3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator

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 EC(50)=2.7 microM, a dose well within the physiological range. Further evidence for its physiological actions came from autoradiographic images obtained following intravenous carrier-free (125)I-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.

Figure 1

LC neurons are activated by local microinfusion of T1AM in the anesthetized rat. Raw traces of activity in an LC neuron before (A) and during (B) microinfusion of 3 μM T1AM from a micropipette adjacent to the recording pipette. C: Composite firing frequencies of LC neural responses to local microinfusion of 3 μM T1AM. Most of the neurons exhibited increased firing frequencies during T1AM microinfusion, though two neurons did not.

Figure 2

Dose-response curve of the magnitude of change in firing frequency during T1AM microinfusion expressed as the average percentage change in impulse activity (± standard error). Increasing doses strongly increased impulse activity in a majority of LC neurons tested (0.1 μM, n = 7; 1 μM, n = 4; 10 μM, n = 3; 100 μM, n = 4). The dose-response relationship suggests T1AM is a high-affinity excitatory agonist of LC neurons.

Figure 3

Autoradiographic and histological images from an animal administered [¹²⁵I]-T1AM three hours prior to decapitation. The autoradiographic image (a) was lined up with the hemotoxylin-eosin stained section (b) for structure identification, such that the yellow arrows in (a) and (b) point to the same brain region. Enlargement of the region outlined by the black box on the left of panel (b) is shown in panel (c), and enlargement of the right hand box is shown in panel (d). The yellow arrows in panels (a) and (b) point to the locus coeruleus. The scale bar in (a) is 1.0 mm and applies to (a) and (b), and the scale bar in (c) is 0.1 mm and applies to (c) and (d).

Figure 4

Autoradiographic images from an animal administered [^125I]-T1AM three hours prior to decapitation. There is enhanced labeling in the cingulate cortex and motor cortex (a) as well as in the retrosplenial cortex, paraventricular nucleus of the hypothalamus (PVH), and the supraoptic nucleus (SON), seen in (b). Both the medial (c) and lateral (d) mamillary nuclei show strong labeling, whereas that in the substantia nigra compacta is less pronounced (arrowhead, d); the cerebellar granule cell layer is more intensely labeled than the molecular layer e) and the pontine nuclei are prominent (f). Note that the most intense labeling is found throughout the ventricular system, as is always the case in animals receiving [¹²⁵I]-labeled compounds.