Effects of ORG 6582 on monoamine uptake in vitro

In vivo studies have indicated that Org 6582 is a potent long acting selective inhibitor of 5HT uptake. The objective of this study was to investigate the effects of Org 6582 on the uptake of ³H]DA into synaptosome-rich homogenates of rat corpus striatum and on the uptake of ³H]NA or ³H]5HT into synaptosome-rich homogenates of rat hypothalamus. Two experimental approaches were adopted. In one, drugs were directly added to the incubation medium. In the other, rats were injected interperitoneally (i.p.) with the drugs under study at various times prior to death and synaptosomal ³H]monoamine uptake subsequently determined. Org 6582 was a competitive inhibitor of ³H]5HT uptake with a K_i value of 8.9 × 10^?8M. The ability of Org 6582 to inhibit ³H]5HT uptake was sixteen and seventy-two times greater than its effect on³H]NA and ³H]DA uptake respectively. At 1 hr after injection, Org 6582 equalled fluoxetine and was more potent than chlorimipramine at blocking ³H]5HT uptake. The duration of inhibition of ³H]5HT uptake by chlorimipramine was appreciably shorter than that of either Org 6582 or fluoxetine. In contrast to both desipramine and chlorimipramine, Org 6582 was essentially devoid of effect on ³H]NA uptake at 1 hr after injection. ³H]DA uptake was also unaffected by 1 hr pretreatment with Org 6582. The findings of this study confirm that Org 6582 is a potent long acting selective inhibitor of 5HT uptake.