ROLE OF 5-HT1A AUTORECEPTORS IN THE MECHANISM OF ACTION OF SEROTONINERGIC ANTIDEPRESSANT DRUGS - RECENT FINDINGS FROM IN-VIVO MICRODIALYSISSTUDIES

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 wi th 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 eve nts. With the coupling of this new experimental method to very sensiti ve analytical assays such as liquid chromatography with electrochemica l detection, it has recently been possible to obtain two major argumen ts 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 extrac ellular 5-HT concentrations in the vicinity of the cell body and the d endrites of serotoninergic neurones of the raphe nuclei. This effect i s more marked than that observed in regions rich in nerve endings (fro ntal cortex). The magnitude of the activation of the serotoninergic ne urotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous ac tivation 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 chronicall y: 5-HT autoreceptors may have gradually desensitized during the 2-4 w eeks of treatment with SSRIs. Preliminary studies of patients with dep ression appear to confirm these experimental results, as co-administra tion of a 5-HT1A autoreceptor antagonist and a SSRI accelerated the on set of the antidepressant effect (< 1 week).