Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine

Naunyn Schmiedebergs Arch Pharmacol. 1995 Aug;352(2):141-8. doi: 10.1007/BF00176767.


Electrophysiological and autoradiographic approaches were used to assess possible changes in 5-hydroxytryptamine (serotonin) 5-HT1A receptors in the rat dorsal raphe nucleus after a subchronic treatment with fluoxetine or paroxetine, two specific serotonin reuptake inhibitors with antidepressant properties. Fluoxetine or paroxetine were injected daily (5 mg/kg, i.p.) for various time periods up to 21 days. Electrophysiological recordings performed 24 h after the last injection showed that the potency of the 5-HT1A receptor agonist, 8-OH-DPAT, to depress the firing of serotoninergic neurons in the dorsal raphe nucleus within brain stem slices was significantly reduced as early as after a 3-day treatment with either drug. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT1A autoreceptors increased along the treatment from approximately 40% on the 3rd day to 60-80% on the 21st day. At no time during the treatment, was the specific binding of [3H]8-OH-DPAT (agonist radioligand) or [3H]WAY-100 635 (antagonist radioligand) to 5-HT1A receptors modified in the dorsal raphe nucleus or in other brain areas, suggesting that neither the density nor the coupling of these receptors to G-proteins were probably altered in rats injected with fluoxetine or paroxetine for up to 21 days. These results show that adaptive desensitization of somatodendritic 5-HT1A autoreceptors within the dorsal raphe nucleus can already be detected after a 3-day treatment with selective serotonin reuptake inhibitors. Rather than the desensitization per se, it may be the progressive increase in the number of serotoninergic neurons with desensitized 5-HT1A autoreceptors which plays a critical role in the (slowly developing) antidepressant action of these drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Autoradiography
  • Brain Stem / drug effects
  • Brain Stem / physiology
  • Electrophysiology
  • Fluoxetine / pharmacology*
  • In Vitro Techniques
  • Male
  • Neurons / drug effects
  • Neurons / physiology
  • Paroxetine / pharmacology*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Raphe Nuclei / cytology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology


  • Piperazines
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Fluoxetine
  • Paroxetine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin