SEROTONIN SELECTIVE REUPTAKE INHIBITORS

A new generation of selective serotonin reuptake inhibitors (SSRI) has recently been introduced in therapeutics as antidepressant drugs. The pharmacological properties of these drugs have extensively been demonstrated in vitro, but limited data had provided direct support for the ability of these compounds to inhibit serotonin reuptake selectively in vivo. In recent years, in vivo cerebral microdialysis coupled to very sensitive analytical methods such as liquid chromatography with electrochemical cal detection has permitted the measurement of basal serotonin (5-hydroxytryptamine, 5-HT) levels in extracellular fluid from various brain areas. Thus, this method allowed us to observe increases in extracellular serotonin concentrations following acute systemic or local administration of SSRI. Surprisingly, low doses of SSRI (i.e. 1 mg/kg or less) induced, in rats, a significant increase in extracellular 5-HT in the cell body-containing raphe region but not in forebrain regions where serotoninergic nerve terminals are mainly located. The enhancement in serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRI administered to rats: as an adaptive response to the increased amount of serotonin in extracellular fluid, serotonin neurons decrease their firing rate and release of the neurotransmitter to limit the magnitude of the activation of the serotoninergic system. Some recently described in vivo microdialysis experiments suggested that somatodendritic 5-HT1A autoreceptors mainly located in the raphe are involved in the release-attenuating properties of 5-HT uptake blockers. Conversely, large increases in extracellular 5-HT levels have been observed following chronic treatment with SSRI: serotonin autoreceptors may have desensitized during the long-term treatment, so that serotoninergic neurotransmission may increase further after 2-4 weeks of treatment with SSRI. That phenomenon may account for the delayed efficacy of antidepressant drugs reported in rodents as well as in human.