5-HT1A autoreceptors and the mode of action of selective serotonin reuptake inhibitors (SSRI).

The clinical efficacy of antidepressant drugs that block serotonin (5-HT) reuptake may be restrained in the short term by the indirect activation of autoreceptors. In vivo microdialysis in rat hippocampus was used to study the putative release-inhibitory properties of the SSRI citalopram and paroxetine. With 5-HT reuptake first blocked by local 'reverse-dialysis' infusion of citalopram (1 microM) into the hippocampus, acute systemic administration of citalopram or paroxetine resulted in a marked decrease in hippocampal 5-HT overflow. This presumably reflected the inhibition of 5-HT neuronal discharge and release, subsequent to reuptake blockade in the raphe nuclei and thus, activation of somatodendritic autoreceptors. In support of this hypothesis, pretreatment with (+/-)-pindolol or (+)-WAY100135, to block 5-HT1A autoreceptors, abolished the decrease in extracellular 5-HT produced by acute systemic injection of the reuptake blockers. The results suggest that the clinical efficacy of antidepressants that block 5-HT reuptake could be enhanced by co-administration of a 5-HT1A autoreceptor antagonist.