Intraneuronal site of action for imipramine in rat striatal slices

The uptake of 3H-labeled imipramine ([3H]IMI) in rat carpus striatum slices was found to be strongly temperature-dependent. The accumulation was shown to be saturable and two apparent Km's were found: 2.2 x 10(-8) and 3.5 x 10(-7) M. Once incorporated, the labeled drug was released from superfused slices by K+ (55 mM) depolarization in the presence of calcium ions. Imipramine was also studied for its ability to induce the release of [3H]dopamine ([2H]DA) which had been previously accumulated by striatal slices. It was found that striatal slices superfused during 1 or 6 min with imipramine (10(-6) - 10(-4) M) release substantial amounts of radioactive dopamine, independently of the presence of Ca2+ in the medium. This release is completely abolished after reserpine pretreatment. It is proposed that imipramine enters the dopaminergic storage vesicles and displaces dopamine. An intraneuronal mechanism of action for imipramine is discussed.