Role of uptake inhibition and autoreceptor activation in the control of 5‐HT release in the frontal cortex and dorsal hippocampus of the rat

Using brain microdialysis, we compared the relative role of 5‐hydroxytryptamine (5‐HT; serotonin) blockade and somatodendritic 5‐HT1A and/or terminal 5‐HT1B autoreceptor activation in the control of 5‐HT output. Fluoxetine (10 mg kg−1 i.p.) doubled the 5‐HT output in frontal cortex and dorsal hippocampus. The 5‐HT1A receptor antagonist WAY 100635, (0.3 mg kg−1 s.c.) potentiated the effect of fluoxetine only in frontal cortex (to ∼500 % of baseline). Methiothepin (10 mg kg−1 s.c.) further enhanced the 5‐HT rise induced by fluoxetine+WAY 100635, to 835±179% in frontal cortex and 456±24% in dorsal hippocampus. Locally applied, methiothepin potentiated the fluoxetine‐induced 5‐HT rise more in the former area. The selective 5‐HT1B receptor antagonist SB‐224289 (4 mg kg−1 i.p.) enhanced the effect of fluoxetine (10 mg kg−1 i.p.) in both areas. As with methiothepin, SB‐224289 (4 mg kg−1 i.p.) further enhanced the 5‐HT increase produced by fluoxetine+WAY 100635 more in frontal cortex (613±134%) than in dorsal hippocampus (353±59%). Locally applied, fluoxetine (10–300 μM; EC50=28–29 μM) and citalopram (1–30 μM; EC50=1.0–1.4 μM) increased the 5‐HT output two to three times more in frontal cortex than in dorsal hippocampus. These data suggest that the comparable 5‐HT increase produced by systemic fluoxetine in frontal cortex and dorsal hippocampus results from a greater effect of reuptake blockade in frontal cortex that is offset by a greater autoreceptor‐mediated inhibition of 5‐HT release. As a result, 5‐HT autoreceptor antagonists preferentially potentiate the effect of fluoxetine in frontal cortex. British Journal of Pharmacology (2000) 130, 160–166; doi:10.1038/sj.bjp.0703297