A. J. Prange

EFFECTS OF THYROTROPIN-RELEASING HORMONE IN DEPRESSION☆

Abstract Ten euthyroid women with unipolar depression were treated with a single injection of thyrotropin-releasing hormone (T.R.H.) and a single injection of saline in a double-blind, crossover comparison. T.R.H. caused a prompt, brief improvement in depression without causing significant side-effects Most patients showed a reduced thyrotropin (T.S.H.) response to T.R.H. injection, though none had abnormal thyroid function tests or clinical findings suggesting pituitary or thyroid disease.

Enhancement of ethanol-induced sedation and hypothermia by centrally administered neurotensin, β-endorphin and bombesin

Abstract Intracisternal administration of three endogenous neuropeptides (neurotensin, β-endorphin, or bombesin) potentiated the duration of sedation induced by a fixed dose of ethanol (5.2 g/kg) in mice. The minimally effective dose of each peptide that enhanced ethanol-induced sedation was: neurotensin, 0.18 nmoles; β-endorphin, 1.79 nmoles; and bombesin, 0.06 nmoles. The enhancement of ethanol-induced sedation was correlated with the potentiation of ethanol-induced hypothermia for all three peptides. None of the neuropeptides studied significantly altered blood or brain ethanol concentrations, suggesting that the observed effects were not due to differences in ethanol metabolism.

Modification of pentobarbital-induced sedation by natural and synthetic peptides

Abstract The effect of intraperitoneal (i.p.) and intracisternal (i.e.) injection of various endogenous peptides and related analogues on the sedation induced by a fixed intraperitoneal dose of sodium pentobarbital in mice was examined. Several peptides were found to antagonize the effects of pentobarbital while one (neurotensin) markedly potentiated them. Certain peptides were active only after intracisternal injection, while others were effective by either route of administration. However, peptides active after intraperitoneal administration were always active after intracisternal administration. Thyrotropin-releasing hormone was the most effective antagonist and was active by both routes. Neurotensin was the most potent potentiator but was active only after central administration. Although few general structural requirements for the analeptic activity of peptides are discernable, it appears that such activity is mediated by the central nervous system.

Interaction between thyrotropinreleasing hormone and the mesolimbic dopamine system

The involvement of the mesolimbic dopamine (DA) system in the excitatory behavioral effects of thyrotropin-releasing hormone (TRH) has been a controversial topic. In this study TRH was injected into the nucleus accumbens, lateral ventricles or ventral tegmental area and changes in spontaneous motor activity and metabolism of DA in the nucleus accumbens and striatum measured. Injection of TRH into all three areas of the brain produced an increase in photocell counts of locomotor activity and, in the nucleus accumbens, a significant decrease in photocell counts of rearing was measured. Injection of TRH into the nucleus accumbens caused a marked increase in metabolism of DA in both the nucleus accumbens and striatum. A smaller increase in metabolism of DA was also observed after injection of TRH into the lateral ventricles, but no significant change was found after intra-ventral tegmental administration of TRH. These data indicate that while TRH probably acts in the nucleus accumbens to enhance the metabolism of DA, and presumably release of DA, the excitatory behavioral effect of TRH is only partially mediated by this dopaminergic mechanism.

The TRH test in normal subjects: methodological considerations

Changes in serum TSH, PRL, GH, T3, T4 and FT4-Index after injection of TRH (500 micrograms i.v.) were measured in 13 normal women and 12 normal men. In both sexes, TSH and PRL concentrations rose significantly over baseline after TRH injection (p less than 0.01). The PRL response, but not the TSH response, was significantly lower in men than in women. Although most TSH and PRL peaks occurred about 30 min after TRH injection, a delayed PRL peak was seen in four men. Thyroid hormones also rose significantly after TRH, with T3 peaking earlier (60 min) than T4 and FT4-Index (greater than or equal to 180 min). The TSH area under the curve correlated well with the TSH peak value (p less than 0.001), with the TSH value at 30 min (p less than 0.001), with the delta max TSH (p less than 0.001), and with the delta TSH measured at 30 min (delta 30 TSH) (p less than 0.001). The PRL area under the curve correlated well with the PRL peak value (p less than 0.005) and with delta max PRL (p less than 0.05) in both sexes, but the PRL value at 30 min was significantly correlated with the area under the curve only in women (p less than 0.005). These data indicate that in both sexes a baseline sample and a 30-min sample provide an excellent index of the entire TSH secretory response to TRH; the PRL response to TRH is clearly related to sex; and the 30-min value of PRL in women, but not in men, is an adequate measure of the PRL secretory response to TRH.

NEUROTENSIN-NEUROLEPTIC SIMILARITIES: AN EXAMPLE OF PEPTIDE-CATECHOLAMINE INTERACTIONS

ABSTRACT The interactions of centrally administered neurotensin (NT), an endogenous tridecapeptide, with dopamine (DA) mediated systems have been investigated. NT produces hypothermia, potentiates barbiturate anesthesia and antagonizes behaviors elicited by amphetamine. Its resemblance to neuroleptics in these tests is striking.

Chapter 4. Peptides in the Central Nervous System: Focus on Thyrotropin Releasing Hormone and Neurotensin

Publisher Summary This chapter discusses the extensive data generated by study on the various peptides discovered. It discusses the findings in animals and on pharmaco-behavioral effects at the expense of peripheral and endocrine effects. A consideration of the actions and interactions of thyrotropin-releasing hormone (TRH) and neurotensin (NT) is done to provide with a beginning sense of an aspect of current central nervous sytem (CNS) peptide research. In peptides, various hypothalamic hypophysiotropic hormones, anterior pituitary peptides, posterior pituitary peptides, and other neuropeptides, their origin, composition, and actions have been discussed in the chapter. On TRH, their isolation, localization, synthesis, receptor binding, and central nervous system effects are mentioned in the chapter. Similarly the NT isolation, localization, interactions with barbiturates and ethanol, effects on thermoregulation, interactions with dopaminergic drugs, and antinociceptive effects are delved upon. The chapter describes that after they had demonstrated the analeptic properties of TRH, they examined a series of substances for activity in the pentobarbital-sedated mouse. Several substances, like TRH, shortened barbiturate-induced sleep but only one reliably extended it-NT. Dualism of central action between TRH and NT has been extended to a variety of parameters and this dualism, along with the quality of effects exerted by the two peptides, allows the broad hypothesis that TRH subserves the ergotropic functions of the organism, NT its trophotropic functions. The view is that dualism between the central effects of TRH and NT, whatever its best interpretation is, appears unusual among peptides. At present, NT must be regarded as unique among peptides in its ability to both stimulate and inhibit the activity of a neurochemical pathway, the mesolimbic dopamine system.

HORMONES IN THE TREATMENT OF NERVOUS AND MENTAL DISEASE: PRESENT STATUS AND DEVELOPMENT

Abstract Advances in basic neuroendocrinology have led to renewed interest in the role of hormones in mental and neurological disorders. One aspect of this trend has been the use of hormones as therapeutic agents. Traditionally hormones of target gland origin have been used for this purpose; more recently attention has turned to secretions of the pituitary gland and the hypothalamus. In neurology certain hormones have earned a place as therapeutic agents chiefly for their antiinflammatory and immunosuppressive properties. In psychiatry the use of hormones is more controversial. While thyroid hormones have been shown to potentiate the actions of tricyclic antidepressants in a reliable fashion, no hormone, used by itself, has yet been shown to be competitive with standard treatments. Nevertheless, a variety of hormones exert psychological effects and the description of these effects may contribute to understanding of fundamental brain processes.