Chronic fluoxetine induces opposite changes in G protein coupling at pre and postsynaptic 5-HT1A receptors in rat brain

Neuropharmacology. 2003 Jan;44(1):93-101. doi: 10.1016/s0028-3908(02)00340-4.


Chronic treatment with the antidepressant fluoxetine may lead to changes in the properties of pre- and postsynaptic 5-HT(1A) receptors due to modifications in the receptor-G protein coupling process. We have evaluated, in rats, the effect of chronic fluoxetine (10 mg/kg/day) at brain 5-HT(1A) receptors using different techniques. The density of 5-HT(1A) receptors was unchanged in fluoxetine-treated rats vs. vehicle group. Stimulation of [(35)S]GTPgammaS binding induced by (+/-)8-OH-DPAT was significantly attenuated in dorsal raphe nucleus after fluoxetine (+3.7 vs. +31.2% in vehicle). The inhibition of dorsal raphe firing by (+/-)8-OH-DPAT (ED(50) in vehicle = 2.1 microg/kg, i.v.) was also attenuated in rats treated with fluoxetine (ED(50)=4.7 microg/kg). In contrast, a significant increase on (+/-)8-OH-DPAT-induced stimulation of [(35)S]GTPgammaS binding was observed in CA(1) (+53.4 vs.+20.2% in vehicle) and dentate gyrus (+105.7 vs. +52.6% in vehicle) but not in entorhinal cortex. Our data demonstrate that fluoxetine-induced desensitization of 5-HT(1A) autoreceptors occurs at G protein level. Moreover, a relevant finding is the region-specific hypersensitivity of postsynaptic 5-HT(1A) receptors, in the hippocampus but not in entorhinal cortex, following chronic fluoxetine. These differential adaptive changes in brain 5-HT(1A) receptors could underlie the mechanism of action of antidepressants and also contribute to their clinical effects.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Autoradiography
  • Autoreceptors / drug effects
  • Autoreceptors / metabolism
  • Brain / anatomy & histology
  • Brain / drug effects*
  • Brain / metabolism
  • Fluoxetine / administration & dosage
  • Fluoxetine / pharmacology*
  • GTP-Binding Proteins / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • In Vitro Techniques
  • Male
  • Organ Specificity
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Presynaptic / drug effects*
  • Receptors, Presynaptic / metabolism
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists / pharmacology
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / pharmacology*
  • Synapses / metabolism


  • Autoreceptors
  • Receptors, Presynaptic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • GTP-Binding Proteins