Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies
1. The effects of acute administration of SCH 23390 (0.05 and 0.25 mg/kg s.c.), a dopamine D-1 receptor antagonist having also a moderate serotonin-S2 (5-HT-2) receptor blocking activity, and ritanserin (0.5 mg/kg), a specific 5-HT-2 antagonist, on dopamine (DA) and serotonin (5-HT) turnover were investigated in dopaminergic (nucleus caudatus, nucleus accumbens, substantia nigra, A10 area) and serotonergic (nucleus raphe dorsalis and nucleus raphe medialis) rat brain nuclei. 2. Acute SCH 23390 (both doses) increased the metabolism of DA and tended to augment the rate of DA synthesis (accumulation of DOPA after inhibition of aromatic acid decarboxylase) in the nucleus accumbens, but not in the nucleus caudatus. In addition, SCH 23390 had a moderate effect on DA metabolism in substantia nigra. SCH 23390 did not alter the turnover of 5-HT in any of the nuclei studied. 3. Acute administration of ritanserin did not modify 5-HT or DA turnover in any of the nuclei studied. 4. In conclusion, these results suggest that acute SCH 23390 administration preferentially activates the mesolimbic DA system. The lack of effect of ritanserin on DA or 5-HT turnover in nigrostriatal and mesolimbic DAergic areas suggests that under basal conditions the blockade of 5-HT2 receptors do not change monoamine metabolism in these areas. The role of 5-HT-2 blockade in the actions of SCH 23390 on DA turnover appears thus to be of a minor importance.