Peptides in the brain: the new endocrinology of the neuron.

A. The Existence of Brain Peptides Controlling Adenohypophvsial Functions. Isolation and Characterization of Their Primary Molecular Structures In the early 1950s based on the anatomical observations and physiological experimentation from several groups in the USA and Europe, it became abundantly clear that the endocrine secretions of the anterior lobe of the hypophysis-well known by then to control all the functions of all the target endocrine glands, (thyroid, gonads, adrenal cortex) plus the overall somatic growth of the individual-were somehow entirely regulated by some integrative mechanism located in neuronal elements of the ventral hypothalamus (review Harris, 1955). Because of the peculiar anatomy of the junctional region between ventral hypothalamus (floor of the 3rd ventricle) and the parenchymal tissue of the anterior lobe of the pituitary (Fig. 1), the mechanisms involved in this hypothalamic control of adenohypophysial functions were best explained by proposing the existence of some secretory product(s) by some (uncharacterized) neuronal elements of the ventral hypothalamus, the products of which would somehow reach the adenohypophysis by the peculiar capillary vessels observed as if to join the floor of the hypothalamus to the pituitary gland. That concept was definitely ascertained in simple experiments using combined tissue cultures of fragments of the pituitary gland and of the ventral hypothalamus (Guillemin and Rosenberg, 1955). The search for characterizing the hypothetical hypothalamic hypophysiotropic factors started then. Simple reasoning and early chemical confirmation led to the hypothesis that these unknown substances would be small peptides. After several years of pilot studies involving both biology and relatively simple chemistry in several laboratories in the USA, Europe and Japan, it became clear that characterizing these hypothalamic hypophysiotropic substances would be a challenge of (originally) unsuspected proportions. Entirely novel bioassays would have to be devised for routine testing of a large number of fractions generated by the chemical purification schemes; more sobering still was the realization in the early 1960s that enormous amounts of hypothalamic fragments (from slaughter house animals) would have to be obtained to have available a sufficient quantity of starting material to attempt a meaningful program of chemical isolation. The early pilot studies had indeed shown the hypothalamic sub-