Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: Recent findings from in vivo microdialysis studies

Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5-HT1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5-HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5-HT1A autoreceptors by endogenous 5-HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5-HT concentrations in the nerve endings when administered chronically: 5-HT autoreceptors may have gradually desensitized during the 2-4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co-administration of a 5-HT1A autoreceptor antagonist and a SSRI accelerated the onset of the antidepressant effect (< 1 week).