Pre- and postsynaptic serotonergic manipulations in an animal model of depression

Rats working on a food-reinforced operant schedule and exhibiting behavioral depression following administration of D,L-5-hydroxytryptophan (5-HTP) were pretreated with one of three drugs: methysergide, fluoxetine, or amitriptyline. The former two drugs were used to establish a basis for distinguishing between pre- and postsynaptic events. We found that methysergide, a known postsynaptic blocker of serotonin, almost completely abolished the depressive effect of 5-HTP, whereas fluoxetine, a known specific uptake blocker of serotonin, potentiated the depressive effect of the 5-hydroxytryptamine (5-HT) precursor. Amitriptyline, one of the commonly prescribed antidepressive drugs, reduced the behavioral depression following 5-HTP by approximately 50%. These data indicate that amitriptyline can act as an antagonist of 5-HT at the postsynaptic receptor. The results of this study, as well as those recently reported from CNS membrane binding studies, suggest that the therapeutic effects of some antidepressive drugs may be explained by their postsynaptic rather than presynaptic properties at central serotonergic receptors. Thus, these studies support the hypothesis that some types of human depression may be primarily due to an excess of free 5-HT acting at postsynaptic receptors.