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Section on Neural Gene Expression (SNGE) Section on Neural Gene Expression (SNGE)

Some Selected History of Oxytocin and Vasopressin

Over a century ago, Oliver and Schafer (1895) demonstrated that a component of the pituitary gland would elevate blood pressure. A decade later, Sir Henry Dale (1906) demonstrated that a component of the pituitary causes contractions of the mammalian uterus, adding to the list of oxytocics (a term, derived from the Greek (ωκνξ, τoκoxξ) for "quick birth" for its activity, in common use in the 1800s (e.g., Velpeau, 1829; Cory, 1840) and likely much earlier). The discovery that a component of the pituitary causes milk secretion followed within a few years (Ott, Scott, 1910; Schafer, Mackenzie, 1911). The antidiuretic property of pituitary extract was discovered in 1913 (Farini, 1913; Vongraven, 1913). By 1927, oxytocin (Oxt) was separately purified from vasopressin (Avp) into pitocin and pitressin, respectively, by Kamm and colleagues at Parke, Davis and Company (they also coined the terms oxytocin and vasopressin) and made available for research (JAMA, 1928). The nine amino acid sequences and structures of Avp (Turner et al., 1951; Acher, Chauvet, 1953; du Vigneaud et al., 1953a) and the related Oxt (Tuppy, 1953; du Vigneaud et al., 1953b) were elucidated, followed shortly by their synthesis (du Vigneaud et al., 1954a,b). In 1955, du Vigneaud won the Nobel Prize in chemistry due, in part, to his early descriptions and syntheses of Avp and Oxt.

Once the sequences were known, efforts were made to determine where and how Oxt and Avp were synthesized. Studies by Howard Sachs and his colleagues demonstrated that Avp initially appeared in the hypothalamus and was then transported to the posterior pituitary. Because the synthesis was inhibited by protein synthesis inhibitors, they proposed that Oxt and Avp were intially incorporated into protein precursors that would be cleaved into the bioactive components (Sachs and Takabatake, 1964; Takabatake and Sachs, 1964; Sachs et al., 1969). This hypothesis was confirmed by Gainer, Brownstein and colleagues. They identified a putative precursor protein in the hypothalamus that was subsequently processed to the peptides and neurophysins in the secretory vesicles as they traveled within axons from the supraoptic nuclei to the posterior pituitary (Gainer et al., 1977a,b; Brownstein et al., 1980). The definitive structures of the precursors were determined by Schutz, Richter and their colleagues (Land et al., 1982; 1983) using recombinant DNA techniques.

The Avp and Oxt genes were cloned and sequenced shortly thereafter (Ivell, Richter, 1984). Subsequently, three Avp receptors were cloned that accounted for Avp's pressor (Avpr1a; Morel et al, 1992), antidiuretic (Avpr2; Birnbaumer et al., 1992; Lolait et al.,1992) and adrenocorticotropin-releasing (Avpr1b; Antoni, 1984; Sugimoto et al., 1994; Lolait et al., 1995) effects. Numerous studies followed exploring the regulation of these genes' expression. Knockout mice were created for the Avpr1a (Hu et al. 2003), Avpr1b (Wersinger et al., 2002), and Avpr2 (Yun et al., 2000) genes, all at the National Institutes of Health (USA).

The identification of the rat Oxt gene (Ivell, Richter, 1984) was followed by cloning of the single Oxt receptor (Oxtr) (Kimura et al., 1992). These results enabled the subsequent studies on the regulation of the genes' expression and the creation of Oxt (Young et al., 1996; Nishimori et al., 1996) and total (Takayanagi et al., 2005) and conditional (Lee et al., 2008) Oxtr gene knockouts.

Recent reviews of behavioral aspects of Oxt and AVP are available.

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Corrections or additions to this brief history for consideration are welcome!