ABSTRACT: A very important element controlling serotonin (5-HT) release throughout the brain is the 5-HT1A autoreceptor present on the soma and dendrites of 5-HT neurons since it exerts a negative feedback influence on their firing activity. This 5-HT1A autoreceptor receives an increased activation by endogenous 5-HT at the beginning of a treatment with a selective 5-HT reuptake inhibitor (SSRI) and, consequently, a decreased 5-HT neuronal firing activity is obtained. As the SSRI treatment is prolonged, the 5-HT1A autoreceptor desensitizes and firing activity is restored in the presence of the SSRI. That this adaptive change underlies, at least in part, the delayed therapeutic effect of SSRI in major depression is supported by the acceleration of the antidepressant response by the concomitant administration of the 5-HT1A autoreceptor antagonist pindolol with SSRIs.