DEXFENFLURAMINE ENHANCES STRIATAL DOPAMINE RELEASE IN CONSCIOUS RATS VIA A SEROTONINERGIC MECHANISM

The effects of dexfenfluramine on the release of brain dopamine and se rotonin into striatal dialysates were measured in freely moving rats. Samples collected every 20 min were assayed for dopamine and serotonin by high-performance liquid chromatography in a single run. The admini stration of a lower anorectic dose of dexfenfluramine (0.5 or 1.0 mg/k g intraperitoneally) significantly increased dialysate serotonin conce ntrations without affecting those of dopamine. A higher dexfenfluramin e dose (2.5 mg/kg intraperitoneally) increased both serotonin and dopa mine. The increase in dopamine could be blocked by administering the m ixed-acting serotonin antagonist methiothepin (20 mu M), and was repro duced by applying serotonin (3-10 mu M) directly to striatal neurons. Tetrodotoxin (1 mu M) added to the striatal perfusates decreased the b asal release of dopamine and serotonin; it also blocked the effect of dexfenfluramine (2.5 mg/kg intraperitoneally) on dopamine release and decreased the increment in serotonin release (by approximate to 70%). Amphetamine (1 mg/kg subcutaneously) or phentermine (2 mg/kg intraperi toneally) increased dialysate dopamine concentrations without affectin g those of serotonin, and tetrodotoxin (1 mu M) failed to block the re sponse to amphetamine. These findings suggest that (1) lower anorectic doses of dexfenfluramine release serotonin but not dopamine, and (2) higher doses of dexfenfluramine also increase dopamine release by an i ndirect mechanism mediated via serotonin.