Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin.

Systemic administration of selective serotonin reuptake inhibitors (SSRIs) elicits larger increases in serotonin (5-HT) in raphe than in forebrain sites. Because serotonergic neuronal activity is suppressed, the mechanism underlying SSRI-induced increases in extracellular 5-HT is unclear. This study determined whether local infusion of SSRIs also elicited regionally selective increases in extracellular 5-HT, and whether changes depended on serotonergic neuronal depolarization. Conventional microdialysis methods were used to measure 5-HT in dorsal raphe (DRN), median raphe, nucleus accumbens (NAcc), and frontal cortex of unanesthetized rats. During infusion of SSRIs into each site, the maximum response was an approximately 6- to 7-fold increase in 5-HT in NAcc and frontal cortex, and an approximately 20-fold increase in DRN and median raphe. The larger increase in 5-HT in raphe was confirmed using zero-net-flux microdialysis. In NAcc, baseline 5-HT was 0.7 nM, and levels increased to a maximum of 3.1 nM during infusion of the SSRI citalopram. Baseline 5-HT in DRN was greater, 1.3 nM, and increased to 12.4 nM in response to citalopram. Consistent with evidence that autoreceptor activation inhibits serotonergic neuronal discharge, SSRI infusion into DRN produced a moderate decrease in 5-HT in NAcc. However, increases in 5-HT in DRN elicited by SSRI infusion were attenuated by 8-hydroxydipropylaminotetralin and tetrodotoxin. These data indicate that depolarization-dependent 5-HT release was not fully inhibited during SSRI infusion into DRN. In summary, SSRIs produce larger increases in extracellular 5-HT in raphe than in forebrain sites. Increases depend in part on depolarization-induced release, which may be greater in raphe than in forebrain.