2 ACTIONS ARE BETTER THAN ONE - AVOIDING SELF-INHIBITION OF SEROTONERGIC NEURONS ENHANCES THE EFFECTS OF SEROTONIN UPTAKE INHIBITORS

The serotonin (5-HT)-increasing action of 5-HT uptake or monoamine oxi dase inhibitors is limited by a negative feedback at somatodendritic l evel. The excess 5-HT produced by these antidepressant drugs in the in terstitial space of the midbrain raphe activates somatodendritic 5-HT1 A autoreceptors, thereby attenuating terminal 5-HT release. This effec t is maximal in forebrain areas innervated by the dorsal raphe nucleus and can be prevented by the administration of non-selective [(-)pindo lol, (-)tertatolol] and selective (WAY-100635) 5-HT1A antagonists. In keeping with these observations, the combined administration of select ive serotonin reuptake inhibitors (SSRIs) and 5-HT1A antagonists incre ase the cortical and striatal extracellular 5-HT concentration more th an the former alone. Also, concurrent inhibition of the 5-HT and norad renaline transporters with 20 mg/kg imipramine increases cortical extr acellular 5-HT concentration more than SSRI doses which maximally bloc k the 5-HT transporter. Moreover, the effects of fluoxetine on frontal cortex 5-HT are potentiated by a dose of desipramine that does not mo dify extracellular 5-HT by itself. Given the relevance of increased se rotonergic transmission in the treatment of depression, these experime ntal data indicate that dual-action antidepressant treatments may be m ore effective than those which selectively inhibit the 5-HT transporte r.