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

Abstract

BACKGROUND AND PURPOSE3-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 APPROACHT1AM (0.13, 0.4, 1.32 and 4 mg·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. RESULTST1AM 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 IMPLICATIONST1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative-induced memory disorders. AbbreviationsCREB, cyclic AMP-responsive element binding; PBST, PBS plus Tween; T1AM, 3-iodothyronamine; T3, triiodothyroxine; T4, thyroxine; TA1 receptor, trace amine-associated receptor 1

The impact of scopolamine pretreatment on 3-iodothyronamine (T1AM) effects on memory and pain in mice

“…Under these conditions, T1AM completely reversed the mice's scopolamine-induced amnesia, consolidating memory at 1 h and 24 h post training. Interestingly enough, in the presence of scopolamine, the lowest effective anti-amnestic dose was 0.13 μg/kg T1AM, which has also been found to be ineffective as pro-learning (Manni et al, 2013). To note the dose-effect curve of T1AM as antiamnesic is bell-shaped, thus confirming that already described (Manni et al, 2013) and possibly indicating desensitization mechanisms at increasing T1AM doses.…”

“…To note, this dose was never found effective in any of the behavioural tests performed previously, and thus represents the lowest effective dose of T1AM in-vivo to date. The anti-amnestic effect of T1AM, as already reported for the pro-learning effect (Manni et al, 2013), is abolished under conditions of MAO inhibition, suggesting that the formation TA1 takes part of the anti-amnestic effect of T1AM (Fig. 2).…”

“…A significant reduction of mouse pain threshold to hot stimulus was instead reached when 0.13 and 0.4 but not 1.32 μg/kg T1AM were "added" to scopolamine. Under these conditions, 0.13 μg/kg becomes the minimum effective hyperalgesic dose of T1AM while at 1.32 μg/kg T1AM is ineffective (Manni et al, 2013). To explain this behaviour one can postulate that sub-effective doses of the muscarinic antagonist and of T1AM might have additive effects on reducing the murine pain threshold, a condition which makes effective also the 0.13 μg/kg T1AM.…”

“…The test was performed according to the step-through method described by Manni et al (2013). The experimental apparatus consisted of a two-compartment acrylic box consisting of an illuminated platform 59-64 m (60 W, 840 lx) connected to a dark chamber by a guillotine door.…”

“…In fact, T1AM pharmacologically administered at low doses (1.32 and 4 μg/kg i.c.v. injected) quickly modifies murine behavior, including stimulation of learning, memory consolidation, and produces hyperalgesia (Manni et al, 2013). Interestingly, the T1AM pro-learning effect depends on its oxidative deamination producing 3-iodothyroacetic acid (TA1; Musilli et al, 2014) and by the release of histamine (Laurino et al, 2015a).…”