On the role of the central noradrenergic and dopaminergic systems in the regulation of TSH secretion in the rat.

Systemic administration of drugs affecting central noradrenergic and dopaminergic systems was used to evaluate their role in the regulation of TSH secretion in the rat. Alpha-methyl-p-tyrosine (alpha-MT) caused a depletion of brain norepinephrine and dopamine and a gradual decrease of serum TSH levels. Specific inhibitors of dopamine-beta-hydroxylase, diethyldithiocarbamate (DDC) and FLA 63, depleted central norepinephrine only and led to a simultaneous striking decrease of serum TSH. Blockade of alpha adrenergic receptors with phenoxybenzamine, but not with phentolamine, also depressed serum TSH. Blockade of beta receptors with propranolol had no effect. In contrast, the centrally and peripherally acting alpha receptor agonist, clonidine, increased serum TSH, whereas the peripherally acting methoxamine caused a decrease, probably due to non specific stress effect. A dose-related rapid inhibition of TSH secretion was observed following stimulation of dopamine receptors with apomorphine. Injection of L-Dopa had a similar effect. Blockade of the dopamine receptors with pimozide did not alter serum TSH, while blockade with spiroperidol led to a slight increase. The cold-induced surgeof TSH was abolished by pretreatment with DDC or phenoxybenzamine, reduced by apomorphine, but unaffected by pimozide or propranolol. The pituitary responsiveness to exogenous TRH was unaffected by administration of DDC or apomorphine. On the basis of these results, it is assumed that the central noradrenergic system has a stimulatory effect on the release of TRH from the hypothalamus, reflected in our experiments by the changes of serum TSH levels. It probably provides the drive for the tonic release of TRH in resting conditions and stimuli for the enhanced secretion during cold exposure. The effect is probably mediated by a central alpha-adrenergic mechanism. Activation of the dopaminergic system is inhibitory, but the physiological role of this effect remains to be established.

A renin-like activity in the human hypophysis.

A renin-like enzyme was determined in the acetone-dried tissue of human pituitaries, in both the anterior and posterior pituitaries using Boucher micromethod. The mean pituitary concentration of the renin-like activity (RA) was equivalent to 60.4+/-7.1 (SEM) ng angiotensin II/g tissue protein/h. The possible functional relationship between the hypophyseal and the brain renin-like enzyme is discussed.

Effect of acute exposure to cold on the activity of the hypothalamic-pituitary-thyroid system.

The effects of a sudden but sustained exposure to cold (1 to 6C) on serum TSH, thyroxine (T4) and triiodothyronine (T3) (all measured by radioimmunoassay), pituitary TSH concentration, pituitary TSH secretory responsiveness to hypothalamic extract or synthetic thyrotropin-releasing hormone (TRH) in vitro as well as in vivo, and the changes of the thyrotropin-releasing activity in three TRF-rich hypothalamic areas were determined. In normal animals, serum TSH underwent a series of oscillations, first rising then returning to the basal levels, then rising again, whereas serum T4 and T3 increased within 2 h of cold exposure and remained elevated. Pituitary TSH concentration and the in vitro pituitary responsiveness declined after an initial elevation, whereas the in vivo responsiveness to TRH was diminished throughout the whole exposure to cold. Thyroid-blocked animals with steady, low levels of serum T4 and T3 showed a step by step increase of serum TSH levels and no changes in the other parameters. It is therefore assumed that the decrease of TSH secretion following the initial rise is due to a feedback inhibition by the increased levels of thyroid hormones as is the decreased pituitary responsiveness of TRH in vivo. The pituitary responsiveness in vitro seems to be determined by TSH pituitary concentrations, the changes of which are probably also secondary to the changes of the thyroid hormone levels. The mechanism of the second rise of serum TSH levels is not clear. Thyrotropin-releasing factor (TRF) activity was higher after 2 and 24 h of cold exposure in the median eminence and after 8 h in the anterior hypothalamus-preoptic area, but lower after 8 and 24 h in the dorsomedial hypothalamus. Since the changes of TRF activity in the median eminence coincided with the elevated serum TSH, they are assumed to reflect increased TRF production and secretion. The significance of the TRF changes in the other two areas is not clear.

Effect of hypothalamic deafferentation on the secretion of thyrotropin during thyroid blockade and exposure to cold in the rat.

Complete hypothalamic deafferentation, either limited to the median eminence, arcuate nucleus, and basal parts of ventromedial nuclei, or comprising ventromedial nuclei and dorsomedial hypothalamus as well reduced considerably the rise of immunoassayable serum TSH in adult male rats rendered hypothyroid by administration of methimazole. Complete hypothalamic deafferentation extended rostrally to include also the caudal half of the anterior hypothalamus did not affect the TSH response to thyroid blockade. Administration of triiodothyronine (T3) to the goitrogen-treated rats reduced serum TSH rapidly and with equal speed in controls and in deafferented animals, which indicates a direct effect of T3 on the pituitary. Animals which, in addition to the hypothalamic deafferentation, had electrolytic lesions in the median eminence, responded both to thyroid blockade and to T3, but the responses were greatly reduced. The cold-stimulated increase of serum TSH was reduced, but not abolished, in animals deafferented several weeks beforehand, but it was absent in rats deafferented 4 days prior to cold exposure. These results suggest that most, if not all of the thyrotropin-releasing factor (TRF) necessary for normal TSH secretion in resting conditions or during the hypothyroid state, is produced and released in the median eminence-arcuate nucleus area, the adequate activity of which, in turn, depends on intact connections with the anterior hypothalamus. Other hypothalamic and extra-hypothalamic areas containing large amounts of TRF do not seem to be required under these conditions.

Effect of hypothalamic deafferentation on the secretion of thyrotropin in resting conditions in the rat.

Complete hypothalamic deafferentation in normal male rats, either limited to the median eminence, arcuate nucleus, and basal parts of ventromedial nuclei, or including, in addition, the ventromedial nuclei, dorsomedial hypothalamus, and a large part of the posterior hypothalamus, caused a decrease of resting serum TSH levels and a marked lowering of the pituitary TSH concentration. Partial frontal anterior cuts caused similar changes, whereas partial posterolateral cuts, or a complete deafferentation extended rostrally to include suprachiasmatic nuclei and caudal parts of the anterior hypothalamus, were without effect. Serum thyroxine (T4) and triiodothyronine levels in animals with the effective types of deafferentations were, after an initial short-lived decrease, within normal range despite persistent low TSH levels. Destruction of the median eminence-arcuate nucleus by electrolytic lesions in either normal or deafferented animals lowered serum TSH more than deafferentations alone, and caused a lasting decrease of serum T4 levels. We have concluded that the low serum TSH levels of the deafferented animals are caused by a partial impairment of TRF release from the median eminence-arcuate nucleus complex. This impairment seems, in turn, to be caused by the severance of the connection of the basal mid-hypothalamic structures with the more rostal parts of the hypothalamus. Our results also indicate that normal circulating levels of thyroid hormones can be maintained even at reduced serum TSH levels.

Mechanism of the effects of hypothalamic deafferentation on prolactin secretion in the rat.

Male rats with complete hypothalamic deafferentation had consistently lower serums prolactin concentrations than controls when the blood samples were obtained under other anesthesia. However, when rats were decapitated, both groups had similar low prolactin levels. Posterolateral deafferentation was as effective as complete deafferentation in preventing the stress-induced prolactin release, whereas anterior frontal deafferentation had only a small effect, L-Dopa (100 mg/kg body wt, ip) decreased prolactin titers in both control and deafferented animals, whereas reserpine (1 mg/kg body wt, ip) had the opposite effect. Since both drugs inhibited prolactin release from pituitaries in vitro, the decrease of prolactin levels following L-dopa in vivo might have been caused not only by stimulation of PIF release but also at least partly by the direct effect of the drug on the pituitary. However, the increase of serum prolactin following reserpine was in all probability caused by inhibition of PIF secretion. Electrolytic lesions in the median eminence of deafferented rats caused an elevation of serum prolactin which was more marked in female than in male rats. On the contrary, deafferentation in the females affected prolactin levels less than in males. It is concluded that hypothalamic deafferentation prevents ether-induced release of prolactin and that the "low" levels of the deafferented animals are probably due to a tonic release of prolactin-inhibiting factor (PIF) from the isolated island. It is though that this continuous release of PIF might be maintained by persisting autonomous activity of the adrenergic, presumably dopaminergic, neurons contained in the isolated island.