Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold

Abstract

Background and purpose: 3-Iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behaviour and metabolism. To determine whether brain thyroid hormone levels contribute to these effects, we investigated the effect of central administration of T1AM on learning and pain threshold of mice either untreated or pretreated with clorgyline (2.5 mg·kg(-1) , i.p.), an inhibitor of amine oxidative metabolism.

Experimental approach: T1AM (0.13, 0.4, 1.32 and 4 μg·kg(-1) ) or vehicle was injected i.c.v. into male mice, and after 30 min their effects on memory acquisition capacity, pain threshold and curiosity were evaluated by the following tests: passive avoidance, licking latency on the hot plate and movements on the hole-board platform. Plasma glycaemia was measured using a glucorefractometer. Brain levels of triiodothyroxine (T3), thyroxine (T4) and T1AM were measured by HPLC coupled to tandem MS. ERK1/2 activation and c-fos expression in different brain regions were evaluated by Western blot analysis.

Results: T1AM improved learning capacity, decreased pain threshold to hot stimuli, enhanced curiosity and raised plasma glycaemia in a dose-dependent way, without modifying T3 and T4 brain concentrations. T1AM effects on learning and pain were abolished or significantly affected by clorgyline, suggesting a role for some metabolite(s), or that T1AM interacts at the rapid desensitizing target(s). T1AM activated ERK in different brain areas at lower doses than those effective on behaviour.

Conclusions and implications: T1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative-induced memory disorders.

Figure 1

(A) Mice were injected i.c.v. with T1AM (0.13, 0.4, 1.32 or 4 μg·kg⁻¹) or with vehicle (Veh) and subjected to the passive avoidance test as described in the Methods section. Results are expressed as mean ± SEM; n = 20 in each group; *P < 0.05; ***P < 0.001 versus vehicle. (B) Mice pretreated with clorgyline (2.5 mg·kg⁻¹, i.p.), received either vehicle (Veh) or T1AM (0.4 or 1.32 μg·kg⁻¹) i.c.v and were then subjected to the passive avoidance test as described in the Methods section. Results are expressed as mean ± SEM; n = 10 in each group.

Figure 2

The object recognition task was performed on fed mice, which were injected on day 2 with 1.32 μg·kg⁻¹ T1AM or vehicle (n = 20 per group). The retention session was performed 24 h later (A). Animal movements in the arena (locomotor activity) were not significantly different between the two groups (B). Results are expressed as mean ± SEM; ***P < 0.001 versus vehicle.

Figure 3

Mice were injected i.c.v. with T1AM (0.4, 1.32 and 4 μg·kg⁻¹) or vehicle and put on the hole-board platform. Movements and exploratory activities were monitored as described in the Methods section. Results are expressed as mean ± SEM; n = 20 in each group; ***P < 0.001 and **P < 0.01 versus vehicle.

Figure 4

(A) Mice were placed on the hot plate 30 min after i.c.v. injection of T1AM (0.13, 04, 1.32 and 4 μg·kg⁻¹) or vehicle. The latency to respond to the insult was evaluated as described in the Methods section. Results are expressed as mean ± SEM; n = 20 in each group; *P < 0.05 and **P < 0.01 versus vehicle. (B) Mice were pretreated with clorgyline (2.5 mg·kg⁻¹, i.p.), received either vehicle (Veh) or T1AM (0.13, 0.4 or 1.32 or 4 μg·kg⁻¹) i.c.v and after 30 min were placed on the hot plate. The latency to respond to the insult was evaluated as described in the Methods section. Results are expressed as mean ± SEM; n = 10 in each group; ∧P < 0.05 versus vehicle without clorgyline (A) and *P < 0.05 versus vehicle (with clorgyline).

Figure 5

Blood samples were collected from the tail vein of fed mice injected i.c.v. with vehicle or with T1AM at dosages of 0.13, 0.4, 1.32 μg·kg⁻¹ (n = 5 in each group). Glycaemia was measured by a glucorefractometer 30 min after i.c.v. injections. Results are expressed as mean ± SEM;*P < 0.05 versus vehicle.

Figure 6

Thirty minutes after i.c.v injection of T1AM (0.04, 0.13 μg·kg⁻¹) or vehicle, mice (n = 3 per group) were killed and brain regions separated as described in the Methods section. Immunodetection for pERK was carried out on protein lysates from each region separated on SDS-PAGE gels. Results are the mean ± SEM of the densitometry of three different gels. (A) Results of a typical experiment. (B) Cumulative results. *P < 0.05 versus vehicle.