Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain

Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. Ln rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA(3) pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased. indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [H-3]5-HT from preloaded slices was enhanced in the mid-brain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A, autoreceptors. In addition, evoked release of [H-3]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha(2)-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [H-3]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [H-3]NA was enhanced In the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [H-3]NA release were most likely due to the desensitization of the alpha(2)-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex. respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.