Abstract
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 5HT1A 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 ∼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-OHDPAT (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.
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Le Poul, E., Laaris, N., Doucet, E. et al. Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine. Naunyn-Schmiedeberg's Arch Pharmacol 352, 141–148 (1995). https://doi.org/10.1007/BF00176767
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DOI: https://doi.org/10.1007/BF00176767