite loss of firing-dependent 5-HT release.
Sprouse
J
J
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. sprousejs@groton.pfizer.com
Braselton
J
J
Reynolds
L
L
Clarke
T
T
Rollema
H
H
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011903:Raphe Nuclei / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005473:Fluoxetine; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors