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The effects of the acute administration of phencyclidine hydrochloride (PCP) on the release of corticosterone, growth hormone and prolactin in the rat
Life Sciences, Vol. 38, pp. 291-296 Printed in the U.S.A.
Pergamon Press
THE EFFECTS OF THE ACUTE ADMINISTRATION OF PHENCYCLIDINE HYDROCHLORIDE (PCP) ON THE RELEASE OF CORTICOSTERONE, GROWTH HORMONE AND PROLACTIN IN THE RAT I R o b e r t N. P e c h r i c k , R o b e r t George 2, R a n d a l l J. Lee a n d R u s s e l l E. Poland D e p a r t m e n t of P h a r m a c o l o g y School of Medicine, the Brain Research Institute and the L a b o r a t o r y of N e u r o e n d o c r i n o l o g y U n i v e r s i t y of C a l i f o r n i a Los A n g e l e s , CA 90024 and Division of Biological P s y c h i a t r y H a r b o r - U C L A Medical C e n t e r T o r r a n c e , CA 90502 (Received in final form November i, 1985) Summary There is little information on the neuroendocrine effeets of PCP. The present study examined the effects of the acute subcutsneous administration of P C P on serum levels of cortieosterone, growth hormone and prolaetin in the male r a t . P C P increased serum levels of cortieosterone, decreased serum levels of prolactin and failed to affect growth hormone levels. The results indicate that like other drugs of abuse, P C P alters neuroendocrine function. Phencyclidine (PCP) is a major drug of abuse in the United States. It has been found to be the most frequently identified drug on toxicology screens (I) and its use appears to be increasing (2). P C P is most commonly used by adolescents and y o u n g adults (3,4); however, intoxication has been reported in infants and y o u n g children (5,6). P C P is frequently abused during pregnancy (3) and is k n o w n to be found in breast milk, amniotic fluid, and can cross the placenta (?,8). It has become apparent that ~ c o m m o n denominator of drugs of abuse is that they markedly disrupt normal neuroendocrine function and alter the plasma and tissue levels of m a n y hormones (9-13). There is limited information on the neuroendocrine effects of PCP. In a series of papers, Kopin and his associates found that P C P suppresses the release of prolactin (PRL) in the rat (14-16). However, the effects of P C P on the release of other apterior pituitary hormones in the rat have not been reported. There is n o w in vivo and in vitro evidence that P C P and opiates with sigma receptor acti-~tv share a c o m m o n receptor (i?-22). We have previously reported (23) that the sigma agonist (_+)-N-allylnormetazoeine IA preliminary report of this data was made at the Fall meeting of the American Society for Pharmacology and Experimental Therapeutics, 1985. 2To w h o m reprint requests should be sent 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Press Ltd.
292
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(NANM, also known as SKF 10,047) (24) stimulates the release of corticosterone, inhibits the release of PRL, and does not affect the release of growth hormone (GH) in the rat. The purpose of the present study was to test whether the acute administration of PCP affects the release of corticosterone and GH in the rat, and determine if the pattern of hormone release resembles that seen after the administration of NANM. Serum levels of PRL were also measured in order to further compare the effects of PCP with NANM.
Materials and Methods Male Sprague-Dawley rats (300-350 g) were obtained f r o m Charles River Breeding Laboratories (Wilmington, MA) and housed 6 per cage under a 12 h light/dark cycle (lights on 07:00-19:00 h) for 7 days prior to drug administration. The room was maintained at a constant temperature of 21°C and rat chow and water were available ad libitum. For three days prior to drug administration, the rats were removed from their cages, weighed, and injected s.c. behind the neck w i t h 0.9% saline in order to habituate them to the experimental procedure and thereby reduce the stress of handling. The experiments were performed between 10:00 and 12:00 h. Phencyclidine hydrochloride was obtained from NIDA and dissolved in distilled water. The rats were randomly divided into groups, weighed, given a s.c. injection of either PCP ( i . 0 or i0.0 mg/kg) or 0.9% saline, and returned to their cages. The injection volume was 1.0 ml/kg. The rats were sacrificed 30 or 120 min later by decapitation and trunk blood was obtained. The samples were stored at 4°C until the blood clotted. Followingcentrifugation the serum samples were stored at -20°C. Corticosterone, GII and PRL were measured by radioimmunoassay as previously described (25,26). All samples were run in duplicate within the same assay. S i n c e the data were not normally distributed, nonparametric Mann-Whitney U tests were used and the level of significance set at 0.05 to determine differences between drug and saline control groups at each time point.
Results T h e s . c . a d m i n i s t r a t i o n of PCP p r o d u c e d d o s e d e p e n d e n t i n c r e a s e s in t h e s e r u m l e v e l of c o r t i c o s t e r o n e when m e a s u r e d 30 rain a f t e r d r u g administration (Fig. 1). Corticosterone levels remained significantly e l e v a t e d 120 min a f t e r t h e h i g h e r d o s e of PCP (10.0 m g / k g ) . In c o n t r a s t , PCP failed to a f f e c t s e r u m GH l e v e l s ( F i g . 2 ) . PCP p r o d u c e d d o s e d e p e n d e n t d e c r e a s e s in s e r u m PRL ( F i g . 3) a n d PRL l e v e l s w e r e still significantly suppressed 120 rain a f t e r t h e h i g h e r d o s e of PCP (10.0 mg/kg).
Discussion The results indicate that PCP is a potent releaser of corticosterone. This finding is consistent with the report of Boggan et al. (27) who found that PCP stimulated the release of corticosterone in the mouse. It does not appear that this effect is due to PCP producing a stress response since a d e c r e a s e in s e r u m Gtt l e v e l s , a t y p i c a l s t r e s s r e s p o n s e in r a t s ( 2 8 - 3 0 ) , was not o b s e r v e d . T h e o b s e r v a t i o n t h a t PCP a d m i n i s t r a t i o n i n h i b i t s t h e r e l e a s e
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PCP and N e u r o e n d o c r i n e
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• SALINE [ ] PCP (I mg/kg) [ ] PEP ( 10 mg/kg)
////// //////j~ 77777;
300
"////%
200 CORTICOSTERONE (ng/ml)
"/////× 100
30
120 TIME (mln)
FIG. 1 The effects of the s.c. administration of PCP on serum levels of corticosterone. V a l u e s represent the mean + S.E.M. (N=7). *Significantly (p < 0.05) different from the saline controls.
• SALINE [] PCP (I mglkg) ~I PCP (10 mg/kg)
100 80 60 GH (ng/ml) 40 20
30
TIME (rain)
120
FIG. 2 The effects of the s.c. administration of PCP on serum levels of GH. Values represent the mean + S.E.M. (N=7). *Significantly (p < 0.05) different from the saline controls. of PRL while s t r e s s this conclusion.
is k n o w n
to s t i m u l a t e i t s
release
(28,29,31)
supports
While the effects of PCP have been hypothesized to be mediated via specific PCP receptors in the brain (20,22,32,33), it is not known at what leve] PCP acts to alter corticosterone and PRL release. PCP could stimulate the release of corlicosterone by interacting with target sites at the level of the central nervous system via the release of corticotrophin releasing factor, at the level of the pituitary by augmenting the release of ACTII, or by acting directly on the adrenal. Tile PCP-induced suppression of PRL release demonstrates that PCP can affect anterior pituitary hormone release.
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1986
• SALINE [] PCP(I rnglkg) [] PCP (I0 mglkg)
40
30
PRL (nglml) 20
I0.
0 30 TIME(mm)
120
FIG. 3 The effects of the s.c. administration of PCP on serum levels of PRL. Values represent the mean + S.E.M. (N=7). *Significantly (p < 0.05) different from the saline controls.
However, it is not clear if this effect is mediated by affecting the release of hypothalamic release and/or release inhibiting hormones or by a direct action on the pituitary. The finding that there are PCP binding sites located within the hypothalamus (32) suggests that PCP may alter hormone release by acting at the level of the hypothalamus, however, this remains to be determined. The pattern of corticosterone, GH and PRL release produced by PCP is very different from the effects elicited by either morphine-like agonists or naloxone-like antagonists. Morphine produces increases in s e r u m corticosterone, GH and PRL (9,23) while naloxone produces a decrease in serum levels of PRL and does not affect GH. There is some controversy as to whether opiate antagonists augment the release of corticosterone (34,35). However, the pattern of hormone release produced by PCP is identical to that seen after the administration of the sigma agonist NANM (23). Previous studies that have concluded that PCP and opiates with sigma receptor activity share a common receptor (17-22) have based their conclusions either on behavioral or in vitro binding studies. The results of the present study provide neuroendocrine data that support this hypothesis. It remains to be shown that both PCP and NANM act on the same target structures to produce their neuroendocrine effects. PCP has many of the characteristics of an opiate. PCP can produce analgesia (36) and this may account for the extreme force needed to subdue individuals under its influence. PCP is unique in that it is the only hnllucinogen that primates w i l l self-administer (37). There have also been reports of withdrawal behavior in the rat (21), monkey (38,39) and humans (40,41) following cessation of chronic treatment that resembles behavior observed after withdrawal from chronic treatment with opiates. Tolerance to the behavioral effects of PCP has been reported to develop upon repeated administration in the rat (42-44). PCP-induced temperature changes in the rat (45) and analgesia in the mouse (36) have been reported to be naloxone reversible. If PCP-induced release of corticosterone is mediated via the release of ACTH, and since ACTH and B-endorphin are released
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coneommitantly (46), a possible mechanism for some of the "opiate-like" effects of PCP is that they are due to the release of 6-endorphin. B o t h PCP a n d t h e o p i a t e s with s i g m a a c t i v i t y p r o d u c e d y s p h o r i a a n d p s y c h o t o m i m e t i c s y m p t o m a t o l o g y in h u m a n s . L a h t i a n d Collins (47) h a v e s u g g e s t e d t h a t t h e a b i l i t y of an o p i a t e to p r o d u c e d y s p h o r i a c a n b e p o s i t i v e l y c o r r e l a t e d with i t s c o r t i c o s t e r o n e r e l e a s i n g a c t i v i t y . The observation t h a t PCP a n d NANM b o t h a r e p o t e n t s t i m u l a t o r s of c o r t i c o s t e r o n e r e l e a s e s u p p o r t s t h i s h y p o t h e s i s a n d e x t e n d s it to a n o n - o p i a t e c o m p o u n d . The f i n d i n g t h a t PCP s t i m u l a t e s t h e r e l e a s e o f c o r t i c o s t e r o n e is s i g n i f i c a n t b e c a u s e g l u c o c o r t i c o i d s a r e i m p o r t a n t to t h e m s i n t e n a n c e of h o m e o s t a s i s of an o r g a n i s m . T h e r e f o r e , t h e r e a c t i o n a n d a d a p t a t i o n to a c u t e a n d c h r o n i c s t r e s s may b e a l t e r e d b y t h e a c u t e a n d p e r h a p s c h r o n i c a d m i n i s t r a t i o n o f PCP. Acknowledgement We t h a n k Ms. K a r e n R o b e r t s manuscript.
for a s s i s t a n c e in t h e p r e p a r a t i o n
of t h i s
References I. 2. 3. 4. 5. 6. 7. 8. 9. I0. Ii. 12. 13. 14. 15. 16. 17. 18. 19. 20.
C.V. SHOWALTER and E.W. THORNTON, Ill. Med. J. 151, 387-390 (1977). S.N. PRADHAN, Neurosci. Biobehav. Rev. 8, 493-501 (1984). N.L. GOLDEN, B.R. KUHNERT, R.J. SOK~L, S. MARTIER and B.S. BAGBY, Am. J. Obstet. Gynecol. 148, 254-259 (1984). R.A. RAWSON, F.S. TENNANT, Jr. and M . A . McCANN, NIDA Research Monograph 41, 483-487 (1982). H . N . KARP, N . D . --~AUFMAN and S.K. ANAND, J. Pediat. 97, 10056-1009 (1980). M.J. WELCH and G.A. CORREA, Clin. Pediat. 19, 510-514 (1980). K.R. KAUFMAN, R.A. PETRUCHA, F.N. PITTS, Jr. and M.E. WEEKS, J. Clin. Psychiat. 44, 269-270 (1983). J . M . NICHOLAS, J. LIPSHITZ and E.C. SCHREIBER, Am. J. Obstet. Gynecol. 143, 143-146 (1982). R. GEOR~--E-and N. KOKKA, Tissue Responses to Addictive Drugs, D.H. Ford and D . H . Clouet, eds., 527-540, Spectrum Publications, New Y o r k (1976). E . D . SACHAR, P . H . GRUEN, N. ALTMAN, F . S . HALPERN a n d A . G . FRANTZ, Hormones, Behavior and Psychopathology, E.J. Sachar, ed., 161-173, R a v e n P r e s s , New Y o r k (1976). T . J . CICERO, A d v . S u b . A b u s e 1, 201-254 (1980). L. T y r e y , J . P h a r m . E x p . T h e r . 213, 306-308 (1980). J . F . BRUNI, D. VAN VUGT, S. MARSHALL a n d J . MEITES, Life Sci. 21, 461-466 (1977). ~ . F . SALLER, R . L . ZERBE, M . A . BAYORH, D. LOZOVSKY a n d l . J . KOPIN, E u r . J . P h a r m . 83, 309-311 (1982). D. LOZOVSKY, C . F . SALLER, M . A . BAYORH, C . C . CHUIEH, K . C . RICE, T . R . BURKE a n d I . J . KOPIN, Life Sei. 32, 2725-2731 (1983). M . A . BAYORH, D. LOZOVSKY, K . C . RICE, -T-.R. BURKE, J r . a n d I . J . KOPIN, P h a r m . Biochem. B e h a v . 19, 365-367 (1983). S. HERLING a n d J . H . WOODS, Life Sci. 28, 1571-1584 (1981). S . G . HOLTZMAN, J . P h a r m , E x p . T h e r . - 2 - 1 4 , 614-619 (1980). S . G . HOLTZMAN, P s y c h o p h a r m a c o l o g y 7 7 , - - ~ 5 - 3 0 0 (1982). R. QUIRION, R . P . HAMMER, J r . , M. HERKENHAM a n d C . B . PERT, P r o c . Natl. A c a d . Sci. 78, 5881-5885 (1981).
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I. STAFFORD, A. TOMIE and G . C . WAGNER, D r u g Alc. Dep. 12, 151-156 (1983). J.P VINCENT, B. KARTALOVSKI, P. GENESTE, J.M. KAMENKA and M. LAZDUNSKI, Proc. Natl. Acad. Sci. USA 76, 4678-4682 (1979). R. PECHNICK, R. GEORGE and R.E. POLAND, J. Pharm. Exp. Ther. 232, 163-169 (1985). W.R. MARTIN, C . G . EADES, J.A. THOMPSON, R . E . IIUPPLER and P.E. GILBERT, J. Pharm. Exp. Ther. 197, 517-532 (1976). R . E . POLAND, M.E. WEICHSEL and R.T. RUBIN, Endocrinology 108, 1049-1054 (1981). R . E . POLAND, R.T. RUBIN and M.E. WEICHSEL, Psychoneuroendocrinology 5, 209-224 (1980). W.O. BOG-GAN, C.J. WALLIS and M.H. OWENS, Life Sci. 30, 1581-1586 (1982). L. KRULICH, E. HEFCO, P. ILLNER and C . B . READ, Neuroendocrinology 16, 293-311 (1974). S.M. McCANN, K. AJIKA, C.P. FAWCETT, E. HEFCO, P. ILLNER, A. NEGRO-VILAR, R. ORIAS, J.T. WATSON and L. KRULICH, P r o c e e d i n g s of t h e I n t e r n a t i o n a l S y m p o s i u m , Hormones, Metabolism a n d S t r e s s - R e c e n t P r o g r e s s a n d P e r s p e c t i v e s , S. Nemeth, e d . , 67-77, P u b l i s h i n g House of Slovak A c a d e m y of S c i e n c e s , B r a t i s l a v a (1973). R. COLLU, J . - C . JEQUIER, J. LETARTE, G. LEBOEUF a n d J . R . DUCHARME, N e u r o e n d o e r i n o l o g y 11, 183-190 (1973). K.-D. DOHLER, K. G A R T N E R ~ - - A . VON ZUR M['~NCHEN a n d U. DOHLER, Acta E n d o . 86, 489-497 (1977). S.R. ZUKIN, M.L. F I T Z - S Y A G E , R. NICHTENHAUSER a n d R . S . ZUKIN, B r a i n Res. 258, 277-284 (1983). R . Y . HAMPTON, F. MEDZIHRADSKY, J.II. WOODS and P.J. DAHLSTROM, Life Sci. 30, 2147-2154 (1982). R.M. EISENBERG, Life Sci. 34, 1185-1191 (1984). R . N . PECHNICK, R. GEORGE and R . E . POLAND, J. Pharm. Exp. Ther. 232, 170-177 (1985). Y. ITZHAK, A. KALIR, B . A . WEISSMAN and W. COHEN, Eur. J. Pharm. 72, 305-311 (1981). R . L . BALSTER and L.D. CHAIT, Clin. Tox. 9, 513-528 (1976). R . L . BALSTER and W.L. WOOLVERTON, Psy~hopharmaeology 70, 5-10 (1980). B . L . SLIFER, R . L . BALSTER and W.L. WOOLVERTON, J. Pharm. Exp. Ther. 230, 399-406 (1984). M . A . FAUMAN and B.J. FAUMAN, J. Psychedelic Dru~s 12, 307-315 (1980). F.S. TENNANT, J r . , R.A. RAWSON a n d M. McCANN, Am. J. P s y c h i a t . 138, 845-847 (1981). W.L. WOOLVERTON a n d R . L . BALSTE)2, P s y c h o p h a r r n a c o l o g y 64, 19-24 (1979). G . C . WAGNER, J. GARDNER, J. TSIGAS a n d D . B . MASTERS, D r u g a n d Alc. Dep. 13, 225-234 (1984). T . F . MURRAY, Life Sci. 22, 195-202 (1978). S . D . GLICK a n d R . A . GUIDO, Science 217, 1272-1273 (1982). R. GUILLEMIN, T. VARGO, J. ROSSIER, S. MINICK, N. LING, C. RIVIER, W. VALE a n d F. BLOOM, Science 197, 1367-1369 (1977). R . A . LAHTI a n d P . J . COLI,INS, P h a r m . Biochem. B e h a v . 17, 107-109 (1982).
Pergamon Press
THE EFFECTS OF THE ACUTE ADMINISTRATION OF PHENCYCLIDINE HYDROCHLORIDE (PCP) ON THE RELEASE OF CORTICOSTERONE, GROWTH HORMONE AND PROLACTIN IN THE RAT I R o b e r t N. P e c h r i c k , R o b e r t George 2, R a n d a l l J. Lee a n d R u s s e l l E. Poland D e p a r t m e n t of P h a r m a c o l o g y School of Medicine, the Brain Research Institute and the L a b o r a t o r y of N e u r o e n d o c r i n o l o g y U n i v e r s i t y of C a l i f o r n i a Los A n g e l e s , CA 90024 and Division of Biological P s y c h i a t r y H a r b o r - U C L A Medical C e n t e r T o r r a n c e , CA 90502 (Received in final form November i, 1985) Summary There is little information on the neuroendocrine effeets of PCP. The present study examined the effects of the acute subcutsneous administration of P C P on serum levels of cortieosterone, growth hormone and prolaetin in the male r a t . P C P increased serum levels of cortieosterone, decreased serum levels of prolactin and failed to affect growth hormone levels. The results indicate that like other drugs of abuse, P C P alters neuroendocrine function. Phencyclidine (PCP) is a major drug of abuse in the United States. It has been found to be the most frequently identified drug on toxicology screens (I) and its use appears to be increasing (2). P C P is most commonly used by adolescents and y o u n g adults (3,4); however, intoxication has been reported in infants and y o u n g children (5,6). P C P is frequently abused during pregnancy (3) and is k n o w n to be found in breast milk, amniotic fluid, and can cross the placenta (?,8). It has become apparent that ~ c o m m o n denominator of drugs of abuse is that they markedly disrupt normal neuroendocrine function and alter the plasma and tissue levels of m a n y hormones (9-13). There is limited information on the neuroendocrine effects of PCP. In a series of papers, Kopin and his associates found that P C P suppresses the release of prolactin (PRL) in the rat (14-16). However, the effects of P C P on the release of other apterior pituitary hormones in the rat have not been reported. There is n o w in vivo and in vitro evidence that P C P and opiates with sigma receptor acti-~tv share a c o m m o n receptor (i?-22). We have previously reported (23) that the sigma agonist (_+)-N-allylnormetazoeine IA preliminary report of this data was made at the Fall meeting of the American Society for Pharmacology and Experimental Therapeutics, 1985. 2To w h o m reprint requests should be sent 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Press Ltd.
292
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3, 1986
(NANM, also known as SKF 10,047) (24) stimulates the release of corticosterone, inhibits the release of PRL, and does not affect the release of growth hormone (GH) in the rat. The purpose of the present study was to test whether the acute administration of PCP affects the release of corticosterone and GH in the rat, and determine if the pattern of hormone release resembles that seen after the administration of NANM. Serum levels of PRL were also measured in order to further compare the effects of PCP with NANM.
Materials and Methods Male Sprague-Dawley rats (300-350 g) were obtained f r o m Charles River Breeding Laboratories (Wilmington, MA) and housed 6 per cage under a 12 h light/dark cycle (lights on 07:00-19:00 h) for 7 days prior to drug administration. The room was maintained at a constant temperature of 21°C and rat chow and water were available ad libitum. For three days prior to drug administration, the rats were removed from their cages, weighed, and injected s.c. behind the neck w i t h 0.9% saline in order to habituate them to the experimental procedure and thereby reduce the stress of handling. The experiments were performed between 10:00 and 12:00 h. Phencyclidine hydrochloride was obtained from NIDA and dissolved in distilled water. The rats were randomly divided into groups, weighed, given a s.c. injection of either PCP ( i . 0 or i0.0 mg/kg) or 0.9% saline, and returned to their cages. The injection volume was 1.0 ml/kg. The rats were sacrificed 30 or 120 min later by decapitation and trunk blood was obtained. The samples were stored at 4°C until the blood clotted. Followingcentrifugation the serum samples were stored at -20°C. Corticosterone, GII and PRL were measured by radioimmunoassay as previously described (25,26). All samples were run in duplicate within the same assay. S i n c e the data were not normally distributed, nonparametric Mann-Whitney U tests were used and the level of significance set at 0.05 to determine differences between drug and saline control groups at each time point.
Results T h e s . c . a d m i n i s t r a t i o n of PCP p r o d u c e d d o s e d e p e n d e n t i n c r e a s e s in t h e s e r u m l e v e l of c o r t i c o s t e r o n e when m e a s u r e d 30 rain a f t e r d r u g administration (Fig. 1). Corticosterone levels remained significantly e l e v a t e d 120 min a f t e r t h e h i g h e r d o s e of PCP (10.0 m g / k g ) . In c o n t r a s t , PCP failed to a f f e c t s e r u m GH l e v e l s ( F i g . 2 ) . PCP p r o d u c e d d o s e d e p e n d e n t d e c r e a s e s in s e r u m PRL ( F i g . 3) a n d PRL l e v e l s w e r e still significantly suppressed 120 rain a f t e r t h e h i g h e r d o s e of PCP (10.0 mg/kg).
Discussion The results indicate that PCP is a potent releaser of corticosterone. This finding is consistent with the report of Boggan et al. (27) who found that PCP stimulated the release of corticosterone in the mouse. It does not appear that this effect is due to PCP producing a stress response since a d e c r e a s e in s e r u m Gtt l e v e l s , a t y p i c a l s t r e s s r e s p o n s e in r a t s ( 2 8 - 3 0 ) , was not o b s e r v e d . T h e o b s e r v a t i o n t h a t PCP a d m i n i s t r a t i o n i n h i b i t s t h e r e l e a s e
Vol.
38, No.
3, 1986
PCP and N e u r o e n d o c r i n e
Function
293
• SALINE [ ] PCP (I mg/kg) [ ] PEP ( 10 mg/kg)
////// //////j~ 77777;
300
"////%
200 CORTICOSTERONE (ng/ml)
"/////× 100
30
120 TIME (mln)
FIG. 1 The effects of the s.c. administration of PCP on serum levels of corticosterone. V a l u e s represent the mean + S.E.M. (N=7). *Significantly (p < 0.05) different from the saline controls.
• SALINE [] PCP (I mglkg) ~I PCP (10 mg/kg)
100 80 60 GH (ng/ml) 40 20
30
TIME (rain)
120
FIG. 2 The effects of the s.c. administration of PCP on serum levels of GH. Values represent the mean + S.E.M. (N=7). *Significantly (p < 0.05) different from the saline controls. of PRL while s t r e s s this conclusion.
is k n o w n
to s t i m u l a t e i t s
release
(28,29,31)
supports
While the effects of PCP have been hypothesized to be mediated via specific PCP receptors in the brain (20,22,32,33), it is not known at what leve] PCP acts to alter corticosterone and PRL release. PCP could stimulate the release of corlicosterone by interacting with target sites at the level of the central nervous system via the release of corticotrophin releasing factor, at the level of the pituitary by augmenting the release of ACTII, or by acting directly on the adrenal. Tile PCP-induced suppression of PRL release demonstrates that PCP can affect anterior pituitary hormone release.
294
PCP and Neuroendocrine
Function
Vol.
38, No.
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1986
• SALINE [] PCP(I rnglkg) [] PCP (I0 mglkg)
40
30
PRL (nglml) 20
I0.
0 30 TIME(mm)
120
FIG. 3 The effects of the s.c. administration of PCP on serum levels of PRL. Values represent the mean + S.E.M. (N=7). *Significantly (p < 0.05) different from the saline controls.
However, it is not clear if this effect is mediated by affecting the release of hypothalamic release and/or release inhibiting hormones or by a direct action on the pituitary. The finding that there are PCP binding sites located within the hypothalamus (32) suggests that PCP may alter hormone release by acting at the level of the hypothalamus, however, this remains to be determined. The pattern of corticosterone, GH and PRL release produced by PCP is very different from the effects elicited by either morphine-like agonists or naloxone-like antagonists. Morphine produces increases in s e r u m corticosterone, GH and PRL (9,23) while naloxone produces a decrease in serum levels of PRL and does not affect GH. There is some controversy as to whether opiate antagonists augment the release of corticosterone (34,35). However, the pattern of hormone release produced by PCP is identical to that seen after the administration of the sigma agonist NANM (23). Previous studies that have concluded that PCP and opiates with sigma receptor activity share a common receptor (17-22) have based their conclusions either on behavioral or in vitro binding studies. The results of the present study provide neuroendocrine data that support this hypothesis. It remains to be shown that both PCP and NANM act on the same target structures to produce their neuroendocrine effects. PCP has many of the characteristics of an opiate. PCP can produce analgesia (36) and this may account for the extreme force needed to subdue individuals under its influence. PCP is unique in that it is the only hnllucinogen that primates w i l l self-administer (37). There have also been reports of withdrawal behavior in the rat (21), monkey (38,39) and humans (40,41) following cessation of chronic treatment that resembles behavior observed after withdrawal from chronic treatment with opiates. Tolerance to the behavioral effects of PCP has been reported to develop upon repeated administration in the rat (42-44). PCP-induced temperature changes in the rat (45) and analgesia in the mouse (36) have been reported to be naloxone reversible. If PCP-induced release of corticosterone is mediated via the release of ACTH, and since ACTH and B-endorphin are released
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coneommitantly (46), a possible mechanism for some of the "opiate-like" effects of PCP is that they are due to the release of 6-endorphin. B o t h PCP a n d t h e o p i a t e s with s i g m a a c t i v i t y p r o d u c e d y s p h o r i a a n d p s y c h o t o m i m e t i c s y m p t o m a t o l o g y in h u m a n s . L a h t i a n d Collins (47) h a v e s u g g e s t e d t h a t t h e a b i l i t y of an o p i a t e to p r o d u c e d y s p h o r i a c a n b e p o s i t i v e l y c o r r e l a t e d with i t s c o r t i c o s t e r o n e r e l e a s i n g a c t i v i t y . The observation t h a t PCP a n d NANM b o t h a r e p o t e n t s t i m u l a t o r s of c o r t i c o s t e r o n e r e l e a s e s u p p o r t s t h i s h y p o t h e s i s a n d e x t e n d s it to a n o n - o p i a t e c o m p o u n d . The f i n d i n g t h a t PCP s t i m u l a t e s t h e r e l e a s e o f c o r t i c o s t e r o n e is s i g n i f i c a n t b e c a u s e g l u c o c o r t i c o i d s a r e i m p o r t a n t to t h e m s i n t e n a n c e of h o m e o s t a s i s of an o r g a n i s m . T h e r e f o r e , t h e r e a c t i o n a n d a d a p t a t i o n to a c u t e a n d c h r o n i c s t r e s s may b e a l t e r e d b y t h e a c u t e a n d p e r h a p s c h r o n i c a d m i n i s t r a t i o n o f PCP. Acknowledgement We t h a n k Ms. K a r e n R o b e r t s manuscript.
for a s s i s t a n c e in t h e p r e p a r a t i o n
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