DESMETHYLIMIPRAMINE, A POTENT INHIBITOR OF SYNAPTOSOMAL NOREPINEPHRINE UPTAKE, HAS DIVERSE EFFECTS ON THYROID-HORMONE PROCESSING IN RAT-BRAIN .2. EFFECT ON IN-VIVO 5'-DEIODINATION OF [I-125] THYROXINE

We have studied the effects of desmethylimipramine (DMI), a tricyclic antidepressant, on thyroid hormone (TH) handling in rat brain in an ef fort to discover a pharmacological basis for reported interactions bet ween TH, affective disorders and psychotropic drugs. An acute dose bf DMI has been used in order to determine the primary effects of the dru g in brain without perturbations from secondary effects. Recently we h ave reported that a single dose of DMI significantly decreases brain u ptake of both [I-125]thyroxine (T-4) and [I-125]3,3',5-triiodothyronin e (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 in vivo rates of T-4 to T-3 conversion in a se ries of experiments in which DMI (25 mg/kg) was given to HYPO, EU and HYPER male rats in conjunction with i.v. [I-125]T-4. Decreased in vivo conversion ratios (T-3/T-4 ratios) suggest that acute DMI treatment c auses a significant decrease in 5'-deiodinase activity in balance of b rain (but not cerebellum) in all DMI treated rats as compared to their saline treated controls (ANOVA, P < 0.0001). For assurance that reduc ed T-3/T-4 in DMI treated rat brain is not the result of DMI enhanceme nt of 5-deiodination of T-3 or T-4, the effect of DMI on concentration s 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 t reated 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 alt ernative pathway of T-4 metabolism. Rather, acute DMI treatment demons trates dual effects in balance of brain of both reducing TH uptake and , as now shown, reducing 5'-deiodinase activity. Together, these effec ts (resulting in diminished brain T-3) are opposite to what should be predicted from knowledge of TH mechanisms by which uniform concentrati ons of T-3 in brain are maintained. In further investigations of TH in teractions 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.