Acta psychiat. scand. (1979) 59, 173-179 Department of Psychiatry (Chairman: Prof. M. Dongier), McGill University, Montreal General Hospital, Douglas Hospital Centre, the Protein and Polypeptide Laboratory, McGill University, Montreal, Canada
Effect of naloxone or levallorphan on serum prolactin concentrations and apomorphine-induced growth hormone secretion S. LAL,N. P. V. NAIR,P. CERVANTFS, J. PULMAN AND H.GUYDA Naloxone HC1 (0.8 mg intravenously; n = 9) or levallorphan tartrate (0.25 mg subcutaneously; n = 5 ) had no effect on basal prolactin or growth hormone secretion in normal men. Neither narcotic antagonist inhibited the growth hormone secretory response to apomorphine HC1 (0.75 mg subcutaneously). These findings suggest that narcotic antagonists do not block dopamine receptors in the hypothalamic-pituitary axis in man and that if these agents have antischizophrenic properties then these are not mediated by dopamine receptor blockade.
Key words: Naloxone - levallorphan - narcotic antagonists - a p morphine - hypothalamic-pituitary axis - dopaminergic mechanisms - growth hormone - prolactin. There is some evidence that naloxone, an opiate receptor antagonist, exerts clinical antischizophrenic effects (Emrich et al. (1977), Gunne et al. (1977), Orr & Oppenheimer (1978)) though others have found only minimal or no such activity (Davis et al. (1977), Janowsky e? al. (1977), Kurland et al. (1977), Volavka et al. (1977)). Also, naloxone reverses beta-endorphin-induced catatonia (Bloom et al. (1976)) in rats, a behavioural state that has been likened to catatonia found in schizophrenia. These observations have led to the evaluation of other opiate antagonists in schizophrenia (Meikle & Gallant (1977), Simpson et al. (1977)). Neuroleptics characteristically block central dopamine receptors (Seeman et al. (1976)) and this effect may be detected clinically by their ability to stimulate prolactin secretion (Langer et al. (1977)) and to inhibit growth hormone secretion induced by the dopamine receptor agonist apomorphine (La1 et al. (1973, 1977), Nair et al. (1978)). The present study was undertaken to investigate the effect of naloxone and another opioid antagonist, levallorphan, on prolactin secretion and apomorphineinduced growth hormone secretion in normal subjects. MATERIAL AND METHODS Nine physically healthy non-obese male volunteers served as subjects. After an overnight fast at 7:30-8:30 a.m. a 19-gauge scalp vein needle was inserted into 0001-690X/79/020173-07$02.50/0 @ 1979 Munksgaard, Copenhagen
174 an arm vein and kept open with heparin-saline. Samples of blood were drawn at -30, -15, 0, 15, 30, 45, 60, 90, 120 and 150 min commencing 1 hour after insertion of the scalp vein needle. Naloxone HC1 (Narcan@, Endo Laboratories, 0.8 mg intravenously), levallorphan tartrate (LorphanB, Hoffman LaRoche, 0.25 mg subcutaneously) or saline intravenously were administered after the -15 min sample was taken and apomorphine HCl (0.75 mg) or saline were injected subcutaneously immediately after the 0 min specimen was drawn. The blood was centrifuged and the serum stored at -2OOC until assayed for growth hormone (Friesen et al. (1970)) and prolactin (Hwang et al. (1971)) by radioimmunoassay. Subjects remained recumbent throughout the test procedure. In view of the fact that circulating prolactin may increase during a daytime nap (Parker et al. (1973)) subjects were asked to stay awake until sampling was terminated. Subjects were tested with naloxone plus apomorphine, saline plus apomorphine and naloxone plus saline on separate days. Five of these volunteers also received levallorphan plus apomorphine and levallorphan plus saline. The dose of naloxone was chosen because 0.4 mg was reported by Gunne et al. (1977) to block hallucinations. The dose of levallorphan tartrate was based on the report that 0.01 mgAb prevents central nervous system depression induced by 0.03 mgAb apomorphine HC1 (Berry & Lambdin (1963)). Data were analyzed by the paired “t”-test.
-30
0
30
60
TIME
- rnin
80
120
160
Fig. 1. Effect of naloxone on apomorphine-induced growth hormone secretion. Nine male subjects were injected with apomorphine HCl (0.75 mg subcutaneously) at 0 min (.-or with -naloxone -.) HC1 (0.8 mg intravenously) at -15 min and apoSeven of the subjects received naloxone alone morphine at 0 rnin (04). ( A - - - - --A). Each point represents the mean k standard error of the mean. For purposes of clarity several of the standard error bars have been omitted. Naloxone had no significant effect on basal growth hormone concentrations or on the increase induced by apomorphine.
175
RESULTS Apomorphine increased serum growth hormone concentrations in all nine subjects (Fig. 1). When naloxone was administered prior to apomorphine there was no significant difference in mean growth hormone concentration at any of the time intervals studied compared with apomorphine alone. The mean individual peak (nglml) was 20.7 k 3.7 after apomorphine alone and 26.1 k 8.9 with naloxone pretreatment (P = ns). In four of the subjects the peak growth hormone concentration was higher after apomorphine alone and in five subjects higher after pretreatment with naloxone. In one of the volunteers (No. 1) the growth hormone response to apomorphine (peak 20.5 ng/ml) was abolished by naloxone (peak 0.9 ng/ml). Naloxone alone had no effect on baseline growth hormone concentrations. The mean concentrations of growth hormone after apomorphine alone compared with apomorphine after prior treatment with levallorphan were not significantly dif€erent at any of the time intervals studied (Fig. 2). The mean individual peak (ng/ml) was 17.6 k 3.3 after apomorphine and 17.7 k 8.8 after levallorphan pretreatment (P = ns). In subject No. 1 the growth hormone response was abolished by levallorphan (peak 2.7 ng/ml); in three subjects the apomorphine-induced growth hormone increment was higher after levallorphan pretreatment. Levallorphan alone had no effect on basal serum growth hormone levels. Neither naloxone nor levallorphan affected basal prolactin concentrations (Table 1). Naloxone or levallorphan alone produced no side effects. Apomorphine in-
I
T
24
E
0 a Q
~
0
30
80
TIME
- min
90
120
160
Fig. 2. Effect of levallorphan on apomorphine-induced growth hormone secretion. Five male subjects were injected with apomorphine HCl (0.75 mg subcutaneously) at 0 min (*----@), levallorphan tartrate (0.25 mg subcutaneously) at -15 min and apomorphine at 0 min (0-O), or levallorphan alone (A- - - - -A). Each point r e presents the mean k standard error of the mean. For purposes of clarity several of the standard error bars have been omitted. Levallorphan had no significant effect on basal growth hormone concentrations or on the increase induced by apomorphine.
176 Table 1. Eflect of naloxone or levallorphan on serum prolactin concentrations Treatment Naloxone (n = 9) Levallorphan = 5)
(n
Serum prolactin (ng/ml; mean k s.e.m.) Time (min) 0 15 30 45 60 90 11.0 9.5 9.3 10.5 9.7 9.9
-30
-15
10.6
11.4
+
+
+
f
+
k
+
f
1.6
1.4
1.4
1.7
1.4
1.6
1.6
1.4
8.6 + 1.6
8.9 b 1.9
10.1 8.7 9.7 9.0 9.2 8.7 9.2 10.3 k k + k a + + + . 1.3 1.7 1.5 1.0 1.4 1.2 1.0 1.1
120
150
10.6
10.3
f
f
1.7
1.6
Naloxone HCl (0.8 mg intravenously) or levallorphan tartrate (0.25mg subcutaneously) were injected into normal male volunteers at -15 min (see Methods for details). N = number of subjects. Prolactin concentrations following drug administration are not significantly different from values at -30 or -15 min at any of the time intervals shown.
duced yawning in all nine subjects within 10-15 min of injection and lacrimation in two of the individuals. Nausea occurred in four subjects, two of whom vomited. Apomorphine also induced spontaneous penile erections in four of the volunteers. Neither narcotic antagonist affected the apomorphine-induced side effects, except for the attenuation of emesis in one subject by levallorphan. DISCUSSION In man and animals there is evidence that dopamine exerts an inhibitory effect on prolactin and a stimulatory action on growth hormone secretion (La1 et al. (1972, 1973), Martin et al. (1974), Mueller et al. (1976)). Clinically effective antischizophrenic drugs inhibit dopaminergic function. Except for reserpine this inhibition is mediated by dopamine receptor blockade (Seeman et al. (1976), Snyder (1976)) and this results in an increase in prolactin secretion (Langer et al. (1977) and antagonism of growth hormone secretion induced by the dopamine receptor agonist apomorphine (La1 et al. (1973, 1977), Nair et al. (1978)). Naloxone has recently been shown to exert a beneficial effect on certain symptoms of schizophrenia (Emrich et al. (1977), Gunne et al. (1977), Orr & Oppenheimer (1978)). This raises the possibility that naloxone, and perhaps other narcotic antagonists, might block dopamhe receptors in man. Compatible with this view are pharmacological investigations in animals which show that naloxone inhibits the effect of amphetamine on avoidance behaviour (Holtzmann & Jewett (1973)) and locomotor activity (Holtzmann (1974)) in the rat, potentiates the effect of chlorpromazine on operant behaviour in the pigeon (McMillan (1971)) and inhibits apomorphine-induced stereotyped behaviour in the mouse (Malick et al. (1977)) and rat (Cox e f al. (1976)). In some studies, however, naloxone failed to inhibit apomorphme-induced stereotyped behaviour in the rat
177 (Gyfys et al. (1974), Mafick et al. (1977)) or d-amphetamine-induced locomotion in the mouse (Holtzmann (1974)). Naloxone decreases both growth hormone and prolactin secretion under a variety of experimental conditions in animals (Bruni et al. (1977), Cocchi et al. (1977), Gold et al. (1978), Shaar et al. (1977), Van Vugt et al. (1978)). An inhibitory effect of naltrexone on prolactin secretion has also been noted (Grandison & Guidotti (1977)). These observations may indicate that narcotic antagonists exert an inhibitory effect on dopamine mechanisms mediating growth hormone secretion but a stimulatory effect on dopamine mechanisms regulating prolactin secretion. In contrast to findings in animals the present study shows that naloxone has no effect on prolactin secretion. Levallorphan was also without an effect on this anterior pituitary hormone. Neither narcotic antagonist altered basal growth hormone secretion or the mean growth hormone response to apomorphine though in one subject both antagonists abolished the response. Whereas Gunne et al. (1977) found that 0.4 mg naloxone reversed auditory hallucinations in schizophrenic patients within 5 min of injection and lasted 6-1 hours, Emrich et al. (1977) suggested that doses of 4 mg may be required for a central effect on schizophrenic psychopathology. The latter authors found no effect with 4 mg at 60 min but a significant antipsychotic effect at 120 min. In the present study only a single dose.of the two antagonists was used so that it is possible that larger doses are required to alter hypothalamic-pituitary dopaminergic function or to inhibit the effect of 0.75 mg apomorphine HC1. Also, it is possible that a longer interval is required between administration of narcotic antagonist and apomorphine in order to observe an interaction of these drugs. However, intravenous naloxone reverses the effect of narcotics within minutes of injection (Martin (1976), Fink et al. (1968)) and levallorphan is rapidly effective in preventing central nervous system depressant effects of apomorphine (Berry & Lambdin (1963)), which point to prompt central actions of these two antagonists. Neither drug abolished apomorphine-induced nausea, emesis or penile erections which are believed to be mediated by dopamine receptor stimulation (Schlatter & La1 (1972), La1 Kt de la Vega (1975), Sourkes & La1 (1975), Lal et al. (1977)). In this regard naloxone has been found ineffective in blocking apomorphine emesis in the dog (Gylys et al. (1974)). The present results suggest that naloxone or levallorphan do not block dopamine receptors in the hypothalamic-pituitary a x i s of man, and that if narcotic antagonists exert an antischizophrenic action then this effect is unlikely to be due to dopamine receptor blockade.
ACKNOWLEDGEMENTS This work was supported by grants from the MRC (Canada). Additional support was
obtained from the G. W.Stairs Memorial Fund, McGill University, and Merck-Frosst Laboratories, P.Q., Canada.
12
178 REFERENCES Berry, F. A., & M. A. Lambdin (1963): Apomorphine and levallorphan tartrate in acute poisonings. Amer J. Dis. Child. 105, 160-163. Bloom, F., D. Segal, N. Ling & R. Guillemin (1976): Endorphins: profound behavioral effects in rats suggest new etiological factors in mental illness. Science 194, 630-632. Bruni, J . F., D. Van Vugt, S.Marshall & J . Meites (1977): Effects of naloxone, morphine and methionine encephalin on serum prolactin, luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone and growth hormone. Life Sci.
21,461-466. Coechi, D., A. Santagostino, I. Gil-Ad, S.Ferri & E. E. Muller (1977): Leu-enkephalinstimulated growth hormone and prolactin release in the rat: comparison with the effect of morphine. Life Sci. 20, 2041-2046. Cox, B., M. Ary & P. Lomax (1976): Changes in sensitivity to apomorphine during morphine dependence and withdrawal in rats. J. Pharmacol. exp. Ther. 196,637-641. Davis, G. C., W . E. Bunney, E. G. De Fraites, J . E. Kleinman, D. P. Van Kammen, R.M. Post & R. J . Wyatt (1977): Intravenous naloxone administration in schizophrenia and affective illness. Science 197, 74-77. Emrich, H. M., C. Cording, S. Pirke, A. Kolling, D. V . Zerssen & A. Herz (1977): Indication of an antipsychotic action of the opiate antagonist naloxone. Pharmakopsychiat. 10, 265-270. Fink, M., A . Zaks, R. Sharoff, A. Mora, A. Bruner, S.Levit & A . M . Freedman (1968): Naloxone in heroin dependence. Clin. Pharmacol. Ther. 9, 568-577. Friesen, H.G., H. Guyda & J . Hardy (1970): Biosynthesis of human growth hormone and prolactin. J. clin. Endocr. 31, 611624. Gold, M.S.,D. E. Redmond & R. K. Donabedian (1978): Prolactin secretion, a measurable central effect of opiate-receptor antagonists. Lancet i, 323-324. Grandison, L., & A. Guidotti (1977): Regulation of prolactin release by endogenous opiates. Nature (Lond.) 270, 357-359. Gunne, L., L. Lindstrom & L. M. Terenius (1977): Naloxone-induced reversal of schizophrenic hallucinations. J. neural Transm. 40, 13-19. Gylys, J. A., K. Doran & M. Szaraz (1974): Antagonism of morphine and apomorphine in dogs and rats. Fed. Proc. 33, 515. Holtzmann, S.G. (1974): Behavioral effects of separate and combined administration of naloxone and d-amphetamine. J. Pharmacol. exp. Ther. 189, 51-60. Holtzmann, S.G., & R. E. Jewett (1973): Stimulation of behaviour in the rat by cyclazoline: Effects of naloxone. J. Pharmacol. exp. Ther. 287, 380-390. Hwang, P., H. Guyda & H. Friesen (1971): A radioimmunoassay for human prolactin. Proc. nat. Acad. Sci. (Wash.) 68, 1902-1906. Janowsky, D.S., D.S. Segal, F. Bloom, A. Abrams & R. Guillemin (1977): Lack of effect of naloxone on schizophrenic symptoms. Amer. I. Psychiat. 134, 926-927. Kurland, A. A., 0.L. McCabe, T. E. Hanton & D. Sullivan (1977): The treatment of perceptual disturbances in schizophrenia with naloxone hydrochloride. Amer. J. Psychiat. 134, 1408-1410. Lal, S., H. Guyda & S.Bikadoroff (1970): Effect of methysergide and pimozide on apomorphine-induced growth hormone secretion in men. I. clin. Endocr. 44, 766-770. Lal, S., & C.E. de la Vega (1975): Apomorphine and psychopathology. J. Neurol. Neurosurg. Psychiat. 38, 722-726. Lal, S., C.E. de la Vega, T . L. Sourkes & H. G. Friesen (1972): Effect of apomorphine on human growth hormone secretion. Lancet ii, 661. Lal, S., C.E. de la Vega, T. L. Sourkes & H.G. Friesen (1973): Effect of apomorphine on growth hormone, prolactin, luteinizing hormone and follicle-stimulating hormone levels in human serum. J. clin. Endocr. 37, 719-721. Langer, G., E. 1. Sachar, P. H. Gruen & F. S. Halpern (1977): Human prolactin responses to neuroleptic drugs correlate with antischizophrenic potency. Nature (Lond.) 266,639-640. Malick, J. B., M. L. Millingsley, R. K . Kubena & J. M. Goldstein (1977): Evaluation of
179 naloxone in laboratory tests predictive of clinical antipsychotic activity. Commun. Psychopharmacol. 1, 475-488. Martin, J . B., S. La!, G . Tolis & H . G . Friesen (1974): Inhibition by apomorphine of prolactin secretion in patients with elevated prolactin. J. clin. Endocr. 39, 180-182. Martin, W .R. (1976): Naloxone. Ann. intern. Med. 85, 765-768. McMillan, D . E. (1971): Interactions between naloxone and chlorpromazine on behaviour under schedule control. Psychopharmacologia (Berl.) 19, 128-133. Meikle, D., & D . M . Gallant (1977): An oral opiate antagonist in chronic schizophrenia: a pilot study. Amer. J. Psychiat. 134, 1430-1431. Mueller, G . P., J . Simpkins, J . Meites & K . E. Moore (1976): Differential effects of dopamine agonists and haloperidol on release of prolactin, thyroid stimulating hormone, growth hormone and luteinizing hormone in rats. Neuroendocrinology 20, 121-135. Nair, N . P. V., S. Lal, P. Cervantes, R . Yassa & H. Guyda (1978): Effect of clozapine on apomorphine-induced growth hormone secretion and serum prolactin concentrations. Neuropsychobiology (in press). Orr, M., & C. Oppenheimer (1978): Effects of naloxone on auditory hallucinations. Brit. med. J. 1, 481. Parker, D . C., L.G . Rossman & E. F. Vanderlaan (1973): Sleep-related nyctohemeral and briefly episodic variation in human plasma prolactin concentrations. I. clin. Endocr. 36, 1119-1124. Schlafter, E. K . E., & S. La1 (1972): Treatment of alcoholism using Dent’s oral apomorphine method. Quart. J. Stud. Alcohol 33, 430-436. Seeman, P., T . Lee, M . Chau-Wong & K . Wong (1976): Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature (Lond.) 261, 717-719. Shaar, C . J., R. C . A . Fredrickson, N . B. Dininger & L. Jackson (1977): Enkephalin analogues and naloxone modulate the release of growth hormone and prolactinevidence for regulation by an endogenous opioid peptide in brain. Life Sci. 21, 853-860. Simpson, G . M . , M . H . Branchey & J . H . Lee (1977): A trial of naltrexone in chronic schizophrenia. Curr. ther. Res. 22, 909-913. Snyder, S.H. (1976): The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Amer. I. Psychiat. 133, 197-202. Sourkes, T . L., & S. La1 (1975):Apomorphine and its relation to dopamine in the nervous system. Advanc. Neurochem. I, 247-299. Van Vugt, D . A., F. F. Bruni & J . Meites (1978): Naloxone inhibition of stress-induced increase in prolactin secretion. Life Sci. 22, 85-90. Yolavka, J., A . Mallya, S. Baig & J . Perez-Cruet (1977): Naloxone in chronic schizophrenia. Science 196, 1227-1228. Received June 5, 1978
S. Lal, M.D. Department of Psychiatry Montreal General Hospital 1650 Cedar Avenue Montreal, P.Q. Canada H 3 G 1A4
Effect of naloxone or levallorphan on serum prolactin concentrations and apomorphine-induced growth hormone secretion S. LAL,N. P. V. NAIR,P. CERVANTFS, J. PULMAN AND H.GUYDA Naloxone HC1 (0.8 mg intravenously; n = 9) or levallorphan tartrate (0.25 mg subcutaneously; n = 5 ) had no effect on basal prolactin or growth hormone secretion in normal men. Neither narcotic antagonist inhibited the growth hormone secretory response to apomorphine HC1 (0.75 mg subcutaneously). These findings suggest that narcotic antagonists do not block dopamine receptors in the hypothalamic-pituitary axis in man and that if these agents have antischizophrenic properties then these are not mediated by dopamine receptor blockade.
Key words: Naloxone - levallorphan - narcotic antagonists - a p morphine - hypothalamic-pituitary axis - dopaminergic mechanisms - growth hormone - prolactin. There is some evidence that naloxone, an opiate receptor antagonist, exerts clinical antischizophrenic effects (Emrich et al. (1977), Gunne et al. (1977), Orr & Oppenheimer (1978)) though others have found only minimal or no such activity (Davis et al. (1977), Janowsky e? al. (1977), Kurland et al. (1977), Volavka et al. (1977)). Also, naloxone reverses beta-endorphin-induced catatonia (Bloom et al. (1976)) in rats, a behavioural state that has been likened to catatonia found in schizophrenia. These observations have led to the evaluation of other opiate antagonists in schizophrenia (Meikle & Gallant (1977), Simpson et al. (1977)). Neuroleptics characteristically block central dopamine receptors (Seeman et al. (1976)) and this effect may be detected clinically by their ability to stimulate prolactin secretion (Langer et al. (1977)) and to inhibit growth hormone secretion induced by the dopamine receptor agonist apomorphine (La1 et al. (1973, 1977), Nair et al. (1978)). The present study was undertaken to investigate the effect of naloxone and another opioid antagonist, levallorphan, on prolactin secretion and apomorphineinduced growth hormone secretion in normal subjects. MATERIAL AND METHODS Nine physically healthy non-obese male volunteers served as subjects. After an overnight fast at 7:30-8:30 a.m. a 19-gauge scalp vein needle was inserted into 0001-690X/79/020173-07$02.50/0 @ 1979 Munksgaard, Copenhagen
174 an arm vein and kept open with heparin-saline. Samples of blood were drawn at -30, -15, 0, 15, 30, 45, 60, 90, 120 and 150 min commencing 1 hour after insertion of the scalp vein needle. Naloxone HC1 (Narcan@, Endo Laboratories, 0.8 mg intravenously), levallorphan tartrate (LorphanB, Hoffman LaRoche, 0.25 mg subcutaneously) or saline intravenously were administered after the -15 min sample was taken and apomorphine HCl (0.75 mg) or saline were injected subcutaneously immediately after the 0 min specimen was drawn. The blood was centrifuged and the serum stored at -2OOC until assayed for growth hormone (Friesen et al. (1970)) and prolactin (Hwang et al. (1971)) by radioimmunoassay. Subjects remained recumbent throughout the test procedure. In view of the fact that circulating prolactin may increase during a daytime nap (Parker et al. (1973)) subjects were asked to stay awake until sampling was terminated. Subjects were tested with naloxone plus apomorphine, saline plus apomorphine and naloxone plus saline on separate days. Five of these volunteers also received levallorphan plus apomorphine and levallorphan plus saline. The dose of naloxone was chosen because 0.4 mg was reported by Gunne et al. (1977) to block hallucinations. The dose of levallorphan tartrate was based on the report that 0.01 mgAb prevents central nervous system depression induced by 0.03 mgAb apomorphine HC1 (Berry & Lambdin (1963)). Data were analyzed by the paired “t”-test.
-30
0
30
60
TIME
- rnin
80
120
160
Fig. 1. Effect of naloxone on apomorphine-induced growth hormone secretion. Nine male subjects were injected with apomorphine HCl (0.75 mg subcutaneously) at 0 min (.-or with -naloxone -.) HC1 (0.8 mg intravenously) at -15 min and apoSeven of the subjects received naloxone alone morphine at 0 rnin (04). ( A - - - - --A). Each point represents the mean k standard error of the mean. For purposes of clarity several of the standard error bars have been omitted. Naloxone had no significant effect on basal growth hormone concentrations or on the increase induced by apomorphine.
175
RESULTS Apomorphine increased serum growth hormone concentrations in all nine subjects (Fig. 1). When naloxone was administered prior to apomorphine there was no significant difference in mean growth hormone concentration at any of the time intervals studied compared with apomorphine alone. The mean individual peak (nglml) was 20.7 k 3.7 after apomorphine alone and 26.1 k 8.9 with naloxone pretreatment (P = ns). In four of the subjects the peak growth hormone concentration was higher after apomorphine alone and in five subjects higher after pretreatment with naloxone. In one of the volunteers (No. 1) the growth hormone response to apomorphine (peak 20.5 ng/ml) was abolished by naloxone (peak 0.9 ng/ml). Naloxone alone had no effect on baseline growth hormone concentrations. The mean concentrations of growth hormone after apomorphine alone compared with apomorphine after prior treatment with levallorphan were not significantly dif€erent at any of the time intervals studied (Fig. 2). The mean individual peak (ng/ml) was 17.6 k 3.3 after apomorphine and 17.7 k 8.8 after levallorphan pretreatment (P = ns). In subject No. 1 the growth hormone response was abolished by levallorphan (peak 2.7 ng/ml); in three subjects the apomorphine-induced growth hormone increment was higher after levallorphan pretreatment. Levallorphan alone had no effect on basal serum growth hormone levels. Neither naloxone nor levallorphan affected basal prolactin concentrations (Table 1). Naloxone or levallorphan alone produced no side effects. Apomorphine in-
I
T
24
E
0 a Q
~
0
30
80
TIME
- min
90
120
160
Fig. 2. Effect of levallorphan on apomorphine-induced growth hormone secretion. Five male subjects were injected with apomorphine HCl (0.75 mg subcutaneously) at 0 min (*----@), levallorphan tartrate (0.25 mg subcutaneously) at -15 min and apomorphine at 0 min (0-O), or levallorphan alone (A- - - - -A). Each point r e presents the mean k standard error of the mean. For purposes of clarity several of the standard error bars have been omitted. Levallorphan had no significant effect on basal growth hormone concentrations or on the increase induced by apomorphine.
176 Table 1. Eflect of naloxone or levallorphan on serum prolactin concentrations Treatment Naloxone (n = 9) Levallorphan = 5)
(n
Serum prolactin (ng/ml; mean k s.e.m.) Time (min) 0 15 30 45 60 90 11.0 9.5 9.3 10.5 9.7 9.9
-30
-15
10.6
11.4
+
+
+
f
+
k
+
f
1.6
1.4
1.4
1.7
1.4
1.6
1.6
1.4
8.6 + 1.6
8.9 b 1.9
10.1 8.7 9.7 9.0 9.2 8.7 9.2 10.3 k k + k a + + + . 1.3 1.7 1.5 1.0 1.4 1.2 1.0 1.1
120
150
10.6
10.3
f
f
1.7
1.6
Naloxone HCl (0.8 mg intravenously) or levallorphan tartrate (0.25mg subcutaneously) were injected into normal male volunteers at -15 min (see Methods for details). N = number of subjects. Prolactin concentrations following drug administration are not significantly different from values at -30 or -15 min at any of the time intervals shown.
duced yawning in all nine subjects within 10-15 min of injection and lacrimation in two of the individuals. Nausea occurred in four subjects, two of whom vomited. Apomorphine also induced spontaneous penile erections in four of the volunteers. Neither narcotic antagonist affected the apomorphine-induced side effects, except for the attenuation of emesis in one subject by levallorphan. DISCUSSION In man and animals there is evidence that dopamine exerts an inhibitory effect on prolactin and a stimulatory action on growth hormone secretion (La1 et al. (1972, 1973), Martin et al. (1974), Mueller et al. (1976)). Clinically effective antischizophrenic drugs inhibit dopaminergic function. Except for reserpine this inhibition is mediated by dopamine receptor blockade (Seeman et al. (1976), Snyder (1976)) and this results in an increase in prolactin secretion (Langer et al. (1977) and antagonism of growth hormone secretion induced by the dopamine receptor agonist apomorphine (La1 et al. (1973, 1977), Nair et al. (1978)). Naloxone has recently been shown to exert a beneficial effect on certain symptoms of schizophrenia (Emrich et al. (1977), Gunne et al. (1977), Orr & Oppenheimer (1978)). This raises the possibility that naloxone, and perhaps other narcotic antagonists, might block dopamhe receptors in man. Compatible with this view are pharmacological investigations in animals which show that naloxone inhibits the effect of amphetamine on avoidance behaviour (Holtzmann & Jewett (1973)) and locomotor activity (Holtzmann (1974)) in the rat, potentiates the effect of chlorpromazine on operant behaviour in the pigeon (McMillan (1971)) and inhibits apomorphine-induced stereotyped behaviour in the mouse (Malick et al. (1977)) and rat (Cox e f al. (1976)). In some studies, however, naloxone failed to inhibit apomorphme-induced stereotyped behaviour in the rat
177 (Gyfys et al. (1974), Mafick et al. (1977)) or d-amphetamine-induced locomotion in the mouse (Holtzmann (1974)). Naloxone decreases both growth hormone and prolactin secretion under a variety of experimental conditions in animals (Bruni et al. (1977), Cocchi et al. (1977), Gold et al. (1978), Shaar et al. (1977), Van Vugt et al. (1978)). An inhibitory effect of naltrexone on prolactin secretion has also been noted (Grandison & Guidotti (1977)). These observations may indicate that narcotic antagonists exert an inhibitory effect on dopamine mechanisms mediating growth hormone secretion but a stimulatory effect on dopamine mechanisms regulating prolactin secretion. In contrast to findings in animals the present study shows that naloxone has no effect on prolactin secretion. Levallorphan was also without an effect on this anterior pituitary hormone. Neither narcotic antagonist altered basal growth hormone secretion or the mean growth hormone response to apomorphine though in one subject both antagonists abolished the response. Whereas Gunne et al. (1977) found that 0.4 mg naloxone reversed auditory hallucinations in schizophrenic patients within 5 min of injection and lasted 6-1 hours, Emrich et al. (1977) suggested that doses of 4 mg may be required for a central effect on schizophrenic psychopathology. The latter authors found no effect with 4 mg at 60 min but a significant antipsychotic effect at 120 min. In the present study only a single dose.of the two antagonists was used so that it is possible that larger doses are required to alter hypothalamic-pituitary dopaminergic function or to inhibit the effect of 0.75 mg apomorphine HC1. Also, it is possible that a longer interval is required between administration of narcotic antagonist and apomorphine in order to observe an interaction of these drugs. However, intravenous naloxone reverses the effect of narcotics within minutes of injection (Martin (1976), Fink et al. (1968)) and levallorphan is rapidly effective in preventing central nervous system depressant effects of apomorphine (Berry & Lambdin (1963)), which point to prompt central actions of these two antagonists. Neither drug abolished apomorphine-induced nausea, emesis or penile erections which are believed to be mediated by dopamine receptor stimulation (Schlatter & La1 (1972), La1 Kt de la Vega (1975), Sourkes & La1 (1975), Lal et al. (1977)). In this regard naloxone has been found ineffective in blocking apomorphine emesis in the dog (Gylys et al. (1974)). The present results suggest that naloxone or levallorphan do not block dopamine receptors in the hypothalamic-pituitary a x i s of man, and that if narcotic antagonists exert an antischizophrenic action then this effect is unlikely to be due to dopamine receptor blockade.
ACKNOWLEDGEMENTS This work was supported by grants from the MRC (Canada). Additional support was
obtained from the G. W.Stairs Memorial Fund, McGill University, and Merck-Frosst Laboratories, P.Q., Canada.
12
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S. Lal, M.D. Department of Psychiatry Montreal General Hospital 1650 Cedar Avenue Montreal, P.Q. Canada H 3 G 1A4
