Brain Histamine Modulates the Antidepressant-Like Effect of the 3-Iodothyroacetic Acid (TA1)

3-iodothyroacetic acid (TA1), an end metabolite of thyroid hormone, has been shown to produce behavioral effects in mice that are dependent on brain histamine. We now aim to verify whether pharmacologically administered TA1 has brain bioavailability and is able to induce histamine-dependent antidepressant-like behaviors. TA1 brain, liver and plasma levels were measured by LC/MS-MS in male CD1 mice, sacrificed 15 min after receiving a high TA1 dose (330 μgkg^-1). The hypothalamic mTOR/AKT/GSK-β cascade activation was evaluated in mice treated with 0.4, 1.32, 4 μgkg^-1 TA1 by Western-blot. Mast cells were visualized by immuno-histochemistry in brain slices obtained from mice treated with 4 μgkg^-1 TA1. Histamine release triggered by TA1 (20-1000 nM) was also evaluated in mouse peritoneal mast cells. After receiving TA1 (1.32, 4 or 11 μgkg^-1; i.p.) CD1 male mice were subjected to the forced swim (FST) and the tail suspension tests (TST). Spontaneous locomotor and exploratory activities, motor incoordination, and anxiolytic or anxiogenic effects, were evaluated. Parallel behavioral tests were also carried out in mice that, prior to receiving TA1, were pre-treated with pyrilamine (10 mgkg^-1; PYR) or zolantidine (5 mgkg^-1; ZOL), histamine type 1 and type 2 receptor antagonists, respectively, or with p-chloro-phenylalanine (100 mgkg^-1; PCPA), an inhibitor of serotonin synthesis. TA1 given i.p. to mice rapidly distributes in the brain, activates the hypothalamic mTOR/AKT and GSK-3β cascade and triggers mast cells degranulation. Furthermore, TA1 induces antidepressant effects and stimulates locomotion with a mechanism that appears to depend on the histaminergic system. TA1 antidepressant effect depends on brain histamine, thus highlighting a relationship between the immune system, brain inflammation and the thyroid.