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Reasons for the observed lag-time for clinical efficacy of the tricyclic antidepressant drug, protriptyline, have been investigated. t-, • Our results demonstrate that chronic protriptyline administration resulta in several compensatory neural mechanisms: (1) changes in endogeneous cytoplasmic norepinephrine levels, (2) changes in norepinephrine turnover rate/recovery rate following the last dose in a chronic series of test drug administrations and (3) adaptations of the pre-synaptic receptor. The time course for these adaptive changes parallel the time required for the onset of their clinical effectiveness. We propose that acutely the action of the tricyclics on norepinephrine re-uptake is largely negated by compensatory adjustments in turnover rate of the neurotransmitter; but with chronic administration, adaptations in pre-synaptic alpha-receptors occur. This phenomena in turn reduces the extent to which the norepinephrine neurons can offset or compensate for the blockade of norepinephrine re-uptake. Specifically, pre-synaptic alpha-receptors become hyposensitive, and receptor tolerance develops; not to the direct action of the tricyclic drug on neurotransmitter re-uptake, but to the compensatory neural adjustments which offset the action of the acute tricyclic administration and delay their clinical efficacy. OUr results demonstrated that tricyclic antidepressant drugs, when administered chronically, do not alttr monoamine oxidase activity in vivo in any of the three brain regions we examined (corpus striatua, forebrain, and hypothalamus). Similarly, we were not able to identify a noradrengeric relationship other than those that were both toxic and lethal when thyroid hormone was administered with the tricyclic antidepressant drug Protriptyline. We did, however, observe that in the hyperthyroid condition norepinephrine turnover is decreased in hypothalamus when compared to control animals. The results we obtained from chronic protriptyline administration and its effects on norepinephrine levels and turnover, as well as the results we obtained when yohimbine was employed are enlightening. Chronic protriptyline administration produced decreased norepinephrine levels in hypothala11Us, and decreased norepinephrine turnover, when compared to saline administered controls. The alpha-receptor antagonist (yohimbine} produced only minor effects on norepinephrine levels and turnover when experimental animals were pretreated chronically (18 days) with protriptyline. These results suggest an adaptive response (hypo-sensitivity) of the presynaptic alpha-receptor (autoreceptor), and this phenomena also occurs at the post-synaptic alpha-receptor. These results, suggesting receptor adaptation, indicated the existence of another mechanism of action for the tricyclic antidepressants.