Elsevier

Brain Research

Volume 1351, 10 September 2010, Pages 130-140
Brain Research

Research Report
3-Monoiodothyronamine: The rationale for its action as an endogenous adrenergic-blocking neuromodulator

https://doi.org/10.1016/j.brainres.2010.06.067Get rights and content

Abstract

The investigations reported here were designed to gain insights into the role of 3-monoiodothyronamine (T1AM) in the brain, where the amine was originally identified and characterized. Extensive deiodinase studies indicated that T1AM was derived from the T4 metabolite, reverse triiodothyronine (revT3), while functional studies provided well-confirmed evidence that T1AM has strong adrenergic-blocking effects. Because a state of adrenergic overactivity prevails when triiodothyronine (T3) concentrations become excessive, the possibility that T3's metabolic partner, revT3, might give rise to an antagonist of those T3 actions was thought to be reasonable. All T1AM studies thus far have required use of pharmacological doses. Therefore we considered that choosing a physiological site of action was a priority and focused on the locus coeruleus (LC), the major noradrenergic control center in the brain. Site-directed injections of T1AM into the LC elicited a significant, dose-dependent neuronal firing rate change in a subset of adrenergic neurons with an EC50 = 2.7 μM, a dose well within the physiological range. Further evidence for its physiological actions came from autoradiographic images obtained following intravenous carrier-free 125I-labeled T1AM injection. These showed that the amine bound with high affinity to the LC and to other selected brain nuclei, each of which is both an LC target and a known T3 binding site. This new evidence points to a physiological role for T1AM as an endogenous adrenergic-blocking neuromodulator in the central noradrenergic system.

Research Highlights

► 3-Monoiodothyronamine (T1AM) is the first known metabolite of the thyroid hormone reverse triiodothyronine: ► Activates the locus coeruleus in physiological concentrations. ► Acts in vivo as a beta adrenergic blocker. ► Has a chemical structure and in vivo actions that point to a role in the noradrenergic nervous system. ► May activate cAMP.

Introduction

The actions of thyroid hormones are generally attributed to their role in gene expression (Lazar, 2003). However, a genomic mechanism has failed to account for the widely recognized effects of these hormones on the activity of the adrenergic nervous system (Silva and Bianco, 2008). To address this issue, the hypothesis was advanced that, like all other aromatic amino acids, iodothyronines are converted to a family of aminergic neurotransmitters, which function through non-genomic mechanisms as adrenergic neuromodulators (Dratman, 1974).

Evidence for this proposal has come from a coordinated series of observations and experiments in vivo in both rodents and humans (see Table 1). However, despite considerable effort (Gordon et al., 1983, Gordon et al., 1986, Han et al., 1987), no endogenous amine derived from thyroid hormone had been found until monoiodothyronamine (T1AM) and thyronamine (T0AM) were discovered in the rat brain and in rat and human blood (Scanlan et al., 2004, Scanlan, 2009). Both amines have been shown to have the same effect profile but T1AM is far more potent and has therefore received the bulk of experimental attention. Both have been tentatively classified as trace amines based on their ability to bind with high affinity to the G-protein-coupled receptor: trace amine associated receptor 1 (TAAR1).

Additionally, and importantly, the adrenergic-blocking nature of T1AM/T0AM actions, and the position of the iodine substituent in T1AM and its elimination when converted by type III deiodinase to T0AM, have together led to the generally accepted conclusion that those thyronamines are derived from reverse triiodothyronine (revT3) (Piehl et al., 2008, Scanlan et al., 2004, Scanlan, 2009). Yet, there has been a major sticking point in approaching considerations of a role for T1AM: its seemingly intractable failure to act within a physiological concentration range.

The questions raised by the derivation of T1AM from revT3 have refocused attention on the metabolism and fate of thyroid hormones. Upon entering cells, T4 is promptly attacked by deiodinating enzymes yielding two main products, T3 and revT3. Controlled diversion of T4 molecules into the revT3 pathway by type III deiodinase prevents overproduction of T3 from T4 (Dratman et al., 1983, Jennings et al., 1984). Though investigated extensively, no other functions or interesting metabolites of revT3 had been identified until T1AM was discovered within the brain.

While the pathways of T4 metabolism are probably similar throughout the organism, controls for producing and retaining its metabolites in the brain are unlike those in the liver where type I deiodinase provides most of the T3 available to many tissues from the circulation (Dratman et al., 1983). In hypothyroidism (hypoT), the liver appears to react paradoxically to low T4 levels in that it decreases its fractional rate of T4 metabolism and T3 production. As a result, low T3 levels in many peripheral tissues are decreased even further by the apparently anti-homeostatic behavior of the liver (Jennings et al., 1984). However, the hepatic response may be useful for the organism as a whole because at the same time hypoT leads to a dramatic fractional increase in T4 to T3 production in brain (Dratman et al., 1983). Therefore, the less T4 that the liver metabolizes in hypoT, the more T3 (from that unmetabolized T4) will be available for the brain. At the same time, fractional revT3 levels in both liver and brain are reduced to barely perceptible levels. These responses emphasize that under conditions of reduced thyroid hormone availability, brain requirements for T3 may actually preempt those of many peripheral tissues while dispensing with the need for forming revT3 (Dratman et al., 1983, Guadano-Ferraz et al., 1999).

A different state of affairs prevails in hyperthyroidism (hyperT). In response to high T4 levels entering the brain, type III deiodinase activity and revT3 production are up-regulated (Smallridge et al., 1978). This response reflects an (unsuccessful) homeostatic effort to reduce the accumulation of already excessive levels of intracerebral T3 which might otherwise form from the high levels of T4 arriving from the cerebral circulation. It is not surprising that this type III deiodinase response is unequal to the challenge posed by a pathological overproduction of T4 and T3. However, the direction of change in the deiodinase profile in brain indicates the nature of the homeostatic responses which successfully function during day to day variations in thyroid hormone requirements and production rates.

While it is clear that rates of T3 and revT3 production from T4 direct the actions of thyroid hormones into two opposite pathways of action in the organism, the functional consequences of this arrangement are not yet fully evident. However, clinical evidence is often highly informative on this point. As seen during the early phases of cautious T4 treatment of hypothyroid subjects (whose T4 is subject to efficient conversion to T3 in the brain) activation of the adrenergic nervous system is among the known effects of even small increases in T3 availability. In these and similar situations, a responsive small up-regulation of T1AM, with its manifest adrenergic-blocking activity, would seem well-poised to act within the brain to moderate any trend toward overshoot of adrenergic arousal and activating effects. Such effects might constitute a threat to the not yet fully recovered hypothyroid patient.

In deciding to study T1AM, it seemed that the highest priority was to grapple with the issue of its pharmacological status. Since it is now generally accepted that brain metabolism and peripheral thyroid hormone metabolism differ in major ways and are often in direct opposition to one another, it was reasonable to approach studies of fundamental T1AM actions by choosing to look within the brain, where it was originally discovered. Because the pharmacological actions of T1AM are those of an adrenergic-blocking agent, it was appropriate to examine its signaling functions at sites within the adrenergic system. Noradrenergic neurons of the locus coeruleus (LC) perform a similar function in the central nervous system as they do in the peripheral sympathetic nervous system in that they are activated in response to alarming external and internal stimuli, release norepinephrine (NE) and as a consequence lead to a general increase in adrenergic tone.

To test whether LC cells would respond to physiological levels of T1AM we measured their electrophysiological responses to a range of doses injected directly into that nucleus. Further, in an effort to establish some morphological and functional correlates of brain T1AM, we obtained images of selective binding of the i.v.-injected 125I-labeled amine to the LC and other brain nuclei.

Section snippets

Electrophysiology

Forty-seven individual LC neurons were recorded from 17 halothane-anesthetized rats. Average firing frequencies were 2.0 ± 0.2 spikes/s, which is similar to those previously reported from our laboratory (Aston-Jones et al., 2001, Gompf and Aston-Jones, 2008) for the rest period (ZT 5–10). Local microinfusion of vehicle had no effect on LC firing frequency (1.9 ± 0.6 spikes/s pre-injection vs. 1.8 ± 0.5 spikes/s during vehicle, n = 7 neurons and 2 animals, p = 0.36). However, local microinfusion of 3 μM

Discussion

The investigations reported here were designed to gain some insights into the mechanisms of T1AM action in the brain, the site from which this amine was originally retrieved (Scanlan et al., 2004). The results obtained were analyzed in the context of existing but newly assembled data from the T1AM, thyroid and adrenergic nervous system literature. Together they indicate that T1AM may act physiologically in the brain as an endogenous adrenergic-blocking neuromodulator.

Experiments in rodents

Electrophysiology

Adult male Sprague-Dawley rats (250 g, Harlan, Indianapolis, IN) were kept on a 12 h LD cycle (lights on at 0800) for at least 1 week after arriving in the lab before experiments, and were given food and water ad libitum. Before electrophysiological recordings, animals were anesthetized with halothane in air via spontaneous respiration as described previously (Jodo and Aston-Jones, 1997, Shiekhattar and Aston-Jones, 1992). Animals were intubated with a tracheal cannula, continuously anesthetized

Acknowledgments

This work was sponsored by NIH grants MH12654 (H.S.G.), NS057400 (J.H.G.), DA017289 (G.A.-J.), and NS024698 (G.A.-J.).

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