Proteomic search for intracellular binding sites of antidepressants

Background:

Since the discovery of the monoamine oxidase inhibitor iproniazid and the tricyclic chemical imipramine as effective antidepressants in the 1950s, substantial efforts have been made to elucidate the mode of action of the different antidepressants that emerged over time. According to the monoamine hypothesis, one of the major theories in depression, depressive symptoms are caused by a reduction of monoaminergic neuro-transmission. However, the molecular underpinnings of depression seem to be more complex than the reduction of the monoamine concentration. Various research groups have begun to examine the effects of antidepressants on intracellular signalling pathways, but surprisingly, little effort is devoted so far to exploring potential intracellular drug targets.

Methods:

To discover intracellular binding sites of antidepressants a desipramine affinity column was constructed, i.e. desipramine was covalently linked to a solid support. This immobilised desipramine was incubated with a protein extract (the proteome) of the hippocampal cell line HT–22, and specifically bound proteins were determined in comparison to an „empty“ column.

Results/Conclusion:

Preliminary data provide evidence that intracellular proteins could be potential binding-sites of antidepressants. If verified by subsequent experiments, this may open new avenues for the development of antidepressants and the understanding of depression.