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Keywords:

  • 5-Hydroxytryptamine;
  • 5-HT uptake;
  • 5-HT1A receptors;
  • 5-HT1B receptors;
  • antidepressants;
  • citalopram;
  • fluoxetine;
  • frontal cortex;
  • hippocampus;
  • microdialysis
  • 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