I. Hervas et al., Role of uptake inhibition and autoreceptor activation in the control of 5-HT release in the frontal cortex and dorsal hippocampus of the rat, BR J PHARM, 130(1), 2000, pp. 160-166
1 Using brain microdialysis, we compared the relative role of 5-hydroxytryp
tamine (5-HT; serotonin) blockade and somatodendritic 5-HT1A and/or termina
l 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 (t
o similar to 500 % of baseline).
3 Methiothepin (10 mg kg(-1) s.c.) further enhanced the 5-HT rise induced b
y fluoxetine+WAY 100635, to 835+/-179% in frontal cortex and 456 +/- 24% in
dorsal hippocampus. Locally applied, methiothepin potentiated the fluoxeti
ne-induced 5-HT rise more in the former area.
4 The selective 5-HT1B receptor antagonist SB-224289 (4 mg kg(-1) i.p.) enh
anced the effect of fluoxetine (10 mg kg(-1) i.p.) in both areas. As with m
ethiothepin, SB-224289 (4 mg kg(-1) i.p.) further enhanced the 5-HT increas
e produced by fluoxetine+WAY 100635 more in frontal cortex (613 +/- 134%) t
han in dorsal hippocampus (353 +/- 59%).
5 Locally applied, fluoxetine (10-300 mu M; EC50 = 28-29 mu M) and citalopr
am (1 - 30 mu M; EC50 = 1.0-1.4 mu M) increased the 5-HT output two to thre
e 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 autorec
eptor antagonists preferentially potentiate the effect of fluoxetine in fro
ntal cortex.