Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites.

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Abstract
Imipramine inhibits the serotonin uptake by binding with high affinity to regulatory sites of this uptake located on axons that release serotonin. The number of imipramine recognition sites located on crude synaptic membrane preparations is reduced by 2 daily injections of imipramine or desmehtylimipramine for 3 wk. When the binding sites for [3H]imipramine are down-regulated, the Vmax of the neuronal uptake of serotonin is increased. In minces prepared from the brain hippocampus of rats receiving imipramine in a dose regimen that reduces the number of [3H]imipramine recognition sites, the efficiency of imipramine as a blocker of the serotonin uptake is diminished. The high-affinity binding sites for [3H]imipramine may have a physiological role in modulation of serotonin reuptake. Probably this is mediated by an endogenous effector of these regulatory sites. A nonpeptide constituent of rat brain capable of displacing [3H]imipramine from its high-affinity binding site and of inhibiting the serotonin uptake in a dose-related manner was extracted and its partial purification is described.