Displacement of Serotonin from Its Adenosine Triphosphate Complex by Tricyclic Antidepressant Drugs in Vitro

Serotonin forms a high molecular weight micellar complex with ATP, which is assumed to be the storage form of the neurotransmitter in nerve ending granules. Since bound serotonin (5-HT) does not show fluorescence, complex formation is accompanied by quenching of its fluorescence. Using a solution of a 5-HT-ATP complex at a 1:2 molar ratio containing 5 mM 5-HT, we observed fluorescence enhancement upon addition of tricyclic antidepressants in proportion to the amount and nature of the drug. The molar ratio of drug to 5-HT necessary to liberate 50% of bound serotonin was used to characterize the relative efficacy of the drugs in competing with 5-HT for ATP. The drugs also form water-insoluble complexes with ATP in a 2:1 molar ratio even in the presence of 5-HT. The solid complexes were characterized by infrared and NMR spectroscopy as well as by elemental analysis. The liberation of 5-HT from its "storage complex" in vitro suggests that an intraneuronal mode of action of antidepressant drugs is possible, in addition to their known inhibition of reuptake at the presynaptic neuronal membrane.