AN ACUTE DOSE OF DESMETHYLIMIPRAMINE INHIBITS BRAIN UPTAKE OF [I-125]3,3',5-TRIIODOTHYRONINE (T-3) IN THYROXINE-INDUCED BUT NOT T-3-INDUCED HYPERTHYROID RATS - IMPLICATIONS FOR TRICYCLIC ANTIDEPRESSANT THERAPY

The tricyclic antidepressant, desmethylimipramine (DMI), a highly sele ctive inhibitor of presynaptic uptake of norepinephrine (NE), has also been shown to reduce [I-125]3,3',5-triiodothyronine (T-3) uptake in r at brain synaptosomes. Using DMI as a probe to examine I)possible nora drenergic influences on thyroid hormone (TH) actions in brain and 2) T H:affective disorder relationships, we found that a single dose of DMI produces a small (7.4-25%) but significant (P less than or equal to . 05) decrease in brain uptake of both labeled T-3 (T-3(.)) and labeled thyroxine (T-4(.)) across the spectrum of thyroid states from hypothyr oid (HYPO) to euthyroid to T-4-induced hyperthyroid. Therefore, it was noted with considerable interest that DMI appeared not to interfere w ith brain T-3(.) uptake in T-3-induced hyperthyroid (T-3-HYPER) rats. To confirm this finding, thyroidectomized male rats were made T-3-HYPE R through administration of T-3 (20 mu g/kg) for 3 weeks or maintained without TH supplement for 6 weeks, becoming HYPO. Rats were given i.v . T-3(.) and 5 min later i.p. DMI or saline. They were decapitated at 3 hr and brains retrieved for radiochemical analysis. Each experiment was run in three separate trials, with three to four rats in each trea tment category (DMI or saline). Evaluation by analysis of variance sho wed that T-3(.) concentrations (percentage of dose) were significantly lower in DMI than in saline-treated rat brain for HYPO (-15%; P = .00 34) but not T-3-HYPER rats (-2%; P =.6595). These results suggest that , as it does in the case of NE, DMI tends to block TH uptake sites in rat brain. The data also demonstrate a differential affinity for those sites in which T-3 > DMI > T-4 and suggest why T-3 might augment tric yclic antidepressant therapy more effectively than T-4.