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The present study in mice demonstrated that TRH when administered over 5 days remained active in the Everett Dopamine Potentiation Test. No evidence of tolerance was observed. In fact, an accumulative effect of TRH appeared to take place. Ablation of the adrenals, ovaries, testes, pineal, spleen, parathyroid, one kidney, or thymus did not disrupt this behavioral potentiation of dopamine by TRH. TRH was found to potentiate the effects of imipramine. T3, T4, and TSH were found to be active in the DOPA potentiation test. No overt toxicity was observed between TRH and pargyline or between TRH and DOPA. Toxicity was seen only when all three agents were used together. TRH was found active in young and old mice. TRH was also found active in potentiating the central effects of serotonin. Biogenic amine brain levels in mice were not altered by TRH when administered for five days. Alpha-methyl-p-tyrosine reduced the activity of TRH in the dopamine potentiation test, suggesting dopaminergic mechanisms are involved by a direct receptor interaction.

This study demonstrates that TRH potentiated the behavioral effects of DOPA-pargyline in thyroidectomized rats as well as in normal rats. This behavioral effect of TRH therefore can be considered to be independent of the thyroid gland in the DOPA potentiation test. Possible mechanisms and clinical implications are discussed.

A pentapeptide, methionine-enkephalin, which interacts with opiate receptors in the brain, was found to markedly potentiate the behavioral effects of DOPA when administered intraperitoneally into mice. These effects, which were even more striking with D-alanine-2-methionine-5-enkephalin but less with morphine, persisted at least two hours after systemic injection of the peptide. Only a weak effect of enkephalin was seen in a serotonin potentiation test. Systemic injections of enkephalin resulted in a significant reduction of footshock-induced fighting and slight reduction in audiogenic seizures in mice. The results suggest that the CNS effects observed after systemic administration of enkephalin may involve the dopaminergic receptor mechanism.

Publisher Summary This chapter reviews the hypothalamic releasing hormones and catecholamines. Ten women, ages 25-45, with primary, unipolar depression but in good physical health were treated in a double-blind, placebo-controlled, crossover design. Thyrotropin releasing hormone (TRH) acted alone rather than in combination with Imipramine, and that a single injection acted very rapidly though transiently. In this experiment as well as in the experiments with normal and schizophrenic women, psychological and behavioral changes were demonstrated in an environment characterized by pleasant stability and the absence of environmental noise such as may be introduced by intensive psychotherapeutic intervention. That behavioral effects occur in humans, at least with TRH seems certain. The effects have been shown to occur in normal and depressed women and are suggested by a single-blind study of schizophrenic women. The effects of a single injection are rapid, occurring within a few hours, and lasting not more than a few days. They are best demonstrated in a pleasant, stable, and relatively noise free environment. The effects are subtle, and it seems likely that intrinsic hormonal effects may be amplified or dampened by the environment.

Thyrotropin releasing hormone (TRH) antagonizes the behavioral and temperature reducing effects of pentobarbital in rodents. The hormone is effective whether given before or after the barbiturate. This antagonism by TRH of the effects of pentobarbital probably does not depend upon thyroid hormone release as L-triiodothyronine administration is ineffective.

The pituitary peptide hormone α-MSH was found to potentiate the behavioral effects of DOPA but not serotonin. It slightly reduced footshock-induced fighting and decreased audiogenic seizures in susceptible mice, but was inactive in reducing the tremors induced by oxotremorine. The pattern of activity of α-MSH in these neuropharmacological tests differed from that of several other peptides. The results support our concept that naturally occuring peptides exert direct actions on the central nervous system independent of endocrine effects.

Both thyrotropin-releasing hormone (TRH) and amphetamine antagonize pentobarbital. They are more effective in the day than at night. This is true for TRH even when the dose of pentobarbital is increased at night to prolong sedation. Under this condition the day-night difference is lost for amphetamine. Both substances are more effective in cold ambient temperatures (18 degrees C) and less effective in warm temperatures, but their activity at warmer temperatures (37 degrees C) is still substantial. In contrast, somatotropin release-inhibiting factor (SRIF) augments the effects of pentobarbital at room temperature. This action is unaffected by time of day. However, the increase in sleeping time is lost in both a warm environment and in a cold environment.

The hypothalamic hormone GnRH was found to potentiate behavioral effects of DOPA and serotonin. In addition, GnRH was observed to reduce slightly audiogenic seizures as well as spontaneous motor activity. No significant effects were observed against footshock induced fighting or oxotremorine effects. These studies support our concept of the actions of hypothalamic peptides on the central nervous system.

The present study in mice has demonstrated that MIF greatly potentiates the behavioral effects of DOPA. The potentiation by MIF was found to be independent of MSH since MIF was found to potentiate DOPA effects in hypophysectomized mice.

Synthetic thyrotropin releasing hormone (TBH) was administered to albino rats in order to determine the effects of this drug on norepinephrine-H3 metabolism in the brain. With the possible exception of a slight enhancement of release, acute or chronic administration of TRH had little effect on the disposition and metabolism of norepinephrine-H3 in rat brain. In addition, no significant changes were found in brain levels of endogenous norepinephrine, serotonin or dopamine following the injection of TRH. Thus, little evidence was found to support a possible relationship between the reported clinical antidepressant activity of TRH and its effects on norepinephrine metabolism in brain.

Early studies suggested that peptides from the pituitary gland might have affects on the central nervous system (CBS). Murphy and Milicr [I] and Miller and Ogawa [r’] showed that administration of corticotropin (ACTH) resulted in resistance to extinction of a conditioned avoidance response. Dc Wied [3] used this test involving electrical shock to demonstrate that mel~~nocyte-stimulating hormone (MSH) can have the same effuct as AC‘TH and that the active sequence is ACTH/MSH -l II) [AJ. Approaching the problem for the first time from a direct interest in MSH, several different behavioral tests in the rat and man as well as studies of electrical activity (EEG) in the brain of these species were initiated in I966 by Kastin and colleagues. The results from these investigations arc consistent with the hyp~~thesis that MSH results in improved visual memory and sustained levels of attention [S. h]. Thcsc studlcs differed in approach from the previous ones of Krivoy 01 al. [7,8]. who examined the spinal cord and electrical discharge. and from those of Fcrrari OT rri. 19. 10]. who tested stretching activity and yawning. In an unrelated series of iilvestig~~tiol~s, Wilson rt trl. [ 1 I] were investigating the interactions of tricyclic antidepressants and thyroid hormones. Their early findings suggested that the time of onset of antidepressant activity was shortened by the use of thyroid hormone [I 11 (T,, tri-iodothyronine) as well as thyrotropin (TSH) [I?]. a pitlti~lry hormone whose release is stimulated by TRH (thyrotropin-rel~sing hormone). Thus, the stage was sot for the next logical series of studies to dctcrmine whether the relatively newly identified and isolated hypothalamic releasing factors [ l3]. MIF--1 (melanocyte-stimulating hormone release i?lhibiting factor. Pro-L~Ll-Gly-~H~) and TRH. had direct effects in the central nervous system. Later. other hypothalamic hormones like growth hormone release inhibiting hormone (GH-RIH) and gonadotropin-releasing hormone (GnRH) were also tested.

Publisher Summary This chapter examines the effects of prolyl-leucyl-glycine amide (PLG) on 3, 4-dihydroxy-phenylalanine (DOPA) potentiation and brain biogenic amine levels in rats and mice following acute and repeated doses. The central nervous system activity of TRH (thyrotropin-releasing hormone) and MIF (melanocyte-stimulating hormone-release inhibiting factor, PLG was discovered by means of the Everett brain dopamine potentiation test for antidepressant activity and the Everett oxotremorine antagonism test for antiparkinson activity. The finding that thyrotropin-releasing hormone (TRH) is active in the pargyline-DOPA mouse activation test formed in part the motive for trials of the hormone as a remedy for depression. When either TRH or MIF was administered over 5 days the original level of activity was maintained in the dopamine potentiation test. The central effects of TRH or MSH release from the pituitary. Furthermore, ablation of the adrenals, ovaries, testes, pineal, spleen, parathyroid, one kidney, or thymus, did not disrupt the behavioral potentiation of dopamine by TRH or MIF. Biogenic amine brain levels in mice and rats were not altered by TRH or MIF.

Significant potentiation of the behavioral effects of DOPA were observed in mice pretreated with GH-RIH. In addition, a slight reduction of oxotremorine induced symptoms was seen. No significant effects of GH-RIH were observed in several other tests involving the central nervous system (CNS). The results support our concept of the CNS actions of peptides.

SummaryMIF was demonstrated to antagonize the central and peripheral effects of oxotremorine in normal as well as in hypophysectomized mice. Its effectiveness in hypophysectomized mice confirms our earlier report that MIF exerts actions upon the CNS which are independent of its MSH release-inhibiting activity.The authors thank Dr. E. Kimura and Mr. P. Young for the anticholinergic studies in the isolated guinea pig ileum.