We have examined the effects of antidepressant drugs on the morphology and fine-structure of cingulate cortex neurons and synapses in vitro. Dissociated cell cultures from 16-day-old rat fetuses were maintained for up to three weeks in the presence of amitriptyline and desipramine (tricyclic antidepressants) mianserin and citalopram (non-tricyclic antidepressants) or without drugs as controls. Synapses in cultures exposed to amitriptyline and desipramine displayed increased numbers of presynaptic vesicles and more extensive membrane specializations than in control cultures, and increased numbers of coated vesicles both pre- and postsynaptically. In mianserin- and citalopram-treated cultures, synaptic specializations were increased in length, and aggregates of mitochondria at the base of neurites were observed. Our results indicate that long-term exposure to antidepressant drugs results in significant changes in intracellular structure, including changes in synaptic ultrastructure.