2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Hyperthyroidism

1. In this study, the authors examined the effects of chronic (14 days) changes in thyroid function on a major neuromodulatory receptor system in the brain- the adenosinergic system. While previous investigators have examined the effects of alteration in thyroid function on adenosine receptors in peripheral tissues (adipocytes), this is the first study to examine such effects in brain. 2. Three groups of male Sprague-Dawley rats were treated for 14 days with either a) oral PTU (0.00625%), iodine-free diet, and i.p. saline injections, b) i.p. saline injections, or c) i.p. triiodothyronine (25 micrograms/100 g) injections. 3. These manipulations reliably resulted in the production of hypothyroidism (TSH 30.2 +/- 8.6 ng/ml), euthyroidism (TSH 2.1 +/- 0.9), and hyperthyroidism (TSH < 0.4). 4. Treatment had no significant effect on the Bmax or Kd of [3H]DPCPX (A1-antagonist) binding to homogenates from cerebral cortex, cerebellum or hippocampus; similarly, no effect on [3H]CGS-21680 (A2-agonist) binding to striatal homogenates was noted. 5. Similarly, quantitative autoradiographic studies failed to reveal consistent regional alterations unique to either hypo- or hyperthyroidism. 6. Incubation of sections with GppNHp resulted in the expected reduction (approximately 40%) in agonist binding, but there was no differential effect seen for either the hypo- or hyperthyroid tissues. 7. These preliminary findings suggest that alterations in brain adenosine receptors or G-protein-receptor coupling are unlikely to be requisite correlates of abnormal thyroid hormone levels.

Topics: Adenosine; Animals; Antihypertensive Agents; Autoradiography; Body Weight; Brain Chemistry; Hyperthyroidism; Hypothyroidism; Iodine; Male; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Thyroid Hormones; Xanthines

Cyclic AMP (cAMP) is the major intracellular second messenger of thyrotropin (TSH) action on thyroid cells. It stimulates growth as well as the function and differentiation of cultured thyrocytes. The adenosine A2 receptor, which activates adenylyl cyclase via coupling to the stimulating G protein (Gs), has been shown to promote constitutive activation of the cAMP cascade when transfected into various cell types. In order to test whether the A2 receptor was able to function similarly in vivo and to investigate the possible consequences of permanent adenylyl cyclase activation in thyroid cells, lines of transgenic mice were generated expressing the canine A2 adenosine receptor under control of the bovine thyroglobulin gene promoter. Thyroid-specific expression of the A2 adenosine receptor transgene promoted gland hyperplasia and severe hyperthyroidism causing premature death of the animals. The resulting goitre represents a model of hyperfunctioning adenomas: it demonstrates that constitutive activation of the cAMP cascade in such differentiated epithelial cells is sufficient to stimulate autonomous and uncontrolled function and growth.

Topics: Adenosine; Animals; Blotting, Northern; Brain; Cattle; Cell Membrane; Cyclic AMP; Dogs; Hyperplasia; Hyperthyroidism; Kinetics; Methimazole; Mice; Mice, Transgenic; Phenethylamines; Poly A; Promoter Regions, Genetic; Receptors, Purinergic; Receptors, Thyrotropin; Reference Values; RNA; RNA, Messenger; Thyroglobulin; Thyroid Gland; Thyroxine; Triiodothyronine