EARLY DESENSITIZATION OF SOMATO-DENDRITIC 5-HT1A AUTORECEPTORS IN RATS TREATED WITH FLUOXETINE OR PAROXETINE

Electrophysiological and autoradiographic approaches were used to asse ss possible changes in 5-hydroxytryptamine (serotonin) 5-HT1A receptor s in the rat dorsal raphe nucleus after a subchronic treatment with fl uoxetine or paroxetine, two specific serotonin reuptake inhibitors wit h antidepressant properties. Fluoxetine or paroxetine were injected da ily (5 mg/kg, i.p.) for various time periods up to 21 days. Electrophy siological recordings performed 24 h after the last injection showed t hat the potency of the 5-HT1A receptor agonist, 8-OH-DPAT, to depress the firing of serotoninergic neurons in the dorsal raphe nucleus withi n brain stem slices was significantly reduced as early as after a 3-da y treatment with either drug. The proportion of recorded neurons showi ng desensitization of somatodendritic 5-HT1A autoreceptors increased a long the treatment from similar to 40% on the 3rd day to 60-80% on the 21st day. At no time during the treatment, was the specific binding o f [H-3]8-OH-DPAT (agonist radioligand) or [H-3]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 rat s injected with fluoxetine or paroxetine for up to 21 days. These resu lts show that adaptive desensitization of somatodendritic 5-HT1A autor eceptors within the dorsal raphe nucleus can already be detected after a 3-day treatment with selective serotonin reuptake inhibitors. Rathe r than the desensitization per se, it may be the progressive increase in the number of serotoninergic neurons with desensitized 5-HT1A autor eceptors which plays a critical role in the (slowly developing) antide pressant action of these drugs.