Serotonin autoreceptor function and antidepressant drug action

This article briefly summarizes, within the context of a brief review of th e relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)(1A) versus 5-HT1B autore ceptors in the mechanism of action of 5-HT reuptake blocking agents, includ ing putative regional differences in this regard, and (2) autoreceptor resp onsiveness following chronic SSRI administration. First, our data are consi stent with the primacy of 5-HT1A autoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1B autorecepto rs appear to have an accessory role in this regard. Second, there is an imp ortant interplay between cell body and nerve terminal 5-HT autoreceptors, a nd recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particu lar, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and ne rve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more i mportant in the control of 5-HT output in dorsal raphe-frontal cortex and m edian raphe-dorsal hippocampus systems, respectively. Third, 5-HT autorecep tors evidently retain the capability to limit the 5-HT transmission-promoti ng effect of SSRIs after chronic treatment. Thus, although the responsivene ss of these sites is probably somewhat reduced, residual autoreceptor capac ity still remains an effective restraint on large increases in extracellula r 5-HT, even after prolonged treatment. If a further increase in extracellu lar 5-HT is crucial to the remission of depression in patients responding o nly partially to prolonged administration of antidepressants, then sustaine d adjunctive treatment with autoreceptor-blocking drugs may consequently pr ove useful in the long term.