Histamine mediates behavioural and metabolic effects of 3-iodothyroacetic acid, an endogenous end product of thyroid hormone metabolism

Abstract

Background and purpose: 3-Iodothyroacetic acid (TA1) is an end product of thyroid hormone metabolism. So far, it is not known if TA1 is present in mouse brain and if it has any pharmacological effects.

Experimental approach: TA1 levels in mouse brain were measured by HPLC coupled to mass spectrometry. After i.c.v. administration of exogenous TA1 (0.4, 1.32 and 4 μg·kg(-1) ) to mice, memory acquisition-retention (passive avoidance paradigm with a light-dark box), pain threshold to thermal stimulus (51.5°C; hot plate test) and plasma glucose (glucorefractometer) were evaluated. Similar assays were performed in mice pretreated with s.c. injections of the histamine H1 receptor antagonist pyrilamine (10 mg·kg(-1) ) or the H2 receptor antagonist zolantidine (5 mg·kg(-1) ). TA1 (1.32 and 4 μg·kg(-1) ) was also given i.c.v. to mice lacking histidine decarboxylase (HDC(-/-) ) and the corresponding WT strain.

Key results: TA1 was found in the brain of CD1 but not of HDC mice. Exogenous TA1 induced amnesia (at 0.4 μg·kg(-1) ), stimulation of learning (1.32 and 4 μg·kg(-1) ), hyperalgesia (0.4, 1.32 and 4 μg·kg(-1) ) and hyperglycaemia (1.32 and 4 μg·kg(-1) ). All these effects were modulated by pyrilamine and zolantidine. In HDC(-/-) mice, TA1 (1.32 and 4 μg·kg(-1) ) did not increase plasma glucose or induce hyperalgesia.

Conclusions and implications: Behavioural and metabolic effects of TA1 disclosed interactions between the thyroid and histaminergic systems.

Keywords: 3-iodoacetic acid; anti-histaminergic drugs; histamine; learning; pain; thyromimetics.

Figure 1

TA1 modifies learning, reduces nociceptive threshold and increases plasma glucose in mice. Mice (n = 20 for each groups of animals) were injected i.c.v. with TA1 (0.4, 1.32 or 4 μg·kg⁻¹ or with Veh and, after 15 min, were assessed by the passive avoidance paradigm (A) or their nociceptive threshold measured by the the hot plate test (B). **P < 0.01, ***P < 0.001 versus Veh. Plasma glucose was also measured 15 min after TA1 injection, in blood collected from the tail veins of 4 h starved mice (n = 10 for r each groups of animals). Results are expressed as means ± SEM; *P < 0.05 versus Veh.

Figure 2

The effects of histamine H₁ and H₂ receptor antagonists on TA1-induced modification of learning, pain threshold and plasma glucose in mice. Mice (n = 20 for each groups of animals) were pretreated s.c. with a single injection of pyrilamine (10 mg·kg⁻¹) or zolantidine [5 mg·kg⁻¹, 15 min before the i.c.v. injection of T1A (0.4, 1.32 and 4 μg·kg⁻¹) or Veh.]. 15 min after TA1 or Veh injection, mice were assessed by the passive avoidance paradigm (A), or nociceptive thresholds determined by the hot plate test (B). Plasma glucose was also measured 15 min after TA1 (0.4, 1.32 and 4 μg·kg⁻¹) i.c.v. injection in the blood collected from the tail veins of 4 h starved mice (n = 10 for each treatment) (C). Results are expressed as means ± SEM. *P < 0.05, **P < 0.01,***P < 0.001 versus Veh.

Figure 3

TA1 reversed scopolamine-induced amnesia. TA1, 1.32 and 4 μg·kg⁻¹ (n = 10 for each dose) or Veh were injected i.c.v. in mice (n = 20 for each groups of animals) pretreated i.p. with scopolamine (0.3 mg·kg⁻¹, n = 30) or saline. Mice were then assessed by the passive avoidance paradigm. Results are expressed as means ± SEM. §P < 0.05 and §§§P < 0.001 versus Veh. + scopolamine, ***P < 0.001 versus Veh.

Figure 4

T1A failed to induce hyperglycaemia and to raise plasma glucose when injected i.c.v. in HDC^−/− mice. TA1 (1.32 and 4 μg·kg⁻¹), or Veh, were injected i.c.v. in HDC^+/+ and HDC^−/− mice (n = 10 for each group of animals). After 15 min, nociceptive thresholds to a thermal stimulus and plasma glucose were evaluated in HDC^+/+ (A and B) and in HDC^−/− mice (C and D). Results are presented as the means ± SEM. *P < 0.05 versus Veh; **P < 0.01 versus Veh.