Human fibroblast cultures as a tool for the study of antidepressant drug action

Studies and interpretations of results of antidepressant drug action in brain are hampered by the complexity of the target organ. Biochemical and physiological effects of these drugs can, however, be studied profitably in cultured cells. We have investigated the effects of the tricyclic antidepressant desipramine on cultured human fibroblasts. The desipramine-induced changes were compared with effects of further antidepressants and of drugs with other therapeutic indications. In addition to the drug uptake and release, effects on phospholipid metabolism and on beta-adrenoceptor density were studied. The results showed an accumulation of desipramine within the lysosomal compartment and an inhibition of the phospholipid degradation resulting in a specific change of the cellular phospholipid-pattern. Chronic but not single dose exposure to desipramine reduced the number of beta-adrenoceptors and the isoproterenol-stimulated cAMP-response. This beta-adrenoceptor desensitization is thought to be causally related to the specific change of the phospholipid-pattern induced by the drug. It can be speculated that such a drug specific change of the phospholipid-matrix may be responsible for the alterations of a number of neurotransmitter receptors and of other membrane-associated functions, observed in brains of chronically drug treated animals.