Effect of Serotonin Depletion by p-Chlorophenylalanine on Serum Prolactin Levels in Estrogen-Treated Ovariectomized Rats: Insights Concerning the Serotoninergic, Dopaminergic and Opioid Systems

The stimulatory effect of serotonin on prolactin secretion is well documented, and the administration of an inhibitor of serotonin synthesis (p-chlorophenylalanine - pCPA) has the expected inhibitory action on prolactin release in most experimental situations. However, there is evidence that in certain physiological or experimental conditions, activation of the serotoninergic system can also determine inhibition of prolactin secretion. The aim of the present study was to investigate the ability of estrogen to modify the effect of pCPA on prolactin secretion and to evaluate the participation of opioid and/or dopaminergic systems in regulating pCPA-induced prolactin secretion in estradiol-treated rats. We observed that pCPA administration (200 mg/kg/day, s. c., 2 days) to ovariectomized (OVX) female rats treated with estradiol benzoate (300 µg/week for 2 weeks, or 50 µg/week for 4 weeks, s.c.) causes a significant increase in serum prolactin, whereas no effect is observed in intact rats or in OVX rats without treatment. Bromocriptine administration completely reversed prolactin values previously increased by estradiol and by pCPA [OVX rats + estradiol = 86.50 ng/ml (68.90 - 175.02), OVX + estradiol + pCPA = 211.30 ng/ml (142.03 - 311.00), OVX + estradiol + pCPA + bromocriptine = 29.35 ng/ml (23.01 - 48.74), p < 0.05. Naloxone administration partially reduced estrogen-induced high prolactin concentrations, but did not affect prolactin secretion stimulation determined by pCPA. Overall, the data from this report confirm the involvement of the dopaminergic system and, to a lesser degree, of endogenous opioids in prolactin secretion stimulation determined by estradiol. Furthermore, our results suggest that the stimulatory action of pCPA on prolactin secretion in estradiol-treated OVX rats is mediated by serotonin, which may also act indirectly on dopamine neurons.

Prolactin - Serotoninergic System - Dopamine - Endogenous Opioids - Estrogens

References

• 1 Chen C L, Meites J. Effects of estrogen and progesterone on serum and pituitary prolactin levels in ovariectomized rats.  Endocrinology. 1970;  86 503-505
• 2 Oliveira M C, Spritzer P M, Poy M, Coronel A X, Dahlem N, Moraes J T, Barbosa-Coutinho L M. Progestin effects on prolactin secretion and on immunoreactive prolactin cells in estradiol-treated ovariectomized rats.  Horm Metab Res. 1993;  25 600-602
• 3 Spritzer P M, Ribeiro M F, Oliveira M C, Barbosa-Coutinho L M, Silva I S, Dahlem N, Cericatto R, Pavanato M A. Effects of tamoxifen on serum prolactin levels, pituitary immunoreactive prolactin cells and uterine growth in estradiol-treated ovariectomized rats.  Horm Metab Res. 1996;  28 171-176
• 4 Bethea C L. Characterization of dopamine and estrogen interaction on primate prolactin secretion with pituitary cells cultured on extracellular matrix and with pituitary stalk-transected monkeys.  Endocrinology. 1984;  116 863-872
• 5 Cramer O M, Parker Jr C R, Porter J C. Estrogen inhibition of dopamine release into hypophysial portal blood.  Endocrinology. 1979;  104 419-422
• 6 Raymond V, Beaulieu M, Labrie F, Boissier J. Potent antidopaminergic activity of estradiol at the pituitary level on prolactin release.  Science. 1978;  200 1173-1175
• 7 Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone.  Endocr Rev. 1985;  6 564-589
• 8 Gudelsky G A, Nansel D D, Porter J C. Role of estrogen in the dopaminergic control of prolactin secretion.  Endocrinology. 1981;  108 440-444
• 9 Arita J, Kojima Y, Kimura F. Changes in the function of tuberoinfundibular dopaminergic neurons after long-term estradiol treatment in fisher 344 rats.  Neuroendocrinology. 1990;  52 249-255
• 10 Ribeiro M F, Spritzer P M, Barbosa-Coutinho L M, Oliveira M C, Pavanato M A, Silva I SB, Reis F M. Effect of bromocriptine on serum prolactin levels, pituitary weight and immunoreactive prolactin cells in estradiol-treated ovariectomized rats: an experimental model of estrogen-dependent hyperprolactinemia.  Braz J Med Biol Res. 1997;  30 113-117
• 11 Willoughby J O, Pederick H, Jervois P, Menadue M, Judd S J. Responses to prolactin secretagogues in oestrogen-treated rats suggest that the defect in prolactin regulation produced by oestrogen is at the level of the pituitary gland.  J Endocrinol. 1985;  104 447-452
• 12 Cannon M, Hu L, Ye J, Lawson D. Bioactivity of plasma prolactin in ovariectomized, diethylstilbestrol-treated long-evans and Holtzman rats after thyrotropin-releasing hormone or bromocriptine administration.  Proc Soc Exp Biol Med. 1991;  197 465-470
• 13 Woolf P D, Lee L. Effect of the serotonin precursor, tryptophan, on pituitary hormone secretion.  J Clin Endocrinol Metab. 1977;  45 123-126
• 14 Caligaris L, Taleisnik S. Involvement of neurons containing 5-hydroxytryptamine in the mechanism of prolactin release induced by oestrogen.  J Endocrinol. 1974;  62 25-33
• 15 Johnston C A, Fagin K D, Alper R H, Negro-Vilar A. Prolactin release after S-hydroxytryptophan treatment requires an intact neurointermediate pituitary lobe.  Endocrinology. 1986;  118 805-810
• 16 Pan J, Gala R R. The influence of raphe lesions, p-chlorophenylalanine and ketanserin on the estrogen-induced afternoon prolactin surge.  Endocrinology. 1987;  120 2070-2077
• 17 Mistry A M, Voogt J L. Role of serotonin in nocturnal and diurnal surges of prolactin in the pregnant rat.  Endocrinology. 1989;  125 2875-2880
• 18 Jahn G A, Deis R P. Effect of serotonin antagonists on prolactin and progesterone secretion in rats: evidence that stimulatory and inhibitory actions of serotonin on prolactin release may be mediated through different receptors.  J Endocrinol. 1988;  117 415-422
• 19 Balsa J A, Sanchez-Franco F, Pazos F, Lara J I, Lorenzo M J, Maldonado G, Cacicedo L. Direct action of serotonin on prolactin, growth hormone, corticotropin and luteinizing hormone release in cultures of anterior and posterior pituitary lobes: autocrine and / or paracrine action of vasoactive intestinal peptide.  Neuroendocrinology. 1998;  68 326-333
• 20 Genazzani A R, Trentini G P, Petraglia F, De Gaetani C F, Criscuolo M, Ficarra G, De Ramundo B M, Cleva M. Estrogens modulate the circadian rhythm of hypothalamic beta-endorphin contents in female rats.  Neuroendocrinology. 1990;  52 221-224
• 21 Singh M, Millard W J, Layden M P, Romano T M, Simpkins J W. Opiate stimulation of prolactin secretion is reversed by ovarian hormone treatment.  Neuroendocrinology. 1992;  56 195-203
• 22 Ieri T, Chen H T, Campbell G A, Meites J. Effects of naloxone and morphine on the proestrous surge of prolactin and gonadotropin in the rat.  Endocrinology. 1980;  106 1568-1570
• 23 Sagrillo C A, Voogt J L. Mechanisms for the stimulatory effects of opioidergic and serotonergic input signals on prolactin in pregnant rats.  Life Sci. 1992;  50 1479-1489
• 24 Soaje M, Deis R P. A modulatory role of endogenous opioids on prolactin secretion at the end of pregnancy in the rat.  J Endocrinol. 1994;  140 97-102
• 25 Hou Y, Voogt J L. Effects of naloxone infusion on nocturnal prolactin secretion and Fos/FRA expression in pregnant rats.  Endocrine. 1999;  10 145-152
• 26 Arbogast L A, Voogt J L. Endogenous opioid peptides contribute to suckling-induced prolactin release by suppressing tyrosine hydroxylase activity and messenger ribonucleic acid levels in tuberoinfundibular dopaminergic neurons.  Endocrinology. 1998;  139 2857-2862
• 27 Horn A M, Fink G. Parachlorophenylalanine blocks the spontaneous pro-oestrous surge of prolactin as well as LH affects the secretion of oestradiol-17β.  J Endocrinol. 1985;  104 415-418
• 28 Lawson D M, Gala R R. The Influence of pharmacological manipulation of serotonergic and dopaminergic mechanisms on plasma prolactin in ovariectomized, estrogen-treated rats.  Endocrinology. 1978;  102 973-981
• 29 Merchenthaler I, Lennard D E, Cianchetta P, Merchenthaler A, Bronstein D. Induction of proenkephalin in tuberoinfundibular dopaminergic neurons by hyperprolactinemia: the role of sex steroids.  Endocrinology. 1995;  136 2442-2450
• 30 Mathiasen J r, Tomogane H, Voogt J l. Serotonin - induced decrease in hypothalamic tyrosine hydroxylase activity and corresponding increase in prolactin release are abolished at midpregnancy and by transplants of rat choriocarcinoma cells.  Endocrinology. 1992;  131 2527-2532
• 31 Carón R W, Deis R P. Participation of opioid and serotoninergic system in prolactin secretion induced by hypothalamic action of estradiol.  Neuroendocrinology. 1996;  64 124-130
• 32 Goloubkova T, Ribeiro M FM, Rodrigues L P, Cecconello A L, Spritzer P M. Effects of xenoestrogen bisphenol A on uterine and pituitary weight, serum prolactin levels and immunoreactive prolactin cells in ovariectomized Wistar rats.  Arch Toxicol. 2000;  74 92-98
• 33 Yang I C, Pan J T. Effects of serotonin depletion by p-chlorophenylalanine, p-chloroamphetamine or 5,7-dihydroxytryptamine on central dopaminergic neurons: focus on tuberoinfundibular dopaminergic neurons and serum prolactin.  J Biomed Sci. 1999;  6 183-193
• 34 Koe B K, Weissman A. p-Chlorophenylalanine: a specific depletor of brain serotonin.  J Pharmacol Exp Ther. 1966;  154 499-516
• 35 Miller F P, Cox R H, Snodgrass W R, Maickel R P. Comparative effects of p-chlorophenylalanine, p-chloroamphetamine and p-chloro-n-methylamphetamine on rat brain norepinefrine, serotonin and 5-hydroxyindole-3-acetic acid.  Biochem Pharmacol. 1970;  19 435-442
• 36 Burri R, Petersen S L, Barraclough C A. Effects of p-chlorophenylalanine on hypothalamic indoleamine levels and the associated changes which occur in catecholamine dynamics and LH surges in estrogen-treated ovariectomized rats.  Brain Res. 1987;  416 267-276
• 37 Coen C W, Coombs M C, Wilson P MJ, Clement E M, Mac Kinnon P CB. Possible resolution of a paradox concerning the use of p-chlorophenylalanine and 5-hydroxytryptophan: evidence for a mode of action involving adrenaline in manipulating the surge of luteinizing hormone in rats.  Neuroscience. 1983;  8 583-591
• 38 Lynch C O, Johnson M D, Crowley W R. Effects of the serotonin agonist, quipazine, on luteinizing hormone and prolactin release: Evidence for serotonin-catecholamine interactions.  Life Sci. 1984;  35 1481-1484
• 39 MohanKumar P S, MohanKumar S M, Arbogast L, Quadri S K, Voogt J L. Effects of chronic hyperprolactinemia on tuberoinfundibular dopaminergic neurons.  Proc Soc Exp Biol Med. 1998;  217 461-465
• 40 Pan J T, Yang I CH. Central administration of 8-OH-DPAT and MCPP stimulates prolactin secretion in ovariectomized, estrogen-treated rats: lack of an effect on tuberoinfundibular dopaminergic neuron activity.  Life Sci. 1996;  58 1189-1194
• 41 Mistry A M, Vidal G, Voogt J L. Dopaminergic and serotonergic activity in the hypothalamus during early and late pregnancy.  Brain Res. 1991;  550 239-246
• 42 Kehoe L, Janik J, Callahan P. Effects of immobilization stress on tuberoinfundibular dopaminergic (TIDA) neuronal activity and prolactin levels in lactating and non-lactating female rats.  Life Sci. 1992;  50 55-63
• 43 Higuchi T, Honda K, Takano S, Negoro H. Estrogen fails to reduce tuberoinfundibular dopaminergic neuronal activity and to cause a prolactin surge in lactating, ovariectomized rats.  Brain Res. 1992;  576 143-146
• 44 Tai M H, Teo K L, Pan J T. Serotonin-stimulated prolactin secretion may not involve the dopaminergic system.  Chin J Physiol. 1990;  33 345-352