Serotonin in Development of Cyclic Reproductive Function
Drugs, hormones and photoperiods were used to investigate the effect of modified serotonin metabolism during ontogeny on reproductive function in the adult female rat. Testosterone (10 μg or 1.25 mg), which causes precocious vaginal opening and prevents cyclic pituitary gonadotropin secretion was injected into neonatal rats to determine if changes in pineal gland and/or hypothalamic serotonin were associated with effects on the reproductive system. Conversely, p-chlorophenylalanine (PCPA; 70mg/kg on day 3 or 35mg/kg on days 3–12), a drug which blocks brain serotonin synthesis, and exposure to constant light (days 3–160), which abolishes pineal gland serotonin rhythms, were used to determine the effect of altered serotonin metabolism during development, on adult reproductive function.
Single doses of testosterone (1.25mg), PCPA (70mg/kg) or exposure to constant light prevented nyctohemeral serotonin rhythms in hypothalamus and pineal gland on day 20 and caused precocious vaginal opening. The steroid and drug both depressed serotonin levels more than did constant light, though in this case, serotonin levels were always lower than peak levels achieved under light:dark conditions. Low doses of testosterone (10 μg) neither caused early vaginal opening nor depressed brain serotonin rhythms. When PCPA was injected on days 3–12, vaginal opening was delayed, serotonin rhythms and levels on day 20 were depressed and hypothalamic catecholamines were reduced.
Both serotonin rhythms and estrous cycles were absent in heavily androgenized rats at adulthood, while lightly androgenized and all PCPA-treated rats cycled as adults and had hypothalamic and pineal serotonin rhythms. However, rats which received sequential injections of PCPA showed prolonged diestrous phases before regular estrous cycles were established. Persistent estrous developed after a period of irregular cycles in light exposed rats. Brain serotonin rhythms were absent during the period of light-induced reproductive acyclicity, but subsequent exposure to alternating periods of light and dark restored estrous cycles and serotonin rhythms.
Estrous cycles terminated prematurely in lightly androgenized (x = 131 days) and PCPA-treated (x = 268 days) rats, whereas, constant light exposed rats had a normal reproductive lifespan when they were returned to an alternating photoperiod.
These data suggest that precocious puberty, which occurs after treatment of neonatal rats with large doses of testosterone, a single injection of PCPA, or exposure to constant light, results from depressed brain serotonin during ontogeny. Sequential injections of PCPA early in life, depress brain serotonin, but also reduce catecholamines, which probably accounts for the delay in vaginal opening after such treatment.
Heavy androgenization causes irreversible loss of circadian serotonin rhythms which may account for the absence of estrous cycles in these rats. While smaller doses of testosterone do not abolish these rhythms in the juvenile rat, such treatment results in premature loss of estrous cycles which is correlated with a delayed loss of serotonin rhythms in the adult. Similarly, serotonin rhythms are present in adult rats which were treated with PCPA as neonates, but these rhythms failed earlier than normal and estrous cycles were lost prematurely. Depressed serotonin metabolism during ontogeny may inhibit the development of a full complement of neural elements required for cyclic gonadotropin secretion and thereby result in reproductive failure in the adult.
KeywordsPineal Gland Estrous Cycle Precocious Puberty Serotonin Level Constant Light
Unable to display preview. Download preview PDF.
- 3.C.A. Wilson, C.A. Endersby,and P.G. McDonald, Potentiating effect of serotonin on pregnant mare serum gonadotropin induced ovulation in the underweight immature rat, J. Endocr. 61: XXV (1974).Google Scholar
- 11.R.J. Reiter, Circannual reproductive rhythms in mammals related to photoperiod and pineal function: A review, Chronobiol. 1: 365 (1975).Google Scholar
- 16.J. Saavedra, M. Brownstein, and J. Axelrod, A specific and sensitive enzymatic-isotopic microassay for serotonin in tissues, J. Pharm. Exp. Ther. 186: 508 (1973).Google Scholar
- 18.R.J.W. Wurtman, J. Axelrod, and D.E. Kelly, “The Pineal”, Academic Press, New York (1968).Google Scholar
- 19.B.L. Koe, and A. Weissman, P-chlorophenylalanine: A specific depletor of brain serotonin, J. Pharm. Exp. Ther. 154: 499 (1966).Google Scholar
- 21.P. Lehtinen, M. Hyyppä, P. Lampinen, and U.K. Rinne, Sexual behavior after neonatal reserpine and PCPA treatment with comment about hypothalamic indoleamines in the rat, Horm., Brain Func.,Budapest 1971: 305 (1973).Google Scholar
- 23.R.F. Walker, P. Segall, and P.S. Timiras, Neuroendocrinology of Aging, in:“The Aging Nervous System”, G.J. Maletta and F.J. Pirozzolo, eds., Praeger, New York (in press) (1979).Google Scholar