Abstract

The functional modulation of norepinephrine (NE) release by serotonergic receptors in the hippocampus of freely moving rats was studied by use of in vivo microdialysis. To stimulate NE release from the nerve terminals, a high concentration of potassium (K+, 120 mM) was added through the perfusion system. The K(+)-evoked NE release was inhibited in a concentration-dependent manner when serotonin (5-HT, 0.01-10 microM) was coperfused with K+. A selective 5-HT3 receptor agonist, 2-methyl-5-HT, mimicked the 5-HT response at a concentration of 0.01 to 10 microM. The 5-HT-induced (1 microM) inhibition of NE release was blocked by pretreatment with ondansetron (1 and 10 microM), a 5-HT3 receptor antagonist. On the other hand, K(+)-evoked NE release was also reduced by coperfusion with the 5-HT reuptake inhibitor, fluoxetine (10 microM), which caused increases in the dialysate 5-HT concentration. The fluoxetine-induced (10 microM) decreases in the K(+)-evoked NE release were prevented by serotonergic denervation caused by pretreatment with 5,7-dihydroxytryptamine (200 micrograms/rat i.c.v.). These results indicate that the inhibition on NE release by fluoxetine was due to increased synaptic concentrations of endogenous 5-HT. The fluoxetine-induced inhibitory effect was furthermore abolished by pretreatment with ondansetron (1 and 10 microM). These findings indicate the possibility that both exogenous and endogenous 5-HT inhibit NE release occurs from the rat hippocampus by 5-HT3 receptors. Thus, the present study suggests that the functional modulation of NE release by 5-HT3 receptors exists in vivo.