I Introduction UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12) Since the mid 1960s, research on t

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*

The neurobiological consequences of early stress and childhood maltreatment

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions

Maturation of the adrenocortical stress response: Neuroendocrine control mechanisms and the stress hyporesponsive period

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid C-terminally alpha-amidated peptide that was first isolated 20 years ago from an ovine hypothalamic extract on the basis of its ability to stimulate cAMP formation in anterior pituitary cells (Miyata et al., 1989. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-secretin-growth hormone-releasing hormone-glucagon superfamily. The sequence of PACAP has been remarkably well conserved during evolution from protochordates to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide, the activity of which remains unknown. Two types of PACAP binding sites have been characterized: type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP, whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes: the PACAP-specific PAC1-R, which is coupled to several transduction systems, and the PACAP/VIP-indifferent VPAC1-R and VPAC2-R, which are primarily coupled to adenylyl cyclase. PAC1-Rs are particularly abundant in the brain, the pituitary and the adrenal gland, whereas VPAC receptors are expressed mainly in lung, liver, and testis. The development of transgenic animal models and specific PACAP receptor ligands has strongly contributed to deciphering the various actions of PACAP. Consistent with the wide distribution of PACAP and its receptors, the peptide has now been shown to exert a large array of pharmacological effects and biological functions. The present report reviews the current knowledge concerning the pleiotropic actions of PACAP and discusses its possible use for future therapeutic applications.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

Hypothalamic melatonin receptor sites revealed by autoradiography

The neonatal cerebellum: the highest level of glucocorticoid receptors in the brain.

Effect of ACTH on the synthesis of rapidly labelled RNA in the nervous system of mice

The susceptibility of chick embryos to the teratogenic action of intraamniotically injected hydrocortisone increases by several orders during the first four days of incubation. An attempt was made to correlate this phenomenon with the appearance of specific intracellular binding proteins for glucocorticoids. The binding of [3H] corticosterone to the soluble cytoplasmic proteins of the chick embryo was investigated on days 1.5, 2, 3, and 4 of incubation using a gel filtration method. No evidence of high affinity binding was found in embryos on day 1.5. High affinity binding of [3H] corticosterone to the cytosol proteins was first observed in embryos on day 2, but the binding capacity was four times lower than that found in embryos on days 3 and 4. A correlation was obtained between the increasing sensitivity of the chick embryo to hydrocortisone and the appearance of the intracellular binding protein for glucocorticoids. The causal relationship between these two phenomena is further supported by the finding that administration of a nonteratogenic dose of cortexolone completely prevents the teratogenic "cleft beak" action of hydrocortisone, presumably on the basis of competition for binding sites to the glucocorticoid receptor. These findings are consistent with the hypothesis that the teratogenic action of glucocorticoids is mediated by specific cytoplasmic receptors in the chick embryo.

Alfred Pavlík

Papers

Hypothalamic melatonin receptor sites revealed by autoradiography

The neonatal cerebellum: the highest level of glucocorticoid receptors in the brain.

Effect of ACTH on the synthesis of rapidly labelled RNA in the nervous system of mice

Glucocorticoid receptor-mediated teratogenesis in the chick embryo.

Embryotoxicity of 25 psychotropic drugs: a study using CHEST.