Desmethylimipramine, a potent inhibitor of synaptosomal norepinephrine uptake, has diverse effects on thyroid hormone processing in rat brain. II. Effect on in vivo 5′-deiodination of [ 125I]thyroxine

Abstract

We have studied the effects of desmethylimipramine (DMI), a tricyclic antidepressant, on thyroid hormone (TH) handling in rat brain in an effort to discover a pharmacological basis for reported interactions between TH, affective disorders and psychotropic drugs. An acute dose of DMI has been used in order to determine the primary effects of the drug in brain without perturbations from secondary effects. Recently we have reported that a single dose of DMI significantly decreases brain uptake of both [ 125I]thyroxine (T 4) and [ 125I]3,3′,5-triiodothyronine (T 3) across the spectrum of thyroid states from hypothyroid (HYPO) to euthyroid (EU) to T 4-induced hyperthyroid (HYPER). To investigate further the effects of DMI on brain processing of TH, we have measured effects of the drug on vivo rates of T 4 to T 3 conversion in a series of experiments in which DMI (25 mg/kg) was given to HYPO, EU and HYPER male rats in conjunction with i.v. [ 125I]T 4. Decreased in vivo conversion ratios (T 3/T 4 ratios) suggest that acute DMI treatment causes a significant decrease in 5′-deiodinase activity in balance of brain (but not cerebellum) in all DMI treated rats as compared to their saline treated controls (ANOVA, P < 0.0001). For assurance that reduced T 3/T 4 in DMI treated rat brain is not the result of DMI enhancement of 5-deiodination of T 3 or T 4, the effect of DMI on concentrations of labeled I −, rT 3, and T 2 (3,3′- and 3′,5′-) was also observed. In no case was there a significant increase in any metabolite in DMI treated rats for any tissue studied. Moreover, labeled I − was decreased in balance of brain in all experimental groups ( P < 0.0001). Thus it appears that DMI neither accelerates T 3 turnover nor enhances any alternative pathway of T 4 metabolism. Rather, acute DMI treatment demonstrates dual effects in balance of brain of both reducing TH uptake and, as now shown, reducing 5′-deiodinase activity. Together, these effects (resulting in diminished brain T 3) are opposite to what should be predicted from knowledge of TH mechanisms by which uniform concentrations of T 3 in brain are maintained. In further investigations of TH interactions with DMI, it will be of interest to establish whether they are adrenergically mediated and how the sites of diminished TH uptake and 5′-deiodination are related.