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

1 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. 2 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 similar to 500 % of baseline). 3 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. 4 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%). 5 Locally applied, fluoxetine (10-300 mu M; EC50 = 28-29 mu M) and citalopram (1 - 30 mu M; EC50 = 1.0-1.4 mu M) increased the 5-HT output two to three times more in frontal cortex than in dorsal hippocampus. 6 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.