On the selective inhibition of serotonin uptake in vivo by Org 6582

In vivo blockade of 5-HT uptake was studied by investigating the effect of drug pretreatment on the ability of p-chloramphetamine to lower rat brain 5-HT levels. Org 6582 was approximately twice as potent as fluoxetine, five times more potent than chlorimipramine and 14 times more potent than desipramine in blocking the ability of p-chloroamphetamine to lower rat brain 5-HT content. Org 6582 also had a longer duration of action than either fluoxetine or chlorimipramine. Org 6582, whilst having no effect on amine steady state levels, decreased rat brain 5-HT turnover and also lowered rat brain levels of 5-HIAA. In contrast to both desipramine and chlorimipramine, Org 6582 was devoid of effect on the ability of 1-metaraminol and 6-hydroxydopamine to lower rat heart NA levels. The ability of intraventricularly administered 6-hydroxydopamine to lower rat brain NA levels was unaltered by Org 6582 pretreatment. The corresponding i.p. ED50 values for desipramine and chlorimipramine were 7.3 mg/kg and 28.8 mg/kg respectively. Like desipramine and chlorimipramine, Org 6582 had no effect on the ability of intraventricular 6-hydroxydopamine to lower rat brain DA content. Org 6582 had no effect on steady state levels or on the turnover of NA and DA in the rat brain. It is concluded that Org 6582 is a potent long acting selective inhibitor of 5-HT uptake in vivo.