Background and purpose 3-iodothyroacetic acid (TA1) is among the end products of thyroid hormone metabolism. To now, it is unknown if TA1 is present in the brain of rodents and if it has any pharmacological effects. Exeprimental approach We measured TA1 levels in the brain of mice by HPLC coupled to mass spectrometry and then we investigated whether pharmacological administration of TA1 modified memory, pain and plasma glycemia. 15 min after intracerebroventricular (i.c.v.) injection of TA1 (0.4, 1.32 and 4 μgkg-1) mice memory acquisition-retention, pain threshold to hot stimulus (51.5°C) and plasma glycemia were evaluated on the light-dark box, on the hot plate and by a glucorefractometer respectively. Parallel experiments were performed in mice pre-treated with subcutaneous injections of pyrilamine (10 mgkg-1) or zolantidine (5 mgkg-1), antagonists of histamine H1 and H2 receptors respectively. Furthermore, TA1 (1.32 and 4 μgkg-1) was i.c.v. injected in histidine decarboxylase null (HDC-/-) and their HDC+/+ littermate mice. Results TA1 was present in the brain of CD1 but not of HDC mice. Pharmacological activity of TA1 included amnesia (at the dose of 0.4 μgkg-1), stimulation of learning (at 1.32 and 4 μgkg-1), hyperalgesia (at 0.4, 1.32 and 4 μgkg-1 ) and hyperglycemia (at 1.32 and 4 μgkg-1). All these effects were modulated by pyrilamine and zolantidine. In HDC-/- mice, TA1 (1.32 and 4 μgkg-1, i.c.v. injected ) failed to increase plasma glycemia and to reduce pain threshold. Conclusions and implications TA1 behavioral and metabolic effects reveal an interplay between the thyroid and the histaminergic system
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