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Dextroamphetamine infusions in normals result in correlated increases of plasma β-endorphin and cortisol immunoreactivity
Life Sciences, Vol. 29, pp. 1243-1247 Printed in the U.S.A.
Pergamon Press
DEXTROAMPHETAMINE INFUSIONS IN NORMALSRESULT IN CORRELATED INCREASESOF PLASMA B-ENDORPHIN AND CORTISOL IMMUNOREACTIVITY Cohen, Martin R., M~D.I,2, Nurnberger, John I . , M.D.3 Pickar, David, M.D.I, Gershon, E l l i o t , M.D. 3, Bunney, William E., J r . , M.D. i 1 Unit of Studies on Drug Abuse, Biological Psychiatry Branch NIMH, Bethesda, MD 20205 2 Department of Psychiatry, University of Iowa College of Medicine 3 Section on Psychogenetics, BPB, NIMH, Bethesda, MD 20205 (Received in final form 7uly 13, 1981) SUMMARY
Stress induces behavioral and hormonal alterations. In experimental and clinical studies, amphetamine administration may simulate or potentiate such effects. The endogenous opioid system has been implicated in the modulation of stress effects. Dextroamphetamine, 0.3 mg./kg, and placebo were infused on separate days in a double-blind cross over design to eight normal volunteers. At 30 minutes post infusion, plasma B-endorphin immunoreactivity was significantly (p < 0.05) increased. The increase was significantly correlated (r = 0.76, p < 0.05) with volunteers' cortisol responses. Stress is manifested by both behavioral (1) and hormonal alterations. (2) Hormonal alterations may result in behavioral effects or may reflect neurophysiological alterations underlying behavioral changes. In particular, stress often leads to alterations in circulating plasma levels of prolactin, growth hormone and cortisol, although these hormonal effects vary with species and paradigm. (2) Endogenous opioid systems may be important in the modulation of stressinduced behavioral and hormonal changes. (3,4) In the rat, stress induced by inescapable foot shock leads to elevations in both plasma B-endorphin (5) and alterations in central nervous system opioid levels. (6) In clinical studies, elevations of plasma B-endorphin have been demonstrated during labor (7) and to accompany cortisol elevations following surgical stress. (8) In animals, amphetamine administration may simulate or potentiate behavioral effects of stress or arousal paradigms. (1) In the rat, amphetamine (9) or arousal (10) may partially compensate for behavioral deficits following lateral hypothalamic damage. Clinically, amphetamines are utilized in the treatment of disorders involving abnormalities of arousal, such as narcolepsy and hyperactivity. In this study, we evaluate the effects of dextroamphetamine infusions in normal volunteers on plasma B-endorphin and cortisol levels. 0024-3205/81/121243-05502.00/0 Copyright (c) 1981 Pergamon Press Ltd.
1244
Amphetamine and Beta-Endorphin
Vol. 29, No. 12, 1981
Materials and Methods Eight normal (free of psychiatric and physical illness) monozygotic twins (including 3 pairs), ages 18 to 39 were tested from a larger pool of twins utilized in pharmacogenetic studies. Individuals were allowed to eat breakfast but began fasting prior to placement of an intravenous catheter in a forearm vein between 0800 and 0930 hr. Placebo or 0.3 mg./kg, dextroamphetamine was infused in random order on separate days over a two minute period starting l hour after catheter placement. Blood samples for B-endorphin and cortisol determinations were obtained at -5 (0 = time of infusion) and + 30 minutes. Previous clinical studies had shown cortisol and ACTH responses to intravenous stimulants to be maximum at 30 minutes post infusion (11,12). Blind observer ratings of mood and behavioral changes were made from videotapes of the baseline period and the f i r s t hour after infusion; these are described elsewhere (13). Plasma B-endorphin and plasma cortisol in~nunoreactivity (all subsequent references are to immunoreactivity) were determined by radioimmunoassay with reagents supplied by New England Nuclear. All plasma samples were run in the same assay. Intra-assay variations were 3.5% and 6% respectively. There is in the B-endorphin assay less than 50% cross reactivity to B-lipotropin, less than 0.01% cross reactivity to ~-endorphin and e-melanocyte stimulating hormone, less than 0.004% to methionine and leucine-enkephalin and less than 5% cross-reactivity to ACTH. (14) Neither the B-endorphin or cortisol response to amphetamine infusions was correlated within twin pairs (intraclass correlations [ r l = -0.71 and -0.81 respectively]). The significance of hormonal alterations following infusions was determined by means of paired student t - t e s t s , df = 7. Correlations were determined by Pearson Product Moment Correlations, df = 6. Results Individual hormonal responses to amphetamine infusion are detailed in Figure I. Following amphetamine, plasma B-endorphin levels rose in six of the eight volunteers, a mean + SEM increase = 6.8 ~ 5.3 picomolar (I0.2%) (P < 0.05, two t a i l ) . In contrast, Tollowing placebo, levels dropped in seven of eight volunteers (mean = -I0.7 picomolar). I f one defines the B-endorphin response to amphetamine infusion as the change in B-endorphin level following amphetamine minus the change in B-endorphin following placebo, the mean 8-endorphin response = 17.5 picomolar (+ 26%). Following amphetamine infusion, plasma cortisol levels rose in seven of th eight volunteers, a mean + SEM increase = + 5.3 + 3.5 ~gm. % (25.6%) (P < .025, l-tail). Following plac~o administration, cortTsol levels decreased in seven of the eight volunteers (mean = -3.5 ugm. %). Defining the cortisol response to amphetamine infusion as the change in plasma cortisol following amphetamine minus the change in plasma cortisol following placebo, the mean cortisol response = 8.8 ugm. % (+ 42.5%).
Vol. 29, No. 12, 1981
Amphetamine and Beta-Endorphin
1245
Changes in plasma B-endorphin and cortisol levels following amphetamine were significantly correlated (r = +0.76, P < 0.025, l - t a i l ) . In contrast, baseline B-endorphin and cortisol levels and the change in B-endorphin and cortisol following placebo were not significantly correlated. Neither baseline cortisol nor B-endorphin were significantly correlated with their amphetamine responses. No correlation was found between hormonal and behavioral responses to amphetamine.
24 z~--
20
o.=:~
16
o ~]
12
w.>_m ,r-l_ ,,, p O.
8 4
r n (,.) i,,j
zi i 1~_ _Z
0
2
3
4
5
6
•
8
NORMAL VOLUNTEERS _
(j ~_c..) - 1 2 -16
FIG. 1 Individual changes from baseline in plasma B-endorphin (picomolar) and cortisol (~gm.%), 30 minutes following a 0.3 mg./kg, dextroamphetamine infusion in eight normal volunteers. 8-endorphin in black, cortisol in white. Discussion The results of this study confirm previous reports that amphetamine administration in normals results in a modest but significant increase in c o r t i s o l . (15,16) This study is the f i r s t to demonstrate that amphetamine infusion results in correlated increases in plasma B-endorphin. The mechanism of such linkage is uncertain. In normals, amphetamine-stimulated increases in plasma cortisol are thought to be mediated through e-adrenergic receptors although these may l i e outside the blood-brain b a r r i e r . (15,17,18) Whether such receptors are involved in the B-endorphin response is yet to be determined. e-receptor stimulation may be a direct physiological effect of amphetamine or a by-product of arousal or other behavioral a l t e r a t i o n . In turn, e-receptor mediation of hormonal effects may be direct or may be necessary for arousal which might then a l t e r hormonal levels. Previous studies have demonstrated correlations between individual amphetamine-induced behavioral changes and cortisol responses. (16) Such studies, however, do not c l a r i f y the above physiologic alternatives. In our subject group, amphetamine-induced behavioral
1246
Amphetamine and Beta-Endorphin
Vol. 29, No. 12, 1981
responses were not correlated with cortisol or B-endorphin responses. However, using a larger group of volunteers, which included the subsample of the presently reported subjects, a significant correlation between an excitation factor subscale and cortisol was able to be demonstrated. (19) The close linkage in the plasma responses of B-endorphin and cortisol to amphetamine is underlined by previous reports of the lack of correlation of cortisol and growth hormone responses to dextroamphetamine. (16) ACTH and B-endorphin may have the same non-opioid peptide precursor. (20) However, in this study, no correlation between baseline B-endorphin and cortisol levels was found. Also, P.M. dexamethasone administration in normals (21) and obese patients (22) usually results in supressed cortisol but unchanged B-endorphin levels the following A.M. This discordance suggests the p o s s i b i l i t y of separate control mechanisms for baseline B-endorphin and c o r t i s o l , but similar mechanisms for stress induced secretion. The correlated change in B-endorphin and cortisol is further evidence that c l i n i c a l administration of amphetamine may simulate behavioral and hormonal effects of stressful evironmental s t i m u l i i . I t is, therefore, of note that in a study of patients with a diagnosis of schizophrenia, Schulz et al. (23) found no change in plasma B-endorphin following amphetamine infusion. Abnormalities of arousal and attention have been hypothesized in the pathophysiology of this i l l n e s s . (1) Depression may also be considered in part to be related to stress and a disorder of arousal. (24) This is suggested by appetite, memory and hormonal a l t e r a t i o n s , in p a r t i c u l a r , hypothalmic-pituitary-adrenal (HPA) axis d i s i n h i b i t i o n . (25,26,27,28) Although amphetamines have not been widely used in the treatment of depression, an acute euphoric effect following amphetamine administration may predict responsiveness to the anti-depressant, imipramine. (29) Checkley has reported a flattened cortisol response in depressives to methyl-amphetamine infusion in the afternoon. (12) Sachar et al. has demonstrated that amphetamine infusion in the morning in depression may cause a paradoxical supression of c o r t i s o l . There are no reports of the effects of amphetamine infusion on plasma B-endorphin in depressives. In a preliminary study of major depression, basal morning B-endorphin levels have been found to be normal despite the group's s i g n i f i c a n t l y elevated cortisol levels. (31) The physiological effect of changes of plasma B-endorphin in the range found in this study has yet to be demonstrated. However, alterations of behavioral responses to amphetamine in rats have been reported with naloxone pre-treatment. (32) This suggests the involvement of an opioid system in the modulation of amphetamine induced behavior. References I. 2. 3. 4. 5. 6. 7.
S. ANTELMAN and A. CAGGIULA, Psychobiology of Consciousness,( J. Davidson and R.M. Davidson eds.) pp. 65-104, Plenum Press, New York, 1980. J. MASON, Emotions: Their Parameters and Measurements, (L. Levi, ed.) p. 143, Raven Press, New York, 1975. J. MORLEY, and A. LEVINE, Science 209, 1259-61, 1980. J.W. HOLADAY, and H.H. LOH, Neurochemical Mechanisms of Opiate Ligands (H. Lob and D.H. Ross, eds.) pp. 227-257, Raven Press, New York, 1979. J. ROSSlER, E. FRENCH, C. RIVIER, N. LING, R. GUILLEMIN and F. BLUM, Nature 270, 668-620, 1977. J. MADDEN, IV, H. AKIL, R.L. PATRICK, and L.D. RARCHAI, Nature 265, 358-360, 1979. R. GOLAND, S. WARDLAW, R. STARK and A. FRANTZ, Clin, Endocrinol Metab 52, 74-78, 1981.
Vol. 29, No. 12, 1981
8. 9. I0. Iio 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
Amphetamine and Beta Endorphin
1247
M. COHEN, D. PICKAR, M. DUBOIS, Y. ROTH, D. NABERand W.E. BUNNEY, JR, Lancet I , 213-214, 1981. J.L. HENNESSYand S. LEVINE, Physiological Psychology, 8 (J. Sprague, A. Epstein, eds.) pp. 134-178, Academic Press, 1979. S. ANTELMAN, N. ROWLANDand A. FISHNER, Brain Research 102, 346-350, 1976. B.M. BESSER, P.W. BUTLER, J. LANDONand L. REES, Br Med J 29, 528-30, 1969. S.A. CHECKLEY, Psychol Med 9, 107-116, 1979. J. NURNBERGER, E. GERSHON, D. JIMERSON, M. BUCHSBAUM, P. GOLD, G. BROWNand M. EBERT, Genetic Research Strategies in Psychobiology and Psychiatry, (E. Gershon, S. Matthyse, X. Breakefield and R.D. Ciaranello eds.) Boxwood Press, in press. M. COHEN, Unpublished data. G.M. BESSER, P.W. BUTLER, J.G. RATCLIFFE, L. REES, and P. YOUNG, Br J Pharmacol 39(I), 196-197, 1970. W.A. BROWN, D.P. CORRIVEAU, and M.H. EBERT, Psychopharmacology 58 (2), 189-195, 1978. L. REES, P.W. BUTLER, C. GOSLING, and G.M. BESSER, Nature 7, 228(271) 565566, 1970. S.A. CHECKLEY, Physiological Medicine I0, 35-53, 1980. J. NURNBERGER,JR., E. GERSHON, N. SITARAM, J.GILLIN, G. BROWN, M. EBERT, P. GOLD, D. JIMERSON, and L. KESSLER, Psychopharmacol Bull, in press. A.F. BRADBURY, D.G. SMYTH, and C.R. SNELL, Biochem Biophys Res Commun 69, 950-956, 1976. N. KALIN, S. RISCH, R. COHEN, T. INSEL, and D. MURPHY, Science 209, 827828, 1980. M. COHEN, Unpublished data. SCHULZ, D. VAN KAMMEN, A. ROGOL, M. EBERT, D. PICKAR, M. COHENand D. NABER, Psychopharmacology Bulletin, in press. R. COHEN, I. CAMPBELL, M. COHEN, T. TORDA, D. PICKAR, L. SIEVER and D. MURPHY, Psychiatric Research 3, 93-105, 1980. M. HAMILTON, J of Neurol Neurosurg and Psychiat 23, 56-62, 1960. L. STROMGREN,Acta Psychiatrica Scand 56, 109-128, 1977. M. SCHLESSER, Go WINOKUR, and B. SHERMAN, Lancet I I , 739-741, 1979. F. STRICKER, M. ZIGMOND, Progress in Psychobiology and Physiological Psychogy, (J. Sprague and A. Epstein, eds.), pp. 121-188, Academic Press, New York, pp. 121-188, 1976. D. VAN KAMMEN, and D. MURPHY, A J Psych 135, 1179-1183, 1978. E. SACHAR, G. ASNIS, R. NATHAN, U. HALBREICH, M. TABRIZI and F. HALPREN, Arch Gen Psychiatry 371(71), 755-757, 1980. D. PICKAR, Unpublished data. P. ADAMS, R. BEAUCHAMPand C. ALSTON, Life Sciences 28, 629-634, 1981.
Pergamon Press
DEXTROAMPHETAMINE INFUSIONS IN NORMALSRESULT IN CORRELATED INCREASESOF PLASMA B-ENDORPHIN AND CORTISOL IMMUNOREACTIVITY Cohen, Martin R., M~D.I,2, Nurnberger, John I . , M.D.3 Pickar, David, M.D.I, Gershon, E l l i o t , M.D. 3, Bunney, William E., J r . , M.D. i 1 Unit of Studies on Drug Abuse, Biological Psychiatry Branch NIMH, Bethesda, MD 20205 2 Department of Psychiatry, University of Iowa College of Medicine 3 Section on Psychogenetics, BPB, NIMH, Bethesda, MD 20205 (Received in final form 7uly 13, 1981) SUMMARY
Stress induces behavioral and hormonal alterations. In experimental and clinical studies, amphetamine administration may simulate or potentiate such effects. The endogenous opioid system has been implicated in the modulation of stress effects. Dextroamphetamine, 0.3 mg./kg, and placebo were infused on separate days in a double-blind cross over design to eight normal volunteers. At 30 minutes post infusion, plasma B-endorphin immunoreactivity was significantly (p < 0.05) increased. The increase was significantly correlated (r = 0.76, p < 0.05) with volunteers' cortisol responses. Stress is manifested by both behavioral (1) and hormonal alterations. (2) Hormonal alterations may result in behavioral effects or may reflect neurophysiological alterations underlying behavioral changes. In particular, stress often leads to alterations in circulating plasma levels of prolactin, growth hormone and cortisol, although these hormonal effects vary with species and paradigm. (2) Endogenous opioid systems may be important in the modulation of stressinduced behavioral and hormonal changes. (3,4) In the rat, stress induced by inescapable foot shock leads to elevations in both plasma B-endorphin (5) and alterations in central nervous system opioid levels. (6) In clinical studies, elevations of plasma B-endorphin have been demonstrated during labor (7) and to accompany cortisol elevations following surgical stress. (8) In animals, amphetamine administration may simulate or potentiate behavioral effects of stress or arousal paradigms. (1) In the rat, amphetamine (9) or arousal (10) may partially compensate for behavioral deficits following lateral hypothalamic damage. Clinically, amphetamines are utilized in the treatment of disorders involving abnormalities of arousal, such as narcolepsy and hyperactivity. In this study, we evaluate the effects of dextroamphetamine infusions in normal volunteers on plasma B-endorphin and cortisol levels. 0024-3205/81/121243-05502.00/0 Copyright (c) 1981 Pergamon Press Ltd.
1244
Amphetamine and Beta-Endorphin
Vol. 29, No. 12, 1981
Materials and Methods Eight normal (free of psychiatric and physical illness) monozygotic twins (including 3 pairs), ages 18 to 39 were tested from a larger pool of twins utilized in pharmacogenetic studies. Individuals were allowed to eat breakfast but began fasting prior to placement of an intravenous catheter in a forearm vein between 0800 and 0930 hr. Placebo or 0.3 mg./kg, dextroamphetamine was infused in random order on separate days over a two minute period starting l hour after catheter placement. Blood samples for B-endorphin and cortisol determinations were obtained at -5 (0 = time of infusion) and + 30 minutes. Previous clinical studies had shown cortisol and ACTH responses to intravenous stimulants to be maximum at 30 minutes post infusion (11,12). Blind observer ratings of mood and behavioral changes were made from videotapes of the baseline period and the f i r s t hour after infusion; these are described elsewhere (13). Plasma B-endorphin and plasma cortisol in~nunoreactivity (all subsequent references are to immunoreactivity) were determined by radioimmunoassay with reagents supplied by New England Nuclear. All plasma samples were run in the same assay. Intra-assay variations were 3.5% and 6% respectively. There is in the B-endorphin assay less than 50% cross reactivity to B-lipotropin, less than 0.01% cross reactivity to ~-endorphin and e-melanocyte stimulating hormone, less than 0.004% to methionine and leucine-enkephalin and less than 5% cross-reactivity to ACTH. (14) Neither the B-endorphin or cortisol response to amphetamine infusions was correlated within twin pairs (intraclass correlations [ r l = -0.71 and -0.81 respectively]). The significance of hormonal alterations following infusions was determined by means of paired student t - t e s t s , df = 7. Correlations were determined by Pearson Product Moment Correlations, df = 6. Results Individual hormonal responses to amphetamine infusion are detailed in Figure I. Following amphetamine, plasma B-endorphin levels rose in six of the eight volunteers, a mean + SEM increase = 6.8 ~ 5.3 picomolar (I0.2%) (P < 0.05, two t a i l ) . In contrast, Tollowing placebo, levels dropped in seven of eight volunteers (mean = -I0.7 picomolar). I f one defines the B-endorphin response to amphetamine infusion as the change in B-endorphin level following amphetamine minus the change in B-endorphin following placebo, the mean 8-endorphin response = 17.5 picomolar (+ 26%). Following amphetamine infusion, plasma cortisol levels rose in seven of th eight volunteers, a mean + SEM increase = + 5.3 + 3.5 ~gm. % (25.6%) (P < .025, l-tail). Following plac~o administration, cortTsol levels decreased in seven of the eight volunteers (mean = -3.5 ugm. %). Defining the cortisol response to amphetamine infusion as the change in plasma cortisol following amphetamine minus the change in plasma cortisol following placebo, the mean cortisol response = 8.8 ugm. % (+ 42.5%).
Vol. 29, No. 12, 1981
Amphetamine and Beta-Endorphin
1245
Changes in plasma B-endorphin and cortisol levels following amphetamine were significantly correlated (r = +0.76, P < 0.025, l - t a i l ) . In contrast, baseline B-endorphin and cortisol levels and the change in B-endorphin and cortisol following placebo were not significantly correlated. Neither baseline cortisol nor B-endorphin were significantly correlated with their amphetamine responses. No correlation was found between hormonal and behavioral responses to amphetamine.
24 z~--
20
o.=:~
16
o ~]
12
w.>_m ,r-l_ ,,, p O.
8 4
r n (,.) i,,j
zi i 1~_ _Z
0
2
3
4
5
6
•
8
NORMAL VOLUNTEERS _
(j ~_c..) - 1 2 -16
FIG. 1 Individual changes from baseline in plasma B-endorphin (picomolar) and cortisol (~gm.%), 30 minutes following a 0.3 mg./kg, dextroamphetamine infusion in eight normal volunteers. 8-endorphin in black, cortisol in white. Discussion The results of this study confirm previous reports that amphetamine administration in normals results in a modest but significant increase in c o r t i s o l . (15,16) This study is the f i r s t to demonstrate that amphetamine infusion results in correlated increases in plasma B-endorphin. The mechanism of such linkage is uncertain. In normals, amphetamine-stimulated increases in plasma cortisol are thought to be mediated through e-adrenergic receptors although these may l i e outside the blood-brain b a r r i e r . (15,17,18) Whether such receptors are involved in the B-endorphin response is yet to be determined. e-receptor stimulation may be a direct physiological effect of amphetamine or a by-product of arousal or other behavioral a l t e r a t i o n . In turn, e-receptor mediation of hormonal effects may be direct or may be necessary for arousal which might then a l t e r hormonal levels. Previous studies have demonstrated correlations between individual amphetamine-induced behavioral changes and cortisol responses. (16) Such studies, however, do not c l a r i f y the above physiologic alternatives. In our subject group, amphetamine-induced behavioral
1246
Amphetamine and Beta-Endorphin
Vol. 29, No. 12, 1981
responses were not correlated with cortisol or B-endorphin responses. However, using a larger group of volunteers, which included the subsample of the presently reported subjects, a significant correlation between an excitation factor subscale and cortisol was able to be demonstrated. (19) The close linkage in the plasma responses of B-endorphin and cortisol to amphetamine is underlined by previous reports of the lack of correlation of cortisol and growth hormone responses to dextroamphetamine. (16) ACTH and B-endorphin may have the same non-opioid peptide precursor. (20) However, in this study, no correlation between baseline B-endorphin and cortisol levels was found. Also, P.M. dexamethasone administration in normals (21) and obese patients (22) usually results in supressed cortisol but unchanged B-endorphin levels the following A.M. This discordance suggests the p o s s i b i l i t y of separate control mechanisms for baseline B-endorphin and c o r t i s o l , but similar mechanisms for stress induced secretion. The correlated change in B-endorphin and cortisol is further evidence that c l i n i c a l administration of amphetamine may simulate behavioral and hormonal effects of stressful evironmental s t i m u l i i . I t is, therefore, of note that in a study of patients with a diagnosis of schizophrenia, Schulz et al. (23) found no change in plasma B-endorphin following amphetamine infusion. Abnormalities of arousal and attention have been hypothesized in the pathophysiology of this i l l n e s s . (1) Depression may also be considered in part to be related to stress and a disorder of arousal. (24) This is suggested by appetite, memory and hormonal a l t e r a t i o n s , in p a r t i c u l a r , hypothalmic-pituitary-adrenal (HPA) axis d i s i n h i b i t i o n . (25,26,27,28) Although amphetamines have not been widely used in the treatment of depression, an acute euphoric effect following amphetamine administration may predict responsiveness to the anti-depressant, imipramine. (29) Checkley has reported a flattened cortisol response in depressives to methyl-amphetamine infusion in the afternoon. (12) Sachar et al. has demonstrated that amphetamine infusion in the morning in depression may cause a paradoxical supression of c o r t i s o l . There are no reports of the effects of amphetamine infusion on plasma B-endorphin in depressives. In a preliminary study of major depression, basal morning B-endorphin levels have been found to be normal despite the group's s i g n i f i c a n t l y elevated cortisol levels. (31) The physiological effect of changes of plasma B-endorphin in the range found in this study has yet to be demonstrated. However, alterations of behavioral responses to amphetamine in rats have been reported with naloxone pre-treatment. (32) This suggests the involvement of an opioid system in the modulation of amphetamine induced behavior. References I. 2. 3. 4. 5. 6. 7.
S. ANTELMAN and A. CAGGIULA, Psychobiology of Consciousness,( J. Davidson and R.M. Davidson eds.) pp. 65-104, Plenum Press, New York, 1980. J. MASON, Emotions: Their Parameters and Measurements, (L. Levi, ed.) p. 143, Raven Press, New York, 1975. J. MORLEY, and A. LEVINE, Science 209, 1259-61, 1980. J.W. HOLADAY, and H.H. LOH, Neurochemical Mechanisms of Opiate Ligands (H. Lob and D.H. Ross, eds.) pp. 227-257, Raven Press, New York, 1979. J. ROSSlER, E. FRENCH, C. RIVIER, N. LING, R. GUILLEMIN and F. BLUM, Nature 270, 668-620, 1977. J. MADDEN, IV, H. AKIL, R.L. PATRICK, and L.D. RARCHAI, Nature 265, 358-360, 1979. R. GOLAND, S. WARDLAW, R. STARK and A. FRANTZ, Clin, Endocrinol Metab 52, 74-78, 1981.
Vol. 29, No. 12, 1981
8. 9. I0. Iio 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
Amphetamine and Beta Endorphin
1247
M. COHEN, D. PICKAR, M. DUBOIS, Y. ROTH, D. NABERand W.E. BUNNEY, JR, Lancet I , 213-214, 1981. J.L. HENNESSYand S. LEVINE, Physiological Psychology, 8 (J. Sprague, A. Epstein, eds.) pp. 134-178, Academic Press, 1979. S. ANTELMAN, N. ROWLANDand A. FISHNER, Brain Research 102, 346-350, 1976. B.M. BESSER, P.W. BUTLER, J. LANDONand L. REES, Br Med J 29, 528-30, 1969. S.A. CHECKLEY, Psychol Med 9, 107-116, 1979. J. NURNBERGER, E. GERSHON, D. JIMERSON, M. BUCHSBAUM, P. GOLD, G. BROWNand M. EBERT, Genetic Research Strategies in Psychobiology and Psychiatry, (E. Gershon, S. Matthyse, X. Breakefield and R.D. Ciaranello eds.) Boxwood Press, in press. M. COHEN, Unpublished data. G.M. BESSER, P.W. BUTLER, J.G. RATCLIFFE, L. REES, and P. YOUNG, Br J Pharmacol 39(I), 196-197, 1970. W.A. BROWN, D.P. CORRIVEAU, and M.H. EBERT, Psychopharmacology 58 (2), 189-195, 1978. L. REES, P.W. BUTLER, C. GOSLING, and G.M. BESSER, Nature 7, 228(271) 565566, 1970. S.A. CHECKLEY, Physiological Medicine I0, 35-53, 1980. J. NURNBERGER,JR., E. GERSHON, N. SITARAM, J.GILLIN, G. BROWN, M. EBERT, P. GOLD, D. JIMERSON, and L. KESSLER, Psychopharmacol Bull, in press. A.F. BRADBURY, D.G. SMYTH, and C.R. SNELL, Biochem Biophys Res Commun 69, 950-956, 1976. N. KALIN, S. RISCH, R. COHEN, T. INSEL, and D. MURPHY, Science 209, 827828, 1980. M. COHEN, Unpublished data. SCHULZ, D. VAN KAMMEN, A. ROGOL, M. EBERT, D. PICKAR, M. COHENand D. NABER, Psychopharmacology Bulletin, in press. R. COHEN, I. CAMPBELL, M. COHEN, T. TORDA, D. PICKAR, L. SIEVER and D. MURPHY, Psychiatric Research 3, 93-105, 1980. M. HAMILTON, J of Neurol Neurosurg and Psychiat 23, 56-62, 1960. L. STROMGREN,Acta Psychiatrica Scand 56, 109-128, 1977. M. SCHLESSER, Go WINOKUR, and B. SHERMAN, Lancet I I , 739-741, 1979. F. STRICKER, M. ZIGMOND, Progress in Psychobiology and Physiological Psychogy, (J. Sprague and A. Epstein, eds.), pp. 121-188, Academic Press, New York, pp. 121-188, 1976. D. VAN KAMMEN, and D. MURPHY, A J Psych 135, 1179-1183, 1978. E. SACHAR, G. ASNIS, R. NATHAN, U. HALBREICH, M. TABRIZI and F. HALPREN, Arch Gen Psychiatry 371(71), 755-757, 1980. D. PICKAR, Unpublished data. P. ADAMS, R. BEAUCHAMPand C. ALSTON, Life Sciences 28, 629-634, 1981.