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Blockade of stress-induced prolactin release in monosodium glutamate-treated rats
Brtrin Rrsrcwh
Bullcrin, Vol. 10, pp. 23-26. 1983. Printed in the U.S.A.
Blockade of Stress-Induced Prolactin Release in Monosodium Glutamate-Treated Rats H. MIZUNUMA, ~epa~t~~le~t
0. KHORRAM
AND S. M. MCCANN
of Physiology,
university cif Texas wealth Scimce Center at ~a~la~~, 5323 Harry Hines Boulevard, Dallas, TX 75235 Received
27 July 1982
MIZUNUMA, H., 0. KHORRAM AND S. M. M&ANN. Bi~~~~de of ~tr~ss-~~d~~ed prnlactin release in rn~~n~~~~~~rf~utn ,$utamatr-treated rats. BRAIN RES BULL lO{1)23-26, 1983.-To elucidate the role of the medial basal hypothalamus (MBH) in stress-induced prolactin (Prl) release, adult male rats which had received monosodium glutamate (MSG 4 mg/g) on alternate days for the first IO days of life were subjected to ether stress for 2 min. Blood samples were drawn at 0, 15,30 and 60 min after etherization through an indwelling jugular catheter implanted 1 day before the experiment. Sixty minutes after etherization the dopamine receptor blocker spiroperidol (0.1 mgikg) was injected intravenously and another blood sample was withdrawn 60 min later. Although there were no differences in basal levels of plasma Prl between control and MSG-treated animals, a dramatic elevation of plasma Prl was observed in control rats 15 min after etherization, whereas no significant change was seen in MSG-treated animals. Spirope~dol sign~~cantly increased plasma Prl in both groups of animals, but the magnitude of the increase in Prl levels of MSG-treated rats was roughly one-third (p
Stress
Prolactin
Dopamine
IT is well established that the secretion of Prl is under the inhibitory influence of the tuberoinfundibular dopaminergic system and that the central serotonergic system has a stimulatory effect on Prl release [7, 10, 141; yet the mechanism mediating acutely induced Prl release such as occurs in stress [ 1,181 or pseudopregnancy [19] is not clearly understood. Marchlewska-Koj and Krulich fl5] suggested the mediation of stress-induced Prl release by the serotonergic system, since pretreatment of animals with the serotonin antagonist methysergide blocked the P&releasing effect of repeated etherization and bleeding. However, methysergide is now known to have dopamine receptor agonist properties as well and to inhibit PrI secretion from the pituitary gland directly [t 1J. The possible direct or indirect intervention of the serotonergic and the dopaminergic systems in stressinduced Prl release has also been proposed [12,13]. On the other hand, naloxone is known to attenuate stress-induced Prl release [5, 16, 25, 281, which suggests a role for the endogenous opioid peptides in this response. Monos~ium glutamate (MSG) administered during the neonatal period exerts a toxic effect on neurons in the retina and the arcuate nucleus (ARC) [2,21]. Because of the characteristic mode of action of MSG which destroys 80-9(yToof the cell bodies within the ARC while sparing axons “en passage” [20, 22, 261, ARC levels of dopamine [3, 6, 201,
Copyright
o 1983 ANKHO
International
P-endorphin [9], LU-MSH [4], ACTH [91 and choline acetyltransferase [3, 6, 301 are markedly reduced, while LH-RH, TRH, and serotonin in the area remain unchanged 1201. In this study, we examined the effect of acute stress on Prl secretion in MSG-treated rats and also their ability to release Prl after the intravenous administration of the dopamine receptor blocker, spiroperidol, and an opiate, morphine. METHOD
Rats of the Sprague-Dawley strain were bred in our laboratory, and the day of birth was designated as day 1 of the neonatal period. Four mg/g of MSG (Sigma, St. Louis) was injected intraperitoneally on days 2,4,6,8 and 10. On day 21 the pups were weaned, their sex was determined, and they were housed under controlled conditions of lighting (on 0500 to 1900) and temperature (25°C) with free access to Purina rat chow and water. Only males were used in this experiment. Animals of the same strain and age were purchased from Holtzman Laboratories and served as controls. They were acclimatized in our laboratory for 14 days before use.
When the animals were 8 months old, a Silastic catheter
Inc.-0361”9230/83/010023-04$03.00/O
MIZUNUMA.
KHORKAM
AND iLIcCANN
FIG. 1. Effect of ether stress on plasma Prl levels in control (O-0, N=9) and MSG-treated (O-O, N=8) rats. In this and subsequent figures vertical lines indicate SEM. *p
was inserted into the external jugular vein a day before the experiment. One day iater an extension of polyethylene tubing filled with heparinized saline (0.9% NaCI) was attached to the distal end of the cannnla. The animals were left undisturbed for at least 45 min, then a baseline blood sample (0.7 ml) was withdrawn slowly over a period of 1 min. Ether stress was produced by placing the animals for 2 min in a glass jar saturated with ether, the animals were returned to their ind~~du~ cages, and hepar~niz~d blood samples were collected from the external jugular cannula IS, 30 and 60 min later after the animals were exposed to ether stress. When the last sample had been withdrawn, spiroperidol (Jansen Pharmaceutical), was injected intravenously at a dose of 0.1 mpJkg. The cannula was washed with 500 (~1 saline, and a blood sample was collected 60 min later. In another group of animals morphine was injected (3 mg/kg) through the venous catheter, and a blood sample was drawn 10 and 30 min later. The volume of all samples was replaced ~mmediate~y after each bleeding by an equal volume of saline. Plasma was separated by centrifugation at 4°C and stored at -20°C until assay. RIA cd
Stutisrics
h-1 was measured by the RlA kit supplied by NZAMDD, and the results were expressed in terms of the RP- I reference standard provided with the kit, Sign~~~~~e of differences in sequential changes in hormone levels was analyzed by analysis of variance with repeated measures followed by the Student-Newman-Keul’s multiple comparison test. Significance of differences between two groups was analyzed by Student’s I-test. RESULTS
There were no significant differences in basal levels ofPr1 between the contro$ and the MSG-treated animals. Etherization caused a 3 fold increase in Prl levels in con&-of rats within 15 min @
FIG. 2. Effect of spiroperidoI(O.1 maJkg BW) un plasma Prl levels in control (striped bar) and MS&treated topen bar) rats. The values obtained 60 min after etherization were considered to be the pretreatment Prl levels. Number at top of bar indicates the number of animals. *p<.O.OOl vs pretreatment t pc: 0.W vs control.
respectively) (Fig. 2). The increase of PrI Levels in cwtrot animals was of greater magnitude than that observed in MSG-treated rats (F,
The principle finding of this study was the ability of MSG treatment of infantile animals to block completely stressinduced release of Prl. Even though a 5&6VX reduction of basal hypothalamic dopamine concentration has been rtported in MSG-treated animals [3. 6. 20}, the remaining dopaminergic neurons in the area appeared to function to maintain Pri at low basal values. However, since Prl did not rise as high in animais given the dopamine receptor blocker. spiroperidol, as in the controls there appears to be some defect in the dopaminergic inhibitory control of Prl. It is possible that Prl is kept low in the MSG-treated animals by the combined action the dopaminergic system and another system. This w&d acccmnt for the failure of Prl to rise as high in spiroperidol-treated animals which had received
of
STRESS, PRL, MSG
25
150-O
CONTROL
O-O
MSG n=6
n=6
-I! 'IOOF 2 a !! g 50c
0
f 0
I 10
I 20
I 30
Time (min 1 FIG. 3. Effect of morphine (3 mg/kg BW) on plasma Prl levels in control (O-O, N=6) and MSG-treated (O-O, N=6) rats. ***~
MSG treatment. Although the size of the pituitary gland and its Prl content are decreased in MSG treated animals [ 17,231, it is unlikely that the decreased elevation of plasma Prl in response to spiroperidol is attributable to decreased stores of Prl since the elevation of Prl in response to morphine was as great as that in the controls. Furthermore, pituitary function to release LH in response to exogenous LHRH is unaffected in MSG-treated animals, another indication that the pituitary is competent to respond [3]. Since the dopaminergic inhibitory system was functioning in the MSG-treated animals, the failure of ether stress to NOTE
ADDED
induce a significant elevation in Prl release in MSG-treated animals indicates that the tuberoinfundibular dopaminergic system is not solely responsible for stress-induced Prl release. The pathway of stress-induced prolactin release may involve the central serotonergic system since Prl release is induced by central serotonergic stimulation [7, 10, 141, and the serotonin receptor blocker methysergide suppresses the Prl release from stress [15]. However, methysergide is now known to have dopamine receptor agonist properties as well [ 111, which raises the possibility that its ability to block stress-induced Prl release may have been due to a direct action at the pituitary. Furthermore, recent evidence does not support the role of the serotonin system in the stress response, since it was not blocked by depletion of central serotonin stores by PCPA nor by destruction of the central serotoninergic neuronal system by 5-7-dihydroxytryptamine 1271. It is possible that the system which is impaired in the MSG-treated animals is the endogenous p-endorpin system. P-endorphin cell bodies are found in the arcuate nucleus. Administration of MSG lowers the endorphin content in the medial basal hypothalamus [9]. Exogenous administration of /3-endorphin enhances Prl release by an action at a central nervous system site [24]. Naloxone blocks not only the effects of p-endorphin but also stress-induced Prl release [5, 8, 16, 25, 281. Furthermore, giving morphine to mimic the action of p-endorphin was equally effective in releasing Prl in control and MSG-treated rats. Therefore, the most likely explanation of the current results is that there is reduced release of arcuate p-endorphin due to stress in the MSGtreated animal. In conclusion, this study presents evidence that the defect in stress-induced prolactin release in MSGtreated rats may be related to an impairment in the arcuate P-endorphin neuronal system. ACKNOWLEDGEMENTS
This work was supported by NIH Grants HD-09988 and AM10073. We wish to thank Mrs. Diane Doach for typing the manuscript. IN PROOF
In more recent experiments, rats which had been treated neonatally with hypertonic saline showed an identical rise in plasma prolactin levels in response to ether stress as the neonatally uninjected rats used as controls in this study. REFERENCES I. Ajika, K., S. P. Kalra, C. P. Fawcett, L. Krulich and S. M. McCann. The effect of stress and nembutal on plasma levels of gonadotropins and prolactin in ovariectomized rats. Endoc~rinology 90: 707-715, 1972. 2. Burde, R. M., B. Shanker and J. Kayes. Acute effect oforal and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rat. Nafurc 233: 5860, 1971. 3. Clemens, J. A., M. E. Roush, R. W. Fuller and C. J. Shaar. Changes in luteinizing hormone and prolactin control mechanisms produced by glutamate lesions of the arcuate nucleus. Endocrinology 103: 1304-1312, 1978. 4. Eskay, R. L., M. J. Brownstein and R. T. Lang. cr-melanocyte-stimulating hormone: reduction in adult rat brain after monosodium glutamate treatment of neonates. Scicmr 205: 827-829, 1979. 5. Grandison, L. and A. Guidotti. Regulation of prolactin release by endogenous opiates. Nature 270: 357-359, 1977.
6. Greeley, Jr., G. H., G. F. Nicholson, C. B. Nemeroff, W. W. Youngblood and J. S. Kizer. Direct evidence that the arcuate nucleus-median eminence tuberoinfundibular system is not of primary importance in the feedback regulation of luteinizing hormone and follicle-stimulating hormone secretion in the castrated rats. Endocrinology 103: 170-175, 1978. 7. Kamberi, I. A., R. S. Mica1 and J. C. Porter. Effect of melatonin and serotonin on the release of FSH and prolactin. Endocrinolagy 88: 1288-1293,
1971.
8. Koenig, J. I., M. A. Mayfield, S. M. McCann and L. Krulich. Stimulation of prolactin secretion by morphine: role of the central serotonergic system. Li’ Sci 25: 853-864, 1979. 9. Krieger, D. T., A. S. Liotta, G. Nicholson and J. S. Kizer. Brain ACTH and endoruhin reduced in rats with monosodium glutamate-induced arc&e nuclear lesions. Natuw 278: 562563, 1979.
26
IO. Krulich, L., A. Giachetti, R. 5. Coppings, S. M. McCann and M. A. Mayfield. On the role of the central serotonergic system in the regulation of the secretion of TSH and prolactinin the rat: TSH inhibiting and orolactin releasinn effects of 5-OH trvotamine and quipazind. Encfocrinology iOS: 276-283, 1979. . . 11. Krulich, L., S. M. McCannand M. A. Mayfield. On the mode of the prolactin receding-inhibiting action of the serotonin receptor blockers metergoline, methysergide, and cyproheptadine. E~ciocrinology 10s: 1115-1124, 1981. 12. Lawson, D. M. and R. R. Gala. The interaction of dopaminergic and serotonergic drugs on plasma prolactin in ovariectomized, estrogen-treated rats. Ekfocrinotogy 98: 42-47, 1976. 13. Lawson, D. M. and R. R. Gala. The influence of pharmacoiogical manipulation of serotonergic and dopaminergic mechanisms on plasma prolactin in ovariectomized. estrogen-treated rats. Enducrinotogy 102: 973-981, 1978. 14. Lu, K.-H and J. Meites. Effect of serotonin precursors and melatonin on serum prolactin release in rats. ~~~~~[,rj~~~~~~~~ 93: 152-155. 1973. 15. Marchlewska-Koj, A. and L. Krulich. The role of central monoamines in the stress-induced proiactin release in the rat. Fed Proc 34: 2S2, 1975. 16. Meites. J., J. F. Bruni, D. A. VanVugt and A. F. Smith. Relation of endogeneous opioid peptide and morphine to neuroendocrine function. Life Sci 24: 1325-1336, 1979. 17. Nagasawa, M., R. Yanai and S. Kikuyama. Irreversible inhibition of pituitary prolactin and growth hormone secretion of mammary gland development in mice by monosodium glutamate administered neonatally. Amr E~~~~ri~[il lCr>prnht 75:
MIZUN UMA. KHI>RKAM AND MrCAN N
20. Nemeroff. C. B.. R. J. Konkol. G. Bissette. W. Youngblood. J. B. Martin, P. Brazeau, M. S. Rone. A. 3. Prange, Jr.. G. R. Breese and J. S. Kizer. Analysis of the disruption in hypoth~amic-p~t~tary regulatiun in rats treated neonatally with monosodium L-glutamate (MSG): evidence for the involvement of tuberoinfundibular cholinergic ;md dopaminergic system irk neuroendocrine regulation. I~~l~fot.~itrctirt~~ 101: 613-622, 1977. 21. Olney, J. W. Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. .S(.i<,nc.rp164: 719721, 1969. 22. Olney. J. W. Excitotoxic mechanrsm of ncurotoxicity. In: t:.~ ~~,‘mc~ntai N& Ctinicul rv’c,/crorri.ril.rit~~~~~. Baltimore: Williams and Wilkins, 1980, pp. 272-294. 23. Redding. T. W., A. V. Scholl\. A. Arimur;) ;ind J. W~abayashi. Effect of ,~~,~,s~~d~~~rng~u~rn~te on some: endocrine functions. Nc,rtror,nri’t)(.,inr,to,~i’?‘ 8: 245-255. 1971 24. Rivier. C.. W. Vale. N. Ling. M. Brown and R. Guillemin. Stimulation i~ vitro of the secretion of prolactin and growth hormone by fi-endorphin. En&~c~ri/~,&~~:r: 100: 238-241. 1077. 2s. Rossier, J.. 13. French. C. Rivier. T. Shibasaki. R. Guiliemin and F. E. Bloom. Stress-induced release of prolactin: Blockade by dcxamethasone and naloxone may indicate a-endorphin mediation, Proc Nrrfl AUI~ SC,;, li\‘rl 77: f&6.-669. 1980. 26. Simson, E. I,.. R. M. Gold. I_. .I. Standish and P. L Peilett. Axon-sparing brain lesioning technique: the uhe ol’ monos~ium-I_-glutamate and other amino acids. S(~ir,,~c~~~ 198: 515-517, 1977. 21 Steele. M. K., R. J. Coppings, M. jj. Mayfield and I,. Krulich. Evidence that the central serotonrrgic ISHT) system does not 249-259, 1974. mediate changes in the secretion of prolactin (P) and TSH induced by other stress. Ph?~ir,lr~~i.ti 22: 74. 1979. 18. Neill, J. D. Effect of stress on serum prolactin and luteinizing hormone levels during the estrus cycle of the rat. E~~~~~.~i~i~~~~i~~~28 Van Vugt, D. A.. J. F. Bruni and .I. Me&i. Naloxonc iIlhib~ti[~r~ 87: 1192-I 197, 1970. of stress-induced increase in prolactin secretion. I.$2 I’(-; 22: x5-90. 1978 19. Neil]. J. D. Neuroendocrine regulation of proiactin secretion. In: Frontiers in NeuroenLfocrinolrtgv. vol. 6. New York: Raven Press, 1980, pp. 129-155.
Bullcrin, Vol. 10, pp. 23-26. 1983. Printed in the U.S.A.
Blockade of Stress-Induced Prolactin Release in Monosodium Glutamate-Treated Rats H. MIZUNUMA, ~epa~t~~le~t
0. KHORRAM
AND S. M. MCCANN
of Physiology,
university cif Texas wealth Scimce Center at ~a~la~~, 5323 Harry Hines Boulevard, Dallas, TX 75235 Received
27 July 1982
MIZUNUMA, H., 0. KHORRAM AND S. M. M&ANN. Bi~~~~de of ~tr~ss-~~d~~ed prnlactin release in rn~~n~~~~~~rf~utn ,$utamatr-treated rats. BRAIN RES BULL lO{1)23-26, 1983.-To elucidate the role of the medial basal hypothalamus (MBH) in stress-induced prolactin (Prl) release, adult male rats which had received monosodium glutamate (MSG 4 mg/g) on alternate days for the first IO days of life were subjected to ether stress for 2 min. Blood samples were drawn at 0, 15,30 and 60 min after etherization through an indwelling jugular catheter implanted 1 day before the experiment. Sixty minutes after etherization the dopamine receptor blocker spiroperidol (0.1 mgikg) was injected intravenously and another blood sample was withdrawn 60 min later. Although there were no differences in basal levels of plasma Prl between control and MSG-treated animals, a dramatic elevation of plasma Prl was observed in control rats 15 min after etherization, whereas no significant change was seen in MSG-treated animals. Spirope~dol sign~~cantly increased plasma Prl in both groups of animals, but the magnitude of the increase in Prl levels of MSG-treated rats was roughly one-third (p
Stress
Prolactin
Dopamine
IT is well established that the secretion of Prl is under the inhibitory influence of the tuberoinfundibular dopaminergic system and that the central serotonergic system has a stimulatory effect on Prl release [7, 10, 141; yet the mechanism mediating acutely induced Prl release such as occurs in stress [ 1,181 or pseudopregnancy [19] is not clearly understood. Marchlewska-Koj and Krulich fl5] suggested the mediation of stress-induced Prl release by the serotonergic system, since pretreatment of animals with the serotonin antagonist methysergide blocked the P&releasing effect of repeated etherization and bleeding. However, methysergide is now known to have dopamine receptor agonist properties as well and to inhibit PrI secretion from the pituitary gland directly [t 1J. The possible direct or indirect intervention of the serotonergic and the dopaminergic systems in stressinduced Prl release has also been proposed [12,13]. On the other hand, naloxone is known to attenuate stress-induced Prl release [5, 16, 25, 281, which suggests a role for the endogenous opioid peptides in this response. Monos~ium glutamate (MSG) administered during the neonatal period exerts a toxic effect on neurons in the retina and the arcuate nucleus (ARC) [2,21]. Because of the characteristic mode of action of MSG which destroys 80-9(yToof the cell bodies within the ARC while sparing axons “en passage” [20, 22, 261, ARC levels of dopamine [3, 6, 201,
Copyright
o 1983 ANKHO
International
P-endorphin [9], LU-MSH [4], ACTH [91 and choline acetyltransferase [3, 6, 301 are markedly reduced, while LH-RH, TRH, and serotonin in the area remain unchanged 1201. In this study, we examined the effect of acute stress on Prl secretion in MSG-treated rats and also their ability to release Prl after the intravenous administration of the dopamine receptor blocker, spiroperidol, and an opiate, morphine. METHOD
Rats of the Sprague-Dawley strain were bred in our laboratory, and the day of birth was designated as day 1 of the neonatal period. Four mg/g of MSG (Sigma, St. Louis) was injected intraperitoneally on days 2,4,6,8 and 10. On day 21 the pups were weaned, their sex was determined, and they were housed under controlled conditions of lighting (on 0500 to 1900) and temperature (25°C) with free access to Purina rat chow and water. Only males were used in this experiment. Animals of the same strain and age were purchased from Holtzman Laboratories and served as controls. They were acclimatized in our laboratory for 14 days before use.
When the animals were 8 months old, a Silastic catheter
Inc.-0361”9230/83/010023-04$03.00/O
MIZUNUMA.
KHORKAM
AND iLIcCANN
FIG. 1. Effect of ether stress on plasma Prl levels in control (O-0, N=9) and MSG-treated (O-O, N=8) rats. In this and subsequent figures vertical lines indicate SEM. *p
was inserted into the external jugular vein a day before the experiment. One day iater an extension of polyethylene tubing filled with heparinized saline (0.9% NaCI) was attached to the distal end of the cannnla. The animals were left undisturbed for at least 45 min, then a baseline blood sample (0.7 ml) was withdrawn slowly over a period of 1 min. Ether stress was produced by placing the animals for 2 min in a glass jar saturated with ether, the animals were returned to their ind~~du~ cages, and hepar~niz~d blood samples were collected from the external jugular cannula IS, 30 and 60 min later after the animals were exposed to ether stress. When the last sample had been withdrawn, spiroperidol (Jansen Pharmaceutical), was injected intravenously at a dose of 0.1 mpJkg. The cannula was washed with 500 (~1 saline, and a blood sample was collected 60 min later. In another group of animals morphine was injected (3 mg/kg) through the venous catheter, and a blood sample was drawn 10 and 30 min later. The volume of all samples was replaced ~mmediate~y after each bleeding by an equal volume of saline. Plasma was separated by centrifugation at 4°C and stored at -20°C until assay. RIA cd
Stutisrics
h-1 was measured by the RlA kit supplied by NZAMDD, and the results were expressed in terms of the RP- I reference standard provided with the kit, Sign~~~~~e of differences in sequential changes in hormone levels was analyzed by analysis of variance with repeated measures followed by the Student-Newman-Keul’s multiple comparison test. Significance of differences between two groups was analyzed by Student’s I-test. RESULTS
There were no significant differences in basal levels ofPr1 between the contro$ and the MSG-treated animals. Etherization caused a 3 fold increase in Prl levels in con&-of rats within 15 min @
FIG. 2. Effect of spiroperidoI(O.1 maJkg BW) un plasma Prl levels in control (striped bar) and MS&treated topen bar) rats. The values obtained 60 min after etherization were considered to be the pretreatment Prl levels. Number at top of bar indicates the number of animals. *p<.O.OOl vs pretreatment t pc: 0.W vs control.
respectively) (Fig. 2). The increase of PrI Levels in cwtrot animals was of greater magnitude than that observed in MSG-treated rats (F,
The principle finding of this study was the ability of MSG treatment of infantile animals to block completely stressinduced release of Prl. Even though a 5&6VX reduction of basal hypothalamic dopamine concentration has been rtported in MSG-treated animals [3. 6. 20}, the remaining dopaminergic neurons in the area appeared to function to maintain Pri at low basal values. However, since Prl did not rise as high in animais given the dopamine receptor blocker. spiroperidol, as in the controls there appears to be some defect in the dopaminergic inhibitory control of Prl. It is possible that Prl is kept low in the MSG-treated animals by the combined action the dopaminergic system and another system. This w&d acccmnt for the failure of Prl to rise as high in spiroperidol-treated animals which had received
of
STRESS, PRL, MSG
25
150-O
CONTROL
O-O
MSG n=6
n=6
-I! 'IOOF 2 a !! g 50c
0
f 0
I 10
I 20
I 30
Time (min 1 FIG. 3. Effect of morphine (3 mg/kg BW) on plasma Prl levels in control (O-O, N=6) and MSG-treated (O-O, N=6) rats. ***~
MSG treatment. Although the size of the pituitary gland and its Prl content are decreased in MSG treated animals [ 17,231, it is unlikely that the decreased elevation of plasma Prl in response to spiroperidol is attributable to decreased stores of Prl since the elevation of Prl in response to morphine was as great as that in the controls. Furthermore, pituitary function to release LH in response to exogenous LHRH is unaffected in MSG-treated animals, another indication that the pituitary is competent to respond [3]. Since the dopaminergic inhibitory system was functioning in the MSG-treated animals, the failure of ether stress to NOTE
ADDED
induce a significant elevation in Prl release in MSG-treated animals indicates that the tuberoinfundibular dopaminergic system is not solely responsible for stress-induced Prl release. The pathway of stress-induced prolactin release may involve the central serotonergic system since Prl release is induced by central serotonergic stimulation [7, 10, 141, and the serotonin receptor blocker methysergide suppresses the Prl release from stress [15]. However, methysergide is now known to have dopamine receptor agonist properties as well [ 111, which raises the possibility that its ability to block stress-induced Prl release may have been due to a direct action at the pituitary. Furthermore, recent evidence does not support the role of the serotonin system in the stress response, since it was not blocked by depletion of central serotonin stores by PCPA nor by destruction of the central serotoninergic neuronal system by 5-7-dihydroxytryptamine 1271. It is possible that the system which is impaired in the MSG-treated animals is the endogenous p-endorpin system. P-endorphin cell bodies are found in the arcuate nucleus. Administration of MSG lowers the endorphin content in the medial basal hypothalamus [9]. Exogenous administration of /3-endorphin enhances Prl release by an action at a central nervous system site [24]. Naloxone blocks not only the effects of p-endorphin but also stress-induced Prl release [5, 8, 16, 25, 281. Furthermore, giving morphine to mimic the action of p-endorphin was equally effective in releasing Prl in control and MSG-treated rats. Therefore, the most likely explanation of the current results is that there is reduced release of arcuate p-endorphin due to stress in the MSGtreated animal. In conclusion, this study presents evidence that the defect in stress-induced prolactin release in MSGtreated rats may be related to an impairment in the arcuate P-endorphin neuronal system. ACKNOWLEDGEMENTS
This work was supported by NIH Grants HD-09988 and AM10073. We wish to thank Mrs. Diane Doach for typing the manuscript. IN PROOF
In more recent experiments, rats which had been treated neonatally with hypertonic saline showed an identical rise in plasma prolactin levels in response to ether stress as the neonatally uninjected rats used as controls in this study. REFERENCES I. Ajika, K., S. P. Kalra, C. P. Fawcett, L. Krulich and S. M. McCann. The effect of stress and nembutal on plasma levels of gonadotropins and prolactin in ovariectomized rats. Endoc~rinology 90: 707-715, 1972. 2. Burde, R. M., B. Shanker and J. Kayes. Acute effect oforal and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rat. Nafurc 233: 5860, 1971. 3. Clemens, J. A., M. E. Roush, R. W. Fuller and C. J. Shaar. Changes in luteinizing hormone and prolactin control mechanisms produced by glutamate lesions of the arcuate nucleus. Endocrinology 103: 1304-1312, 1978. 4. Eskay, R. L., M. J. Brownstein and R. T. Lang. cr-melanocyte-stimulating hormone: reduction in adult rat brain after monosodium glutamate treatment of neonates. Scicmr 205: 827-829, 1979. 5. Grandison, L. and A. Guidotti. Regulation of prolactin release by endogenous opiates. Nature 270: 357-359, 1977.
6. Greeley, Jr., G. H., G. F. Nicholson, C. B. Nemeroff, W. W. Youngblood and J. S. Kizer. Direct evidence that the arcuate nucleus-median eminence tuberoinfundibular system is not of primary importance in the feedback regulation of luteinizing hormone and follicle-stimulating hormone secretion in the castrated rats. Endocrinology 103: 170-175, 1978. 7. Kamberi, I. A., R. S. Mica1 and J. C. Porter. Effect of melatonin and serotonin on the release of FSH and prolactin. Endocrinolagy 88: 1288-1293,
1971.
8. Koenig, J. I., M. A. Mayfield, S. M. McCann and L. Krulich. Stimulation of prolactin secretion by morphine: role of the central serotonergic system. Li’ Sci 25: 853-864, 1979. 9. Krieger, D. T., A. S. Liotta, G. Nicholson and J. S. Kizer. Brain ACTH and endoruhin reduced in rats with monosodium glutamate-induced arc&e nuclear lesions. Natuw 278: 562563, 1979.
26
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