An acute dose of desmethylimipramine inhibits brain uptake of [125I]3,3',5-triiodothyronine (T3) in thyroxine-induced but not T3-induced hyperthyroid rats: implications for tricyclic antidepressant therapy.
The tricyclic antidepressant, desmethylimipramine (DMI), a highly selective inhibitor of presynaptic uptake of norepinephrine (NE), has also been shown to reduce [125I]3,3',5-triiodothyronine (T3) uptake in rat brain synaptosomes. Using DMI as a probe to examine 1) possible noradrenergic influences on thyroid hormone (TH) actions in brain and 2) TH:affective disorder relationships, we found that a single dose of DMI produces a small (7.4-25%) but significant (P < or = .05) decrease in brain uptake of both labeled T3 (T3) and labeled thyroxine (T4) across the spectrum of thyroid states from hypothyroid (HYPO) to euthyroid to T4-induced hyperthyroid. Therefore, it was noted with considerable interest that DMI appeared not to interfere with brain T3 uptake in T3-induced hyperthyroid (T3-HYPER) rats. To confirm this finding, thyroidectomized male rats were made T3-HYPER through administration of T3 (20 micrograms/kg) for 3 weeks or maintained without TH supplement for 6 weeks, becoming HYPO. Rats were given i.v. T3 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 treatment category (DMI or saline). Evaluation by analysis of variance showed that T3 concentrations (percentage of dose) were significantly lower in DMI than in saline-treated rat brain for HYPO (-15%; P = .0034) but not T3-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 T3 > DMI > T4 and suggest that T3 might augment tricyclic antidepressant therapy more effectively than T4.
Department of Psychiatry, University of Pennsylvania, Philadelphia.
J T
JT
Gordon
E E
EE
Tomlinson
J
J
Greenberg
M B
MB
Dratman
D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006980:Hyperthyroidism / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007037:Hypothyroidism / Q000188:drug therapy / Q000378:metabolism; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D007457:Iodine Radioisotopes; D007487:Ipodate / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D014284:Triiodothyronine / Q000493:pharmacokinetics* / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D007457:Iodine Radioisotopes; D014284:Triiodothyronine; D007453:Iodide Peroxidase; D007487:Ipodate; D013974:Thyroxine; D003891:Desipramine