THE ROLE OF EXCITATORY AMINO ACID NEUROTRANSMITTERS IN THE CENTRAL REGULATION OF PROLACTIN SECRETION IN NONHUMAN PRIMATES

Abstract

Prolactin (PRL) is secreted by the anterior pituitary gland from cells called mammotrophs or lactotropes. It is the most versatile and diverse of all the pituitary hormones in its physiological actions (Nicoll, 1974; De Velming, 1979; Leong et at., 1983). It serves several functions including osmoregulation, growth, development and reproduction (Nicoll, 1974; Clark and Bern, 1980; Nicoll et al., 1986). The PRL molecule is a single polypeptide containing 198 amino acid residues with a molecular weight (MW) of 22,000 (Shome and Parlow, 1977). The structure is folded to form a globular shape, and three disulphide bonds connect the folds. The hPRL gene was cloned in 1981 (Cooke et aI., 1981). The lactotrope of the adenohypophysis is the cell that synthesizes and secretes PRL. However, immunohistochemical studies indicate that some pituitary cells contain human growth hormone (hGH) as well as hwnan prolactin (hPRL), suggesting that both hormones may be produced and secreted by a single cell (Zimmerman et at. , 1974). In normal pituitaries, lactotropes constitute at least 20 % of the pituitary cell population and aggregated mainly in the posterior lateral wing of the adenohypophysis (Zimmerman et al., 1974). Of all pituitary hormones, PRL has the most diverse actions. According to Nicoll and Bem (1971) there are six distinct functional categories including control of water and electrolyte balance, regulation of growth and development, metabolic effects, control of reproductive functions, effects on integument and ectodermal structures and synergism with steroids. Nicoll in 1980 reported that within the above six categories PRL may have at least 227 different effects. For example death by inhibition of sodium loss through the gills in hypophysectomized killi fish (Fundulus heterclitus) is prevented by PRL (Pickford et aI, 1970). PRL stimulates growth of the tail and tail fin in tadpole of frog and its treatment results in a doubling of body weight and a five-fold increase in the length of larval Rana pipiens (Dent, 1975). The concept that PRL is a metabolic hormone was advanced by Riddle in 1963 . PRL has some of the effects attributed to growth hormone (GH). PRL promotes the growth of the visceral organs of birds. Production of crop milk and stimulation of 2 brooding behavior are examples of the ability of PRL to control reproductive functions in birds (Hodson, 1982). In 1980 Nicoll reported that there were 67 actions of PRL on the integument (Nicoll, 1980). Some examples are hair growth, sebaceous gland activity and mammary gland alterations in mammals, pigmentation in amphibians, cornifications ofthe reptilian skin and secretion of mucus by fish skin glands (Dent, 1975). PRL has been known as a luteotropic hormone especially in rodents. It is involved in initiating luteinization of granulosa cells, in maintaining their levels of progesterone synthesis in luteal cells and inhibiting the activity of progesterone categorizing enzyme particularly in rodents (Rothchild, 1981). PRL has been demonstrated to enhance progesterone production in cultured granulosa cells of rats (Crisp, 1977) and porcine (Veldhius and Hammond, 1980) pre-ovulatory follicles. The appearance of specific receptors in granulosa cells, late follicular development and their induction by follicle stimulating hormone (FSH) in culture indicates the likelihood that PRL may exert a physiological action on granulosa cells at the stage of terminal differentiation when they are transformed into luteal cells. PRL injections (Advis et aI., 1981) or hyperprolactinemia induced by in vivo administration of dopaminergic receptors blocker (Siegal et aI., 1976; Gay et aI., 1970) have been found to induce precocious puberty, as well as to increase ovarian responsiveness to LH in immature rats. In contrast to the stimulatory action of PRL on progesterone secretion, progesterone production by granulosa cells from small immature porcine follicle was markedly inhibited by physiological concentration of PRL (Bex and Goodman, 1975) and can be reversed by estradiol exposure (De Paolo et aI., 1979). Another inhibitory effect of PRL on estradiol secretion was repOlied for cultured rat granulosa cells obtained from follicles at both pre-antral and preovulatory stages (Fujii et al., 1983; Sauder et a!. , 1984). Decreased estradiol secretion in vitro appears to be due, at least in part, to an inhibiting action of PRL on FSH induction of aromatase activity (Welschen et aI., 1980; Chappel and Selker, 1979). PRL has been reported to suppress basal and gonadotropin-stimulated estradiol secretion by human ovaries perfuse in vitro (Lee, 1983). The ability ofPRL to affect the spermatogenesis and growth of male accessory reproductive glands (Bartke, 1976) was described long before it was possible to quantitate peripheral levels of PRL in the male or demonstrate the presence of PRL receptors in tissues thought to respond directly to the action of this hormone. The 3 early suggestions that PRL can act directly on the male reproductive system received strong support from the demonstration that specific PRL receptors are present in the interstitial compmiment of the testis (Aragona et aI., 1977; Charreau et aI., 1977) and in the male accessory reproductive glands (Aragona et aI. , 1977; Charreau et aI. , 1977; Kledzik et aI. , 1976). The ability of PRL to influence testicular function can most readily be demonstrated in PRL-deficient animals. In the golden hamster exposure to a short photoperiod or complete darkness causes a drastic reduction in PRL levels in the pituitary and in peripheral plasma and a more modest reduction in leutinizing hormone (LH) and FSH levels (Berndtson and Desjardins, 1974; Reiter and Johnson, 1974). This is accompanied by testicular atrophy, loss of libido and infertility. Administration of PRL to dwarf mice and to hamsters with photoperiod-induced testicular atrophy stimulates growth of testes and accessory reproductive glands, increases testicular testosterone production and spermatogenesis and induces feliility (Bartke et aI., 1977; Bex et aI., 1978) The mechanism responsible for the stimulation of testicular function by PRL was suggested by the results obtained in hypophysectomized animals. In hypophysectomized rats and mice, PRL significantly augmented the effects of exogenous LH on biosynthesis of testosterone and spermatogenesis (Bartke, 1971 ; Hafiez et aI., 1972). In contrast, PRL did not potentiate the action of exogenous testosterone on spermatogenesis and had little, if any effect when administered alone (Bartke, 1971; Hafiez et al., 1972). It was also demonstrated that treatment of hypophysectomized rat with PRL increases their ability to produce testosterone in response to acute LH stimulation (Bartke et al., 1978). These results suggest that PRL can act on the Leydig cells to increase their responsiveness to LH stimulation. This action of PRL appears to be particularly important during the seasonal changes in gonadal function in the golden hamster. In this species, PRL can both prevent and reverse testicular atrophy induced by binding or by exposure to a short photoperiod (Bex et aI., 1978; Matthews et al., 1978). PRL increases the sensitivity of the testes to LH stimulation by increasing the ability of the leydig cells to bind LH. PRL deficiency in hereditary dwarf mice, in hamsters exposed to short photoperiod and in rats treated with an inhibitor of PRL release is associated with loss of testicular LH receptors (Aragona et al., 1977; Bex and Bartke, 1977; Bohnet and Friesen, 1976). Treatment with PRL increases 4 concentration of LH receptors in the testes of dwarf mice (Aragona et al., 1977; Golder et aI., 1972), hamster (Bex and Bartke, 1977) and hypophysectomized rats (Zipf et aI., 1978). In addition to its effects on testicular LH receptors, PRL can stimulate accumulation of esterified cholesterol and the activities of 3 p- and 17Phydroxysteroid dehydrogenases in the testes (Bartke, 1976). It has been documented that PRL can potentiate the effects of exogenous androgens on the growth of male accessory reproductive glands in castrated animals (Thomas and Keenan, 1976). Administration ofPRL alone to castrated males causes a small but detectable increase in the weight of accessory reproductive glands and it has been shown that this effect of PRL is not mediated through the pituitary or the adrenal gland (Bartke and Lloyed, 1970; Negro-Vilar et aI., 1977). The fact that PRL binding to prostatic membranes and cytosol is androgen-dependent (ChalTeau et al., 1977; Kledzik et al., 1976) provides an explanation for the greatly reduced responsiveness of accessory reproductive glands to PRL in the absence of endogenous or exogenous testosterone. Evidence also suggests that PRL may affect the number of LH receptors in the ovary and thus modulate steroidogenesis in the follicular cells (Zipf et aI., 1978). It appears that the ability of PRL to stimulate growth of accessory reproductive glands in castrated males may be related to physiological action of PRL in intact males. Suppression of endogenous PRL levels by active immunization with heterologous PRL or by treatment with anti-PRL serwn can decrease weight and secretory activity of accessory reproductive glands in rabbit (Asano et aI. , 1971), mouse (Bartke 1974), rat (Hostetter et al., 1977) and ram (Ravault et aI., 1977). Several lines of evidence suggest that PRL can also affect the function of the male reproductive system indirectly, by altering the release of pituitary gonadotropins. In two types of genetically dwarfed mice, treatment with ovine PRL or with PRL producing ectopic pituitary homo grafts caused a significant increase in peripheral FSH levels (Bartke et aI., 1977). The ability of PRL to stimulate FSH release may account for some of its effects on the testis because FSH can increase testicular LH binding and potentiate the effects of LH on testosterone production (Bartke et aI., 1978). The PRL-induced FSH release could also explain why effects of PRL on the testes of hypophysectomized animals are less striking than those observed in intact males with PRL deficiency.