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Phencyclidine-induced decrease of methionine-enkephalin levels in mouse brain
European Journal of Pharmacology, 86 (1983) 271-273
271
Elsevier Biomedical Press
Short communication P H E N C Y C L I D I N E - I N D U C E D D E C R E A S E OF M E T H I O N I N E - E N K E P H A L I N LEVELS IN M O U S E BRAIN T O S H I T A K A N A B E S H I M A +, M A S A Y U K I H I R A M A T S U . M A N A B U A M A N O , HIROSHI F U R U K A W A * and TSUTOMU KAMEYAMA
Department of Chemical Pharmacology and * Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan Received 17 September 1982, accepted 21 October 1982
T. NABESHIMA, M. HIRAMATSU, M. AMANO, H. FURUKAWA * and T. KAMEYAMA, Phencyclidine-induced decrease of methionine-enkephalin levels in mouse brain, European J. Pharmacol. 86 (1983) 271-273. The effects of acute administration of phencyclidine (PCP) on the steady state levels of methionine-enkephalin in discrete brain areas were investigated in mice. The methionine-enkephalin levels in the medulla oblongata-pons and the midbrain were decreased by the administration of PCP. However, PCP induced no change of the methionine-enkephalin levels in other brain areas at the dose range of 5-20 mg/kg. These results suggest that the pharmacological effects of PCP may involve changes in enkephalinergic neuronal activity. Medulla oblongata-pons
Methionine-enkephalin
Midbrain
1. Introduction Reports of psychotomimetic actions of narcotics and certain narcotic antagonists have led to the suggestion that some behavioral disorders may be associated with an excess of natural opiate-like compounds, endorphins at specific sites in the central nervous system (CNS) (Wahlstr6m and Terenius, 1981). One of the most intriguing aspects of endorphins is their possible relation to hallucinatory states in schizophrenia. In an early study, Terenius et al. (1976) have reported that neuroleptic treatment of the symptoms of schizophrenia decreased the level of an endorphin fraction of CSF. In addition, the administration of the opiate antagonist naloxone produced an antianxiety effect in patients with schizophrenia (Gunne et al., 1977; Berger et al., 1979). On the other hand, phencyclidine (PCP) is known to be a potent psychotomimetic agent and produces long-
+ To whom all correspondence should be addressed at the Dept. of Chemical Pharmacology. 0014-2999/83/0000-0000/$03.00 © 1983 Elsevier Biomedical Press
Phencyclidine
lasting psychosis thought to resemble schizophrenia (Burns and Lerner, 1976). In addition, previous pharmacological analyses of the effects of PCP have indicated that this drug produces analgesic effects and interacts with morphine and opiate receptor sites in the CNS (Vincent et al., 1978; Nabeshima et al., 1981). The present study was designed to investigate the effect of acute administration of PCP on steady state levels of methionine-enkephalin in discrete brain areas of mice.
2. Materials and methods Male ddY mice (Shizuoka Laboratory Animal Center, Shizuoka, Japan) were given either saline or PCP-HC1 (5, 10 or 20 m g / k g , i.p.). The mice were sacrificed by microwave irradiation with a microwave applicator (TMW-6402A, Toshiba Co., Tokyo, Japan) for 1.0 s at 5 kW 30, 60 and 120 rain after the injection. Each brain was dissected into 7 discrete areas as follows: the striatum, the hypothalamus, the medulla oblongata-pons, the
272 m i d b r a i n , the cortex, the h i p p o c a m p u s a n d the cerebellum. The c o n c e n t r a t i o n s of m e t h i o n i n e - e n kephalin in 5 different b r a i n areas were det e r m i n e d by a previously described m e t h o d using high-pressure liquid c h r o m a t o g r a p h y with electrochemical detector ( N a b e s h i m a et al., 1982). The m e t h i o n i n e - e n k e p h a l i n levels in the cerebellum a n d the h i p p o c a m p u s were not d e t e r m i n e d since the c o n c e n t r a t i o n s in these areas were very low or not detectable ( N a b e s h i m a et al., 1982). Significant differences were calculated according to the twotailed Student's t-test.
3. Results Table 1 kephalin in with either decrease of
shows the levels of m e t h i o n i n e - e n the discrete b r a i n areas of mice treated PCP or saline. There was a significant the m e t h i o n i n e - e n k e p h a l i n level in the
m e d u l l a o b l o n g a t a - p o n s 60 m i n after the administration of PCP at doses ranging from 5 to 20 m g / k g . F u r t h e r m o r e , the decreased level of m e t h i o n i n e - e n k e p h a l i n in the m e d u l l a oblongatap o n s was also observed 30 a n d 120 m i n after the a d m i n i s t r a t i o n of PCP 10 m g / k g . O n the other hand, at the 5 m g / k g dose, the effect of PCP on m e t h i o n i n e - e n k e p h a l i n level was detected 60 min, b u t not 30 a n d 120 min after its a d m i n i s t r a t i o n . In addition, the m e t h i o n i n e - e n k e p h a l i n level in the m i d b r a i n was also significantly decreased 60 min after the a d m i n i s t r a t i o n of PCP 20 m g / k g compared to the control. However, low doses of PCP (5 a n d 10 m g / k g ) failed to c h a n g e the m e t h i o n i n e - e n k e p h a l i n level in the midbrain. At the 5-20 m g / k g dose range, no significant changes of m e t h i o n i n e - e n k e p h a l i n level were observed in the striatum, the cortex a n d the h y p o t h a l a m u s of PCP-treated mice as c o m p a r e d to the control.
TABLE 1 Effect of PCP administration on the methionine-enkephalin levels in discrete brain areas of mice ~ and time course of the effect of PCP in the medulla oblongata-pons b. Dose (mg/kg)
PCP 0 5 10 20
Dose (mg/kg)
Methionine-enkephalin(ng/g wet tissue) a Striatum
Hypothalamus
Medulla oblonggata-pons
Midbrain
Cortex
C e r e b e l l u m Hippocampus
2024_+119(12) 2430-+305(4) 2297_+139 (4) 2077_+19 (4)
1255+97(4) 1399_+88(4) 1247_+ 109(4) 1264_+ 117(4)
508-+12(12) 437_+24c(4) 443_+ 16 c ( 4 ) 405 _+18 d(4)
443-+13(4) 364_+31(4) 444_+33(4) 343_+9 ~(4)
369-+28(4) 374_+37(4) 308_+ 4(4) 322_+ 19(4)
180_+7(4) N.D. (4) N.D. (4) N.D. (4)
None None None None
Methionine-enkephalin(ng/g wet tissue) in the medulla oblongata-pons b Time after administration (min)
PCP 0 5 10
30
60
120
501+23 (4) 508 _+22 (4) 417 -+20c(4)
521+22 (4) 437 5=24 c (4) 443 _+16 a(4)
502_+21 (4) 522 -+30 (4) 415 -+ 19 c(4)
a Mice were sacrificed by microwaveirradiation 60 min after PCP i.p. administration, b Mice were sacrificed by microwaveirradiation 30, 60 and 120 rain after PCP i.p. administration Each sample of the discrete brain areas was a pool from 3 brains. The numbers in parentheses show the number of experiments, c p < 0.05, 0 p < 0.001 vs. control group. N.C.: not determined.
273 4. Discussion T h e present investigation d e m o n s t r a t e s for the first time that acute P C P t r e a t m e n t can cause r a p i d changes in the m e t h i o n i n e - e n k e p h a l i n level o f restricted areas of the CNS. The effects are clearly limited to two structures, the m e d u l l a obl o n g a t a - p o n s a n d the m i d b r a i n . The decrease in s t e a d y state levels of m e t h i o n i n e - e n k e p h a l i n could result from a c h a n g e in the b a l a n c e b e t w e e n synthesis, release a n d d e g r a d a t i o n of the comp o u n d . F r o m the highly localized action of PCP on the m e t h i o n e - e n k e p h a l i n levels in these areas we can infer that P C P m a y not act on generalized e n z y m e s that m e t a b o l i z e m e t h i o n i n e - e n k e p h a l i n b u t that its action d e p e n d s on some specific regul a t o r y m e c h a n i s m related to the s y n a p t i c organization of the m e d u l l a o b l o n g a t a - p o n s a n d / o r the midbrain. A s d e s c r i b e d in the I n t r o d u c t i o n , the level of e n d o r p h i n s of C S F in the p a t i e n t s with schizophr e n i a is d e c r e a s e d b y a n e u r o l e p t i c which is well k n o w n as d o p a m i n e r e c e p t o r blocker. In a d d i t i o n , h a l o p e r i d o l antagonizes the P C P - i n d u c e d stereo t y p e d b e h a v i o r s a n d l o c o m o t o r activity (Castellani a n d A d a m s , 1981). Therefore, this effect of P C P m a y be due to its direct action on endoge n o u s e n k e p h a l i n e r g i c systems or to the interaction of these e n k e p h a l i n e r g i c systems with o t h e r p h y s i o l o g i c a l systems, such as the central catechola m i n e r g i c system. O n the o t h e r hand, b r a i n levels o f acetylcholine reflect changes in the firing rate of cholinergic n e u r o n e s ( R o m m e l s p a c h e r a n d K u h a r , 1974). The increase in firing rate is a c c o m p a n i e d b y a decrease in the levels of this transmitter. If m e t h i o n i n e - e n k e p h a l i n is a n e u r o t r a n s m i t t e r or n e u r o m o d u l a t o r of n e u r o n a l systems, the decrease of m e t h i o n i n e - e n k e p h a l i n levels in the m e d u l l a o b l o n g a t a - p o n s a n d the m i d b r a i n might reflect a higher e n k e p h a l i n e r g i c n e u r o n a l activity due to an i n c r e a s e d release. A l t h o u g h P C P seems to activate the enk e p h a l i n e r g i c systems in the CNS, this does not necessarily i m p l y that all of the p s y c h o t o m i n e t i c a c t i o n s of P C P are m e d i a t e d b y m e t h i o n i n e - e n kephalin. There are a n u m b e r of p e p t i d e s and
o t h e r n e u r o t r a n s m i t t e r s located in the CNS. The p a r t i c i p a t i o n o f these n e u r o h u m o r s in the p h a r m a c o l o g i c a l actions of PCP, including psychot o m i m e t i c actions, r e m a i n s to b e elucidated.
Acknowledgement This study was supported by a grant No. 57570089 from the Ministry of Education, Japan
References Berger, P.A., S.J. Watson, H. Akil and J.D. Barchas, 1979, Naloxone administration in chronic hallucinating schizophrenic patients, in: Endorphins in Mental Health Research, eds. E. Usdin, W.E. Bunney, Jr. and N.S. Kline (Oxford University Press, New York) p. 423. Burns, R.S. and S.E. Lerner, 1976, Perspectives: Acute phencyclidine intoxication, Clin. Toxicol. 9, 477. Castellani, S. and P.M. Adams, 1981, Effects of dopaminergic drugs on phencyclidine-induced behavior in the rat, Neuropharmacology 20, 371. Gunne, L.-M., L. LindstriSm and L. Terenius, 1977, Naloxoneinduced reversal of schizophrenic hallucinations, J. Neural Transm. 40, 13 Nabeshima, T., M. Hiramatsu, S. Noma, M. Ukai, M. Amano and T. Kameyama, 1982, Determination of methionine-enkephalin, norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid(DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) in brain by high-pressure liquid chromatography with electrochemical detector, Res. Commun. Chem. Pathol. Pharmacol. 35, 421. Nabeshima, T., S.P. Sivam, T. Kameyama and I.K. Ho, 1981, Interaction between morphine and phencyclicine: Intoxication and cross-tolerance, in: Advances in Endogenous and Exogenous Opioids, eds. H. Takagi and E.J. Simon (Kodansha Ltd., Tokyo) p. 338. Rommelspacher, H. and M.J. Kuhar, 1974, Effects of electrical stimulation on acetylcholine levels in central cholinergic nerve terminals, Brain Res. 81,243. Terenius, L., A. Wahlstr0m, L. LindstriSm and E. WiderliSv, 1976, Increased CSF levels of endorphins in chronic psychosis, Neurosci. Lett. 3, 157. Vincent, J.P., D. Cavey, J.M. Kamenka, P. Geneste and M. Lazdunski, 1978, Interaction of phencyclidines with the muscarinic and opiate receptors in the central nervous system, Brain Res. 152, 176. Wahlstr6m, A. and L. Terenius, 1981, Endorphin hypothesis of schizophrenia, in: The role of endorphins in neuropsychiatry, ed. H.M. Emrich (Karger, Basel) p. 181.
271
Elsevier Biomedical Press
Short communication P H E N C Y C L I D I N E - I N D U C E D D E C R E A S E OF M E T H I O N I N E - E N K E P H A L I N LEVELS IN M O U S E BRAIN T O S H I T A K A N A B E S H I M A +, M A S A Y U K I H I R A M A T S U . M A N A B U A M A N O , HIROSHI F U R U K A W A * and TSUTOMU KAMEYAMA
Department of Chemical Pharmacology and * Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan Received 17 September 1982, accepted 21 October 1982
T. NABESHIMA, M. HIRAMATSU, M. AMANO, H. FURUKAWA * and T. KAMEYAMA, Phencyclidine-induced decrease of methionine-enkephalin levels in mouse brain, European J. Pharmacol. 86 (1983) 271-273. The effects of acute administration of phencyclidine (PCP) on the steady state levels of methionine-enkephalin in discrete brain areas were investigated in mice. The methionine-enkephalin levels in the medulla oblongata-pons and the midbrain were decreased by the administration of PCP. However, PCP induced no change of the methionine-enkephalin levels in other brain areas at the dose range of 5-20 mg/kg. These results suggest that the pharmacological effects of PCP may involve changes in enkephalinergic neuronal activity. Medulla oblongata-pons
Methionine-enkephalin
Midbrain
1. Introduction Reports of psychotomimetic actions of narcotics and certain narcotic antagonists have led to the suggestion that some behavioral disorders may be associated with an excess of natural opiate-like compounds, endorphins at specific sites in the central nervous system (CNS) (Wahlstr6m and Terenius, 1981). One of the most intriguing aspects of endorphins is their possible relation to hallucinatory states in schizophrenia. In an early study, Terenius et al. (1976) have reported that neuroleptic treatment of the symptoms of schizophrenia decreased the level of an endorphin fraction of CSF. In addition, the administration of the opiate antagonist naloxone produced an antianxiety effect in patients with schizophrenia (Gunne et al., 1977; Berger et al., 1979). On the other hand, phencyclidine (PCP) is known to be a potent psychotomimetic agent and produces long-
+ To whom all correspondence should be addressed at the Dept. of Chemical Pharmacology. 0014-2999/83/0000-0000/$03.00 © 1983 Elsevier Biomedical Press
Phencyclidine
lasting psychosis thought to resemble schizophrenia (Burns and Lerner, 1976). In addition, previous pharmacological analyses of the effects of PCP have indicated that this drug produces analgesic effects and interacts with morphine and opiate receptor sites in the CNS (Vincent et al., 1978; Nabeshima et al., 1981). The present study was designed to investigate the effect of acute administration of PCP on steady state levels of methionine-enkephalin in discrete brain areas of mice.
2. Materials and methods Male ddY mice (Shizuoka Laboratory Animal Center, Shizuoka, Japan) were given either saline or PCP-HC1 (5, 10 or 20 m g / k g , i.p.). The mice were sacrificed by microwave irradiation with a microwave applicator (TMW-6402A, Toshiba Co., Tokyo, Japan) for 1.0 s at 5 kW 30, 60 and 120 rain after the injection. Each brain was dissected into 7 discrete areas as follows: the striatum, the hypothalamus, the medulla oblongata-pons, the
272 m i d b r a i n , the cortex, the h i p p o c a m p u s a n d the cerebellum. The c o n c e n t r a t i o n s of m e t h i o n i n e - e n kephalin in 5 different b r a i n areas were det e r m i n e d by a previously described m e t h o d using high-pressure liquid c h r o m a t o g r a p h y with electrochemical detector ( N a b e s h i m a et al., 1982). The m e t h i o n i n e - e n k e p h a l i n levels in the cerebellum a n d the h i p p o c a m p u s were not d e t e r m i n e d since the c o n c e n t r a t i o n s in these areas were very low or not detectable ( N a b e s h i m a et al., 1982). Significant differences were calculated according to the twotailed Student's t-test.
3. Results Table 1 kephalin in with either decrease of
shows the levels of m e t h i o n i n e - e n the discrete b r a i n areas of mice treated PCP or saline. There was a significant the m e t h i o n i n e - e n k e p h a l i n level in the
m e d u l l a o b l o n g a t a - p o n s 60 m i n after the administration of PCP at doses ranging from 5 to 20 m g / k g . F u r t h e r m o r e , the decreased level of m e t h i o n i n e - e n k e p h a l i n in the m e d u l l a oblongatap o n s was also observed 30 a n d 120 m i n after the a d m i n i s t r a t i o n of PCP 10 m g / k g . O n the other hand, at the 5 m g / k g dose, the effect of PCP on m e t h i o n i n e - e n k e p h a l i n level was detected 60 min, b u t not 30 a n d 120 min after its a d m i n i s t r a t i o n . In addition, the m e t h i o n i n e - e n k e p h a l i n level in the m i d b r a i n was also significantly decreased 60 min after the a d m i n i s t r a t i o n of PCP 20 m g / k g compared to the control. However, low doses of PCP (5 a n d 10 m g / k g ) failed to c h a n g e the m e t h i o n i n e - e n k e p h a l i n level in the midbrain. At the 5-20 m g / k g dose range, no significant changes of m e t h i o n i n e - e n k e p h a l i n level were observed in the striatum, the cortex a n d the h y p o t h a l a m u s of PCP-treated mice as c o m p a r e d to the control.
TABLE 1 Effect of PCP administration on the methionine-enkephalin levels in discrete brain areas of mice ~ and time course of the effect of PCP in the medulla oblongata-pons b. Dose (mg/kg)
PCP 0 5 10 20
Dose (mg/kg)
Methionine-enkephalin(ng/g wet tissue) a Striatum
Hypothalamus
Medulla oblonggata-pons
Midbrain
Cortex
C e r e b e l l u m Hippocampus
2024_+119(12) 2430-+305(4) 2297_+139 (4) 2077_+19 (4)
1255+97(4) 1399_+88(4) 1247_+ 109(4) 1264_+ 117(4)
508-+12(12) 437_+24c(4) 443_+ 16 c ( 4 ) 405 _+18 d(4)
443-+13(4) 364_+31(4) 444_+33(4) 343_+9 ~(4)
369-+28(4) 374_+37(4) 308_+ 4(4) 322_+ 19(4)
180_+7(4) N.D. (4) N.D. (4) N.D. (4)
None None None None
Methionine-enkephalin(ng/g wet tissue) in the medulla oblongata-pons b Time after administration (min)
PCP 0 5 10
30
60
120
501+23 (4) 508 _+22 (4) 417 -+20c(4)
521+22 (4) 437 5=24 c (4) 443 _+16 a(4)
502_+21 (4) 522 -+30 (4) 415 -+ 19 c(4)
a Mice were sacrificed by microwaveirradiation 60 min after PCP i.p. administration, b Mice were sacrificed by microwaveirradiation 30, 60 and 120 rain after PCP i.p. administration Each sample of the discrete brain areas was a pool from 3 brains. The numbers in parentheses show the number of experiments, c p < 0.05, 0 p < 0.001 vs. control group. N.C.: not determined.
273 4. Discussion T h e present investigation d e m o n s t r a t e s for the first time that acute P C P t r e a t m e n t can cause r a p i d changes in the m e t h i o n i n e - e n k e p h a l i n level o f restricted areas of the CNS. The effects are clearly limited to two structures, the m e d u l l a obl o n g a t a - p o n s a n d the m i d b r a i n . The decrease in s t e a d y state levels of m e t h i o n i n e - e n k e p h a l i n could result from a c h a n g e in the b a l a n c e b e t w e e n synthesis, release a n d d e g r a d a t i o n of the comp o u n d . F r o m the highly localized action of PCP on the m e t h i o n e - e n k e p h a l i n levels in these areas we can infer that P C P m a y not act on generalized e n z y m e s that m e t a b o l i z e m e t h i o n i n e - e n k e p h a l i n b u t that its action d e p e n d s on some specific regul a t o r y m e c h a n i s m related to the s y n a p t i c organization of the m e d u l l a o b l o n g a t a - p o n s a n d / o r the midbrain. A s d e s c r i b e d in the I n t r o d u c t i o n , the level of e n d o r p h i n s of C S F in the p a t i e n t s with schizophr e n i a is d e c r e a s e d b y a n e u r o l e p t i c which is well k n o w n as d o p a m i n e r e c e p t o r blocker. In a d d i t i o n , h a l o p e r i d o l antagonizes the P C P - i n d u c e d stereo t y p e d b e h a v i o r s a n d l o c o m o t o r activity (Castellani a n d A d a m s , 1981). Therefore, this effect of P C P m a y be due to its direct action on endoge n o u s e n k e p h a l i n e r g i c systems or to the interaction of these e n k e p h a l i n e r g i c systems with o t h e r p h y s i o l o g i c a l systems, such as the central catechola m i n e r g i c system. O n the o t h e r hand, b r a i n levels o f acetylcholine reflect changes in the firing rate of cholinergic n e u r o n e s ( R o m m e l s p a c h e r a n d K u h a r , 1974). The increase in firing rate is a c c o m p a n i e d b y a decrease in the levels of this transmitter. If m e t h i o n i n e - e n k e p h a l i n is a n e u r o t r a n s m i t t e r or n e u r o m o d u l a t o r of n e u r o n a l systems, the decrease of m e t h i o n i n e - e n k e p h a l i n levels in the m e d u l l a o b l o n g a t a - p o n s a n d the m i d b r a i n might reflect a higher e n k e p h a l i n e r g i c n e u r o n a l activity due to an i n c r e a s e d release. A l t h o u g h P C P seems to activate the enk e p h a l i n e r g i c systems in the CNS, this does not necessarily i m p l y that all of the p s y c h o t o m i n e t i c a c t i o n s of P C P are m e d i a t e d b y m e t h i o n i n e - e n kephalin. There are a n u m b e r of p e p t i d e s and
o t h e r n e u r o t r a n s m i t t e r s located in the CNS. The p a r t i c i p a t i o n o f these n e u r o h u m o r s in the p h a r m a c o l o g i c a l actions of PCP, including psychot o m i m e t i c actions, r e m a i n s to b e elucidated.
Acknowledgement This study was supported by a grant No. 57570089 from the Ministry of Education, Japan
References Berger, P.A., S.J. Watson, H. Akil and J.D. Barchas, 1979, Naloxone administration in chronic hallucinating schizophrenic patients, in: Endorphins in Mental Health Research, eds. E. Usdin, W.E. Bunney, Jr. and N.S. Kline (Oxford University Press, New York) p. 423. Burns, R.S. and S.E. Lerner, 1976, Perspectives: Acute phencyclidine intoxication, Clin. Toxicol. 9, 477. Castellani, S. and P.M. Adams, 1981, Effects of dopaminergic drugs on phencyclidine-induced behavior in the rat, Neuropharmacology 20, 371. Gunne, L.-M., L. LindstriSm and L. Terenius, 1977, Naloxoneinduced reversal of schizophrenic hallucinations, J. Neural Transm. 40, 13 Nabeshima, T., M. Hiramatsu, S. Noma, M. Ukai, M. Amano and T. Kameyama, 1982, Determination of methionine-enkephalin, norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid(DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) in brain by high-pressure liquid chromatography with electrochemical detector, Res. Commun. Chem. Pathol. Pharmacol. 35, 421. Nabeshima, T., S.P. Sivam, T. Kameyama and I.K. Ho, 1981, Interaction between morphine and phencyclicine: Intoxication and cross-tolerance, in: Advances in Endogenous and Exogenous Opioids, eds. H. Takagi and E.J. Simon (Kodansha Ltd., Tokyo) p. 338. Rommelspacher, H. and M.J. Kuhar, 1974, Effects of electrical stimulation on acetylcholine levels in central cholinergic nerve terminals, Brain Res. 81,243. Terenius, L., A. Wahlstr0m, L. LindstriSm and E. WiderliSv, 1976, Increased CSF levels of endorphins in chronic psychosis, Neurosci. Lett. 3, 157. Vincent, J.P., D. Cavey, J.M. Kamenka, P. Geneste and M. Lazdunski, 1978, Interaction of phencyclidines with the muscarinic and opiate receptors in the central nervous system, Brain Res. 152, 176. Wahlstr6m, A. and L. Terenius, 1981, Endorphin hypothesis of schizophrenia, in: The role of endorphins in neuropsychiatry, ed. H.M. Emrich (Karger, Basel) p. 181.