A variety of studies indicate that the amount of tyrosine hydroxylase synthesized in a neuron, and thus ultimately the rate of catecholamine synthesis, is affected, presumably by an interneuronal mechanism, by the amount of catecholinergic activity on the receptors of adjacent neurons (449, 467). This mechanism of regulation depends on induction or repression of enzyme synthesis. It is relatively slow and requires several days to become manifest. Chronic treatment with presumed blockers of catecholamine receptor sites such as chlorpromazine (129, 450-458), thioproperazine (459, 459a), phenoxybenzamine (460-463), or benzoctamine (464) increases the amount of tyrosine hydroxylase in adrenal, brain, and/or sympathetic ganglia. So does treatment with reserpine ( 462-468), which depletes the amines.
Experiments on chicks (469) suggest that the effect of reserpine on brain tyrosine hydroxylase may be permanent, or long lasting, if the reserpine is administered during development. These effects of chlor
promazine (457, 470) and reserpine (466) have been said to be highly dose dependent and, in the brain, may not be evident in NE neurons
(453). Chronic treatment with reserpine also leads to increases in brain tryptophan hydroxylase, presumably by an analogous mechanism (397, 467).
These agents have no effect on tyrosine or tryptophan hydroxylase in vitro (9, 83, 471). Their mechanism of action in vivo probably in
volves induction of enzyme biosynthesis. The reserpine response is blocked by the protein synthesis inhibitors actinomycin D or cyclo-heximide (465).
Catecholamine excretion data on depressed patients under treatment with imipramine have been interpreted as indicating the converse effect, i.e., feedback (interneuronal) repression of synthesis (472, 473), but imipramine has multiple effects on catecholamine transport and metabol
ism that make interpretation uncertain (474)- Recently (475) chronic
2 . AMINO ACID HYDROXYLASE INHIBITORS 89 treatment of rats with 1000 mg/kg of L - D O P A daily for 5-7 days was shown to cause a progessive reduction of adrenal tyrosine hydroxylase.
Brain tyrosine hydroxylase levels were unchanged. The decrease of up to 5 0 % in adrenal tyrosine hydroxylase was attributed to feedback re
pression of synthesis of the enzyme due to the high levels of NE in DOPA-treated animals.
Similar feedback (interneuronal) control mechanisms have been hy
pothesized to explain the effects on tyrosine hydroxylase of 6-hydroxy-dopamine ( 4 6 7 , 468, 476) or amphetamine (468) in the adrenals
(increasing), of amphetamine in the caudate (477) (reducing), and of nicotine in the brain (increasing) (478). Recently it has been suggested (467) that cyclic A M P may play an important role in interneuronal control mechanisms.
It has been reported that LSD-25 reduces both the synthesis and turnover of brain serotonin (479) but, like the hallucinogenic muscinol, it increases brain 5-HT levels (480). The mechanism of action is unclear but may involve interneuronal mechanisms. Brain tryptophan hydroxyl
ase activity is not inhibited by LSD in vitro (83). Interneuronal feed
back has also been suggested as a factor in the inhibition of the conver
sion of tryptophan to serotonin in the brains of cocaine-treated mice (398) and in the increased rate of serotonin synthesis in rats treated with lithium (481) or morphine (see Section V,C).
VI. CONCLUSION
The development of relatively specific metabolic inhibitors of tyrosine, tryptophan, and phenylalanine hydroxylases has added a powerful tool to the armamentarium of scientists attempting to identify the role of the central and peripheral amines in various physiological functions.
Unfortunately, interpretation of the results obtained to date is difficult because the powerful inhibitors of phenylalanine hydroxylase so far dis
covered are likewise inhibitors of other enzymes, generally tryptophan hydroxylase. The full clinical potentiality of these hydroxylase inhibitors also remains to be explored. The limited studies to date suggest that tyrosine hydroxylase inhibitors should find clinical usefulness in the treatment of various chromaffin tissue tumors such as pheochromo-cytomas and other adenomas of this type. Further exploration in essen
tial hypertension may be warranted, although preliminary results are discouraging and a primary defect in catecholamine metabolism in this
90 E. G. MCGEER AND P. L. MCGEER
condition has never been proven. The report that a-MPT reduced excre
tion of DOPA and retarded tumor growth in hamsters with melantotic melanoma (482) suggests another condition in which tyrosine hydroxyl
ase inhibitors might be worth further testing, although the initial clinical trial in a patient with metastatic malignant melanoma was unsuccessful
(483). It is also possible that tyrosine hydroxylase inhibitors may be useful in such extrapyramidal disorders as chorea which might benefit from decreased dopaminergic tone.
Further exploration of the clinical usefulness of tryptophan hydroxyl
ase inhibitors will also undoubtedly be done, with possibilities, suggested by animal studies, lying not only in the field of carcinoid tumors but in sexual problems and drug addiction. The activity of the 5-HT depletor, p-chloro-iV-methylamphetamine, as an antidepressant (378, 484-486) suggests possible use of tryptophan hydroxylase inhibitors, alone or with DOPA, in some forms of depression, while the beneficial effects obtained with a serotonin antagonist in the dumping syndrome (487) suggests another area for clinical trial. Trial of either type of hydroxylase inhibitor in various mental disorders, which are now treated with amine-depleting and -blocking agents, in different types of sleep disorder or in sexual problems may be worthwhile. One difficulty with PCP for such exploration is that it is such a powerful inhibitor in vivo of phenylalanine hydroxylase; other agents such as the 6-halotryp-tophans should probably be tested for their in vivo effects on phenyl
alanine hydroxylase and, if inactive, might prove safer for the exploration of the clinical usefulness of tryptophan hydroxylase inhibitors.
The search for new and more potent inhibitors of these hydroxylases will undoubtedly be continued. It would appear unlikely, however, in view of the wide screening for direct inhibitors of tryptophan and tyrosine hydroxylases, that agents much more potent than those presently known will be found. This probability focuses more attention on the indirect mechanisms of inhibition discussed in Section V, and these will undoubtedly grow in importance as more information is gathered.
REFERENCES
1. S. Kaufman, W . F. Bridgers, F. Eisenberg, and S. Friedman, Biochem. Biophys.
Res. Commun. 9 , 497 (1962).
2. M . Viscontini and G. Mattern, Helv. Chim. Acta 5 3 , 832 (1970).
3. W . F. Coulson, M . J. Powers, and J. B. Jepson, Biochim. Biophys. Acta 2 2 2 , 606 (1970).
4. T . Nagatsu, M . Levitt, and S. Udenfriend, J. Biol. Chem. 2 3 9 , 2910 (1964).
5. K . H e m p l e . a n d H . F. K . Mann, Biochim. Biophys. Acta 1 2 4 , 192 (1966).
6. T . Nagatsu and T . Yamamoto, Experientia 2 4 , 1183 (1968).
2. AMINO ACID HYDROXYLASE INHIBITORS 91
7. T . Nagatsu, M . Levitt, and S. Udenfriend, Anal. Biochem. 9 , 122 (1964).
8. L. Ellenbogen, R . J. Taylor, Jr., and G. B . Brundage, Biochem. Biophys.
Res. Commun. 1 9 , 708 (1965).
9. E. G. McGeer and P. L. McGeer, Can. J. Biochem. 4 5 , 115 (1967).
10. E. G. M c G e e r and P. L. McGeer, unpublished observations (1969).
10a. B . Waldeck, Pharm. Pharmacol. 23, 64 (1971).
11. L. J. Cote and S. Fahn, in "Progress in Neuro-Genetics" ( A . Barbeau and J. R . Brunette, eds.), p. 311. Excerpta M e d . Found., Amsterdam, 1969.
12. E. G. McGeer, S. Gibson, J. A. Wada, and P. L. McGeer, Can. J. Biochem.
4 5 , 1943 (1967).
13. N . Sanpitak, R . H . Kathan, and I. M . Rosenthal, / . Pediat. 7 4 , 834 (1969).
14. M c C . Goodall and N . Kirshner, Circulation 1 7 , 366 (1958).
15. C. N . Gillis and R . H . Roth, Experientia 26, 960 (1970).
16. P. E . Pool, J. W . Covell, M . Levitt, J. Gibb, and E . Braunwald, Circ. Res.
20, 349 (1967).
17. M . Ikeda, M . Levitt, and S. Udenfriend, Biochem. Biophys. Res. Commun.
1 8 , 482 (1965).
18. P. Laduron and F. Belpaire, Nature (London) 217, 1155 (1968).
19. R . Shiman, M . Akino, and S. Kaufman, J. Biol. Chem. 246, 1330 (1971).
20. P. Laduron and F. Belpaire, Biochem. Pharmacol. 1 7 , 1127 (1968).
20a. R . J. Wurzburger and J. M . Musacchio, J. Pharmacol. Exp. Ther. 1 7 7 , 155 (1971).
21. L. Austin, B . G. Livett, and I. W . Chubb, Circ. Res. 21, Suppl. 3, 111 (1967).
22. E. G. McGeer, P. L. McGeer, and J. A. Wada, J. Neurochem. 18, 1647 (1971).
23. S. P. Bagchi and P. L. McGeer, Life Sci. 3, 1195 (1964).
24. P. L. McGeer, S. P. Bagchi, and E . G. McGeer, Life Sci. 4 , 1859 (1965).
25. S. Fahn, J. S. Rodman, and L. J. Cote, J. Neurochem. 16, 1293 (1969).
26. T . Nagatsu and I. Nagatsu, Experientia 26, 722 (1970).
27. S. Fahn and L. J. Cote, Neurology 18, 293 (1968). .
28. M . Ikeda, L. A. Fahien, and S. Udenfriend, J. Biol. Chem. 241, 4452 (1966).
29. S. Ayukawa, T . Takeuchi, M . Sezaki, T . Haro, H . Umezawa, and T . Nagatsu, J. Antibiot. 21, 350 (1968).
30. J. H . Joh, R . Kapit, and M . Goldstein, Biochim. Biophys. Acta 171, 378.
(1969).
31. A . R . Brenneman and S. Kaufman, Biochem. Biophys. Res. Commun. 17, 177 (1964).
32. S. Kaufman, Trans. N.Y. Acad. Sci. [2] 26, 977 (1964).
33. S. Kaufman, Proc. Nat. Acad. Sci. U.S. 50, 1085 (1963).
34. S. Udenfriend, Pharmacol. Rev. 18, 43 (1966).
35. B. Petrack, F. Sheppy, and V. Fetzer, J. Biol. Chem. 243, 743 (1968).
35a. J. M . Musacchio, R. J. Wurzberger, and G. L. D'Angelo, Mol. Pharmacol.
7, 136 (1971).
36. E . G. McGeer, S. Gibson, and P. L. McGeer, Can. J. Biochem. 45, 1557 (1967).
37. T . Nagateu, M . Levitt, and S. Udenfriend, Biochem. Biophys. Res. Commun.
14, 543 (1964).
38. G. Guroff, C. A. Rhoads, and A. Abramowitz, Anal. Biochem. 21, 273 (1967).
39. S. Udenfriend, P. Zaltzman-Nirenberg, and T . Nagatsu, Biochem. Pharmacol.
14, 837 (1965).
92 E. G. MCGEER AND P. L. MCGEER 40. M . Ikeda, M . Levitt, and S. Udenfriend, Arch. Biochem. Biophys. 120, 420
(1967).
41. P. Justice, M . E. O'Flynn, and D . Y . - Y . Hsia, Lancet 1, 928 (1967).
42. W . H . Vogel, H . McFarland, and L. N . Prince, Biochem. Pharmacol. 19, 618 (1970).
43. K . L l o y d and 0 . Hornykiewicz, Brain Res. 22, 426 (1970).
43a. K . Lloyd and O. Hornykiewicz, Science 170, 1212 (1970).
43b. W . Sacks, / . Appl. Physiol. 16, 1050 (1961).
44. S. Spector, Pharmacol. Rev. 18, 599 (1966).
45. S. Udenfriend, P. Zaltzman-Nirenberg, R . Gordon, and S. Spector, Mol. Pharma
col. 2, 95 (1966).
46. S. M . Hess, R . H . Connamacher, M . Ozaki, and S. Udenfriend, J. Pharmacol.
134, 129 (1961).
47. M . Levitt, S. Spector, A. Sjoerdsma, and S. Udenfriend, J. Pharmacol. Exp.
Ther. 148, 1 (1965).
48. G. Guroff, J. W . Daly, D . M . Jerina, J. Renson, B. Witkop, and S. Udenfriend, Science 157, 1524 (1967).
49. J. Renson, J. Daly, H. Weissbach, and D . G. Friend, Biochem. Biophys. Res.
Commun. 25, 503 (1966).
50. H . Green and J. L. Sawyer, Anal. Biochem. 15, 53 (1960).
51. D . A. V. Peters, P. L. McGeer, and E. G. McGeer, J. Neurochem. 15, 1431 (1968).
52. W . Lovenberg, E. Jequier, and A. Sjoerdsma, Advan. Pharmacol. 6, 21 (1968).
53. W . Lovenberg, E. Jequier, and A. Sjoerdsma, Science 155, 217 (1967).
54. E. M . Gal, J. C. Armstrong, and B. Ginsberg, J. Neurochem. 13, 643 (1966).
55. D . G. Grahame-Smith, Biochim. Biophys. Acta 86, 176 (1964).
56. R . Hakanson and G. J. Hoffman, Biochem. Pharmacol. 16, 1677 (1967).
57. A. Ichiyama, S. Nakamura, Y . Nishizuka, and O. Hayaishi, Biol. Chem.
245, 1699 (1970).
58. S. Hosoda and D . Glick, / . Biol. Chem. 241, 192 (1966).
59. S. B. Ross and O. Haljasmaa, Life Sci. 3, 579 (1964).
60. R . J. Levine, W . Lovenberg, and A. Sjoerdsma, Biochem. Pharmacol. 13, 1283 (1964).
61. R . A. Freedland, I. M . Wadzinski, and H . A . Waisman, Biochem. Biophys.
Res. Commun. 5, 94 (1961).
62. J. R . Cooper and I. Melcer, J. Pharmacol. Exp. Ther. 132, 265 (1961).
63. J. Renson, F. Goodwin, H. Weissbach, and S. Udenfriend, Biochem. Biophys.
Res. Commun. 6, 20 (1961).
64. J. Renson, H . Weissbach, and S. Udenfriend, J. Biol. Chem. 237, 2261 (1962);
Fed. Proc, Fed. Amer. Soc. Exp. Biol. 21, 323 (1962).
65. B. B. Brodie, J. Axelrod, P. A. Shore, and S. Udenfriend, J. Biol. Chem.
208, 741 (1954).
66. W . Lovenberg, R . J. Levine, and S. Sjoerdsma, Biochem. Pharmacol. 14, 887 (1965).
67. H. M . Shein, R . J. Wurtman, and J. Axelrod, Nature (London) 213, 730 (1967).
68. S. Nakamura, A . Ichiyama, and O. Hayaishi, Fed. Proc, Fed. Amer. Soc.
Exp. Biol. 24, 604 (1965).
69. D . G. Grahame-Smith, Biochem. Biophys. Res. Commun. 16, 586 (1964).
2. AMINO ACID HYDROXYLASE INHIBITORS 93
70. H . Green and J. L. Sawyer, Fed. Proc, Fed. Amer. Soc. Exp. Biol. 24, 604 (1965).
71. W . v o n Studnitz, Experientia 23, 711 (1967).
71a. D . G. Grahame-Smith, Biochem. J. 105, 351 (1967).
72. N . E . Anden, K . Fuxe, B. Hamberger, and T . Hokfelt, Acta Physiol. Scand.
67, 306 (1966).
73. D . Robinson, W . Lovenberg, and A. Sjoerdsma, Arch. Biochem. Biophys. 123, 419 (1965).
74. R. H . Roth, L. Stjarne, and U. S. v o n Euler, Life Sci. 5, 1071 (1966).
75. T . L. Sato, E. Jequier, and W . Lovenberg, Eur. J. Pharmacol. 1, 18 (1967).
76. O. Hayaishi, S. Okuno, and H . Fujisawa, Biochem. Biophys. Res. Commun.
39, 643 (1970).
77. W . B. Quay, Proc. Soc. Exp. Biol. Med. 114, 718 (1963).
78. H . Green, S. M . Greenberg, R . W . Erickson, J. L. Sawyer, and T . Ellison, /. Pharmacol. Exp. Ther. 136, 174 (1962).
79. E. M . Gal, P. A . Drewes, and C. A . Barraclough, Biochem. Pharmacol. 8, 32 (1961).
80. T . J. Sullivan, Brit. J. Pharmacol. 15, 513 (1960).
81. J. D . Driessehe, P. Allain, and E. Eben-Moussi, C. R. Acad. Sci., Ser. D 266, 1683 (1968).
82. T . L. Sourkes, K . Missala, and M . Oravec, / . Neurochem. 17, 111 (1970).
83. E . G. M c G e e r and D . A. V . Peters, Can. J. Biochem. 47, 501 (1969).
84. D . G. Grahame-Smith, Clin. Sci. 33, 147 (1967).
85. T . P. Waalkes and S. Udenfriend, J. Lab. Clin. Med. 50, 733 (1957).
86. S. Udenfriend and J. R . Cooper, J. Biol. Chem. 196, 227 (1952).
87. S. Kaufman, Arch. Biochem. Biophys. 134, 249 (1969).
88. G. Guroff, M . Levitt, J. Daly, and S. Udenfriend, Biochem. Biophys. Res.
Commun. 25, 253 (1966).
89. G. Guroff and A. Abramowitz, Arch. Biochem. Biophys. 122, 212 (1967).
90. G. Guroff and A. Abramowitz, Anal. Biochem. 19, 548 (1967).
91. S. Kaufman, in "Methods in E n z y m o l o g y " (S. P. Colowick and N . O. Kaplan, eds.), V o l . 5, p. 809. Academic Press, New York, 1962.
92. S. Kaufman, Pharmacol. Rev. 18, 61 (1966).
93. C. B. Storm and S. Kaufman, Biochem. Biophys. Res. Commun. 32, 788 (1968).
94. S. P. Bagchi and E . P. Zarycki, Life Sci. 9 (pt 1), 111 (1970).
95. S. Kaufman and D . B. Fisher, J. Biol. Chem. 245, 4745 (1970).
96. S. Udenfriend and C. Mitoma, in "Amino Acid Metabolism" ( W . D . M c E l r o y and B. Glass, eds.), p. 876. Johns Hopkins Press, Baltimore, Maryland, 1955.
97. A. R. Brenneman and S. Kaufman, J. Biol. Chem. 240, 3617 (1965).
98. A. Jakubiec-Puka and I. Mochnacka, Acta Biochim. Pol. 16, 321 (1969).
99. V. G. Zannoni and E. Moraru, in "Metabolic Regulation and Enzyme Action"
(A. Sols and S. Grisolia, eds.), p. 347. Academic Press, New York, 1970.
100. C . Mitoma, Arch. Biochem. Biophys. 60, 476 (1956).
101. F. T . Kenney, G. H . Reem, and N . Kretchmer, Science 127, 86 (1958).
102. F. T . Kenney and N . Kretchmer, J. Clin. Invest. 38, 2189 (1959).
103. R . A . Freedland, M . C . Krakowski, and H . A . Waisman, Amer. J. Physiol.
202, 145 (1962).
104. S. D . Huff and J. L. Fuller, Science 144, 304 (1964).
94 E. G. MCGEER AND P. L. MCGEER 105. D . L. Coleman, Arch. Biochem. Biophys. 91, 300 (1960).
106. V . G. Zannoni, W . W . Weber, P. van Valen, A . Rubin, R . Bernstein, and B . N . LaDu, Genetics 54, 1391 (1966).
107. L. I. Woolf, A. Jakubovic, F. Woolf, and P. Bory, Biochem. J. 119, 895 (1970).
108. R . W . Fuller, Life Sci. 4, 1 (1965).
109. G . Dolan and C. Godin, Biochemistry 5, 922 (1966).
109a. R . E . Counsell, P. S-. Chan, and P. A. Weinhold, Biochim. Biophys. Acta 215, 187 (1970).
110. G. Guroff, K . K o n d o , and J. Daly, Biochem. Biophys. Res. Commun. 25, 622 (1966).
111. J. Daly and G. Guroff, Arch. Biochem. Biophys. 125, 136 (1968).
112. H . S. Posner, C. Mitoma, and S. Udenfriend, Arch. Biochem. Biophys. 94, 269 (1961).
113. C. Mitoma, H . S. Posner, H . C. Reitz, and S. Udenfriend, Arch. Biochem.
Biophys. 61, 431 (1956).
114. N . H . Sloane, Biochim. Biophys. Acta 81, 408 (1964).
115. L. Lemberger, A . Klutch, and R . Kuntzman, J. Pharmacol. Exp. Ther. 153, 183 (1966).
116. J. B . Jepson, P. Zaltzman, and S. Udenfriend, Biochim. Biophys. Acta 62, 91 (1962).
117. S. Szara and E . Hearst, Ann. N.Y. Acad. Sci. 96, 134 (1962).
118. S. Szara, Experientia 17, 76 (1961).
119. S. Szara and F. Putney, Fed. Proc, Fed. Amer. Soc. Exp. Biol. 20, 172 (1961).
120. I. J. Kopin, C. M . B. Pare, J. Axelrod, and H . Weissbach, J. Biol. Chem.
236, 3072 (1961).
121. S. Kveder and W . M . Mclsaac, J. Biol. Chem. 236, 3214 (1961).
122. I. J. Kopin, C . M . B. Pare, J. Axelrod, and H . Weissbach, Biochim. Biophys.
Acta 40, 377 (1960).
123. R . G. Taborsky, P. Delvigs, and I. H . Page, J. Med. Chem. 8, 855 (1965).
124. R . J. Wurtman and J. Axelrod, Nature (London) 212, 312 (1966).
125. L. Lemberger, R . Kuntzman, A . H . Conney, and J. J. Burns, J. Pharmacol.
Exp. Ther. 150, 292 (1965).
126. W . P. Burkard, K. F. Gey, and A. Pletscher, Med. Pharmacol. Exp. 13, 388 (1965).
127. E . M . Gal, S. K . Chatterjee, and F. D . Marshall, Jr., Biochim. Biophys.
Acta 85, 495 (1964).
128. G. A . Johnson, E . G. K i m , P. A . Platz, and M . M . Mickelson, Biochem.
Pharmacol. 17, 403 (1968).
129. H . Nyback and G. Sedvall, / . Pharmacol. Exp. Ther. 162, 294 (1968).
130. M . Levitt, J. W . Gibb, J. W . Daly, M . Lipton, and S. Udenfriend, Biochem.
Pharmacol. 16, 1313 (1967).
131. J. I. Degraw, M . Cory, and W . A . Skinner, J. Med. Chem. 11, 375 (1968).
132. B. K . K o e , Med. Pharmacol. Exp. 17, 129 (1967).
133. G. C . Cotzias, P. S. Papavasiliou, C. Fehling, B. Kaufman, and I. Mena, N. Engl. J. Med. 282, 31 (1970).
134. M . Goldstein, L. S. Freedman, and T . Backstrom, J. Pharm. Pharmacol. 22, 715 (1970).
135. M . Goldstein, H. Gang, and B. Anagnoste, Life Sci. 6 (pt 2), 1457 (1967).
136. R. J. Taylor, Jr and L . Ellenbogen, Life Sci. 6 (pt 2), 1463 (1967).
2. AMINO ACID HYDROXYLASE INHIBITORS 95
137. R . J. Taylor, Jr., C. S. Stubbs, Jr., and L. Ellenbogen, Biochem. Pharmacol.
18, 587 (1969).
138. B . N . LaDu and V . G. Zannoni, in "Phenylketonuria and Allied Metabolic Diseases" (J. A . Anderson and K . F. Swaiman, eds.), p. 193. U.S. G o v t . Printing Office, Washington, D.C., 1967.
139. B . N . Lutsky and N . Zenker, / . Med. Chem. 11, 1241 (1968).
140. W . S. Saari, J. Williams, S. F. Britcher, D . E. Wolf, and F. A . Kuehl, Jr., J. Med. Chem. 10, 1008 (1967).
141. D . B . McCormick, S. K . Young, and M . N . Woods, Proc. Soc. Exp. Biol.
Med. 118, 131 (1965).
142. J. P. Greenstein, "Biochemistry of Cancer," 2nd rev. ed., p. 97. Academic Press, New York, 1954.
143. D . K . Zhelyaskov, M . Levitt, and S. Udenfriend, Mol. Pharmacol. 4, 445 (1968).
144. P. A . Weinhold and V . B . Rethy, Biochem. Pharmacol. 18, 677 (1969).
145. R . E . Counsell, P. Desai, T . D . Smith, P. S. Chan, P. A. Weinhold, V . B.
Rethy, and D . Burke, J. Med. Chem. 13, 1040 (1970).
146. E . G. McGeer, P. L. McGeer, and D . A. V . Peters, Life Sci. 6, 2221 (1967).
147. E . G. McGeer, D . A . V . Peters, and P. L. McGeer, Life Sci. 7 (pt 2 ) , 605 (1968).
148. M . Goldstein and Z . Weiss, Life Sci. 4, 261 (1965).
149. W . F. Coulson, E . Wardle, and J. B. Jepson, Biochim. Biophys. Acta 167, 99 (1968).
150. R . A. Freedland, I. M . Wadzinski, and H . A. Waisman, Biochem. Biophys.
Res. Commun. 6, 227 (1961).
151. R . K . K o e and A . Weissman, J. Pharmacol. Exp. Ther. 154, 499 (1966).
152. H . Corrodi, K . Fuxe, and T . Hokfelt, Eur. J. Pharmacol. 1, 363 (1967).
153. B. J. Meyerson and T . Lewander, Life Sci. 9, (pt 1), 661 (1970).
154. H . Corrodi, K . Fuxe, and T . Hokfelt, J. Pharm. Pharmacol. 19, 433 (1967).
155. H . Corrodi, K . Fuxe, and T. Hokfelt, Advan. Pharmacol. 6B, 49 (1968).
156. S. B. Ross and O. Haljasmaa, Acta Pharmacol. Toxicol. 24, 55 (1966).
157. H . Corrodi, K . Fuxe, and T . Hokfelt, Acta Physiol. Scand. 71, 224 (1967).
158. B . Falck, C . Owman, and E . Rosengren, Acta Physiol. Scand. 67, 300 (1966).
159. W . C . Chan and G. E. Johnson, Eur. J. Pharmacol. 3, 40 (1968).
160. B. K . K o e and A . Weissman, J. Pharmacol. Exp. Ther. 157, 565 (1967).
161. W . P. Burkard, K . F. Gey, and A . Pletscher, C. R. Suisse Physiol. 6 4 , C109 (1964).
162. W . P. Burkard, K . F. Gey, and A . Pletscher, Life Sci. 3, 27 (1964).
163. H . Nyback, J. Schubert, and G. Sedvall, J. Pharm. Pharmacol. 22, 622 (1970).
164. A. Carlsson and M . Lindqvist, Acta Physiol. Scand. 54, 87 (1962).
165. N . E. Anden, S. G. Butcher, and J. Engel, J. Pharm. Pharmacol. 22, 548 (1970).
166. C. C. Porter, J. J. Totaro, and A . Burcin, J. Pharmacol. Exp. Ther. 150, 17 (1965).
167. N . E . Anden, K . Fuxe, and M . Henning, Eur. J. Pharmacol. 8, 302 (1969).
168. J. F. Moran and T . L. Sourkes, J. Pharmacol. Exp. Ther. 148, 252 (1965).
169. T . L. Sourkes, G. F. Murphy, B. Chavez, and M . Zielinska, J. Neurochem.
8, 109 (1961).
96 E. G. MCGEER AND P. L. MCGEER 170. I. J. Kopin, V. K . Weise, and G. C. Sedvall, J. Pharmacol Exp. Ther. 170,
246 (1969).
171. E . M . Gal, M . Morgan, and F. D . Marshall, Jr., Life Sci. 4, 1765 (1965).
172. R . Laverty, D . F. Sharman, and M . Vogt, Brit. J. Pharmacol. 24, 549 (1965).
173. G. Hausler, H . Thoenen, and W . Haefely, Helv. Physiol. Pharmacol. Acta 26, CR223 (1968).
173a. G. Jonsson and C. Sachs, Acta Physiol. Scand. 80, 307 (1970).
174. C. C. Porter, J. A. Totaro, and C. A. Stone, / . Pharmacol. Exp. Ther. 140, 308 (1963).
175. P. U. Angeletti and R . Levi-Montalcini, Arch. Ital. Biol. 108, 213 (1970).
176. T. Malmfors and C . Sachs, Eur. J. Pharmacol. 3, 89 (1968).
177. J. P. Tranzer and H . Thoenen, Experientia 24, 155 (1968).
178. U. Ungerstedt, Eur. J. Pharmacol. 5, 107 (1968).
178a. G. Bartholini, J. G. Richards, and A . Pletscher, Experientia 26, 142 (1970).
178b. N . J. Uretsky and L. L. Iversen, / . Neurochem. 17, 269 (1970).
178c. L. L. Iversen and N . J. Uretsky, Brain Res. 24, 364 (1970).
178d. L. J. Bell, L. L. Iversen, and N . J. Uretsky, Brit. J. Pharmacol 40, 790 (1970).
178e. R . Laverty and K . M . Taylor, Brit. J. Pharmacol. 40, 836 (1970).
179. G. Haeusler, W . Haefely, and H. Thoenen, J. Pharmacol. Exp. Ther. 170, 50 (1969).
180. A. Carlsson, H . Corrodi, and B. Waldeck, Helv. Chim. Acta 46, 2271 (1963).
181. R . E . Giles and J. W . Miller, J. Pharmacol. Exp. Ther. 158, 189 (1967).
182. M . Goldstein, E. Lauber, and M . R . McKereghan, Biochem. Pharmacol. 13, 1103 (1964).
183. M . Goldstein, E. Lauber, and M . R . McKereghan, Biol Chem. 240, 2066 (1965).
184. H . Ozawa and H . Kawashima, J. Pharm. Soc. Jap. 87, 345 (1967).
185. G. E . Johnson and T. A. Pugsley, Brit. J. Pharmacol. 39, 167 (1970).
186. P. A . Shore, D . Busfield, and H . S. Alpers, J. Pharmacol. Exp. Ther. 146, 194 (1964).
187. H . Thoenen, W . Haefely, K . F. Gey, and A. Huerlimann, Life Sci. 5, 723 (1966).
188. L. Maitre, Life Sci. 4, 2249 (1965).
189. L. A. Loizou, Brit. J. Pharmacol 41, 41 (1971).
190. A . Weissman and B. K . K o e , Psychopharmacologia 11, 282 (1967).
191. A . Weissman, B. K . K o e , and S. S. Tenen, J. Pharmacol. Exp. Ther. 151, 339 (1966).
192. A. Weissman and B. K . K o e , Life Sci. 4, 1037 (1965).
193. S. Spector, A. Sjoerdsma, and S. Udenfriend, J. Pharmacol. Exp. Ther. 147, 86 (1965).
194. C. C . Porter, J. A . Totaro, A. Burcin, and E. R . Wynosky, Biochem. Pharmacol.
15, 583 (1966).
195. D . D . Feist, Life Sci. 9 (pt 1), 117 (1970).
196. N . E . Anden, Eur. J. Pharmacol. 1, 1 (1967).
197. M . Duce, F. Crabai, L. Vargiu, L. Piras, F. Adamo, and G. L. Gessa, Boll.
Soc. Ital Biol. Sper. 43, 1607 (1967).
198. H . Corrodi and T. Malmfors, Acta Physiol Scand. 67, 352 (1966).
2. AMINO ACID HYDROXYLASE INHIBITORS 97
199. N . E. Anden, H . Corrodi, A. Dahlstrom, K . Fuxe, and T . Hokfelt, Life Sci.
5, 561 (1966).
200. N . E. Anden, K . Fuxe, and T . Hokfelt, J. Pharm. Pharmacol. 18, 630 (1966).
201. B. L. Welch and A. S. Welch, Nature (London) 218, 575 (1968).
202. P. M . Diaz, S. H . Ngai, and E. Costa, Fed. Proc, Fed. Amer. Soc. Exp.
Biol. 26, 708 (1967).
203. H. Corrodi, K Fuxe, and T . Hokfelt, Life Sci. 7 (pt 1), 107 (1968).
204. R . Gordon, S. Spector, A . Sjoerdsma, and S. Udenfriend, / . Pharmacol. Exp.
Ther. 153, 440 (1966).
205. A. Dahlstrom, K . Fuxe, D . Kernall, and G. Sedvall, Life Sci. 4, 1207 (1965).
206. K . Fuxe and L. M . Gunne, Acta Physiol. Scand. 62, 493 (1964).
207. L. M . Gunne, J. Jonsson, and K . Fuxe, Eur. J. Pharmacol. 5, 338 (1969).
208. B. L. Welch and A. S. Welch, J. Pharm. Pharmacol. 20, 244 (1968).
209. A . S. Welch and B. L. Welch, Brain Res. 9, 402 (1968).
210. T . C. Westfall, Life Sci. 9 (pt 1), 339 (1970).
211. E . D . Weitzman, P. McGregor, C. M o o r e , and J. Jacoby, Life Sci. 8 (pt 1), 751 (1969).
212. C. Torda, Brain Res. 10, 200 (1968).
213. C. R . Creveling, J. Daly, T. Tokuyama, and B. Witkop, Biochem. Pharmacol.
17, 65 (1968).
214. R . H . Rech, L. A. Carr, and K . E. Moore, J. Pharmacol. Exp. Ther. 160, 326 (1968).
215. M . K . Menon, P. C. Dandiya, and J. S. Bapna, J. Pharmacol. Exp. Ther.
156, 63 (1967).
216. K . E. M o o r e and R . H . Rech, / . Pharm. Pharmacol. 19, 405 (1967).
217. R . I. Schoenfeld and L. S. Seiden, J, Pharmacol. Exp. Ther. 167, 319 (1969).
218. B. P. H . Poschel and F. W . Ninteman, Life Sci. 5, 11 (1966).
219. H . Corrodi, K . Fuxe, and T . Hokfelt, Life Sci. 5, 605 (1966).
220. H . Corrodi and L. C. F. Hanson, Psychopharmacologia 10, 116 (1966).
221. H . Corrodi and K . Fuxe, Life Sci. 6, 1345 (1967).
222. K. Engelman and A. Sjoerdsma, Circ. Res. 18 & 19, Suppl. 1, 104 (1966).
223. A. Sjoerdsma, K . Engelman, S. Spector, and S. Udenfriend, Lancet 2, 1092 (1965).
224. K . Engelman, E . Jequier, S. Udenfriend, and A. Sjoerdsma, J. Clin. Invest.
47, 568 (1968).
225. H. K H . Brodie, D . L. Murphy, F. Goodwin, and W . Bunney, Jr., 4th Annu.
Winter Conf. Brain Res., 1971 p. 1 (1971).
226. W . Bunney, Jr., H . K . H . Brodie, D . L. Murphy, and F. K . Goodwin, Amer.
J. Psychiat. 127, 872 (1971).
226a. S. Gershon, L. J. Hekimian, A. Floyd, Jr., and L. E. Hollister, Psychophar
macologia 11, 189 (1967).
227. L. C. F. Hanson, Psychopharmacologia 11, 8 (1967).
228. S. Gibson, E. G. McGeer, and P. L. McGeer, Exp. Neurol. 27, 283 (1970).
229. S. Spector, R . O. Mata, A. Sjoerdsma, and S. Udenfriend, Life Sci. 4, 1307 (1965).
230. M . A. Goodchild, Brit. J. Pharmacol. 36, 2 0 3 P + (1969).
231. M . Goldstein, B. Anagnoste, and K . Nakajima, Biochem. Pharmacol. 14, 1914 (1965).
98 E. G. MCGEER AND P. L. MCGEER 232. G. A . Johnson, E . G. K i m , W . Veldkamp, and R . Russell, Biochem. Pharmacol.
16, 401 (1967).
233. J. B. Stanbury, A . A . H . Kassenar, J. W . A. Meijer, and J. Terpstra, / . Clin. Endocrinol. Metab. 15, 1216 (1955).
234. P. Murray, J. A. Thomson, E. M . McGirr, and T. J. Wallace, Lancet 1, 183 (1965).
235. R . A . Lahti, P. A. Platz, and R . V . Heinzelman, Biochem. Pharmacol. 18, 1601 (1969).
236. G. A . Johnson, R . A. Lahti, T . L. Lemke, and R . V. Heinzelman, Biochem.
Pharmacol. 18, 1593 (1969).
237. J. A . Dominic and K . E. Moore, Eur. J. Pharmacol. 8, 292 (1969).
238. R . A . Lahti and P. A. Platz, Biochem. Pharmacol. 18, 2363 (1969).
238a. A . G. Roberge, K . Missala, and T . L. Sourkes, Union Med. Can. 100, 475 (1971).
239. M . L. Torchiana, C. C. Porter, C. A. Stone, and H . M . Hanson, Biochem.
Pharmacol. 19, 1601 (1970).
240. P. Stark, R. W . Fuller, and L . W . Hartlery, Life Sci. 9 (pt 1), 41 (1970).
241. W . C . Black and B. R . Cooper, Physiol. & Behav. 5, 1405 (1970).
242. D . A . Stevens, O. Resnick, and D . M . Krus, Life Sci. 6 (pt 2 ) , 2215 (1967).
243. S. S. Tenen, Psychopharmacologia 10, 204 (1967).
244. D . D . Watt and P. R . Martin, Life Sci. 8 (pt 1), 1211 (1969).
245. J. F. Brody, Jr., Psychopharmacologia 17, 14 (1970).
246. S. Takaori and C. Tanaka, Jap. J. Pharmacol. 20, 607 (1970).
247. K . Schlesinger, R . A. Schreiber, and G. T . Pryor, Psychon. Sci. 11, 225 (1968).
248. J. H . Pirch and R . H . Rech, Life Sci. 7, 173 (1968).
249. F. P. Miller, R . H . Cox, and R . P. Maickel, Neuropharmacology 9, 511 (1970).
250. D . A. Stevens and L. D . Fechter, Life Sci. 8 (pt 2), 379 (1969).
250a. L. C. F. Hanson, Psychopharmacologia 8, 100 (1965).
251. K . E. M o o r e and R . H . Rech, J. Pharmacol. Exp. Ther. 156, 70 (1967).
252. R. H . Rech, H . K . Borys, and K . E. M o o r e , / . Pharmacol. Exp. Ther. 153, 412 (1966).
253. K . E. M o o r e , Life Sci. 5, 55 (1966).
254. K . E . Moore, Pharmacologist 7, 170 (1965).
255. V . H . Sethy, R . J. Pradhan, S. S. Mandrekar, and U. K . Sheth, Psychophar
macologia 17, 320 (1970).
256. A. J. Rosen and J. Buga, Arch. Int. Pharmacodyn. Ther. 180, 299 (1969).
257. J. M . Beaton and T . J. Crow, Life Sci. 8 (pt 1), 1129 (1969).
258. R . Schoenfeld and L. S. Seiden, / . Pharm. Pharmacol. 19, 771 (1967).
259. J. H . Copenhaver, M . J. Carver, E. A. Johnson, and M . J. Saxton, Biochem.
Med. 4 , 516 (1970).
260. A . R . Somerville and B. A. Whittle, Brit. J. Pharmacol. Chemother. 31, 120 (1967).
261. R. L. Conner, J. M . Stolk, J. D . Barchas, and S. Levine, Physiol. & Behav.
5, 1215 (1970).
262. L. Volicer, Int. J. Neuropharmacol. 8, 361 (1969).
263. H . C. Fibiger and B. A . Campbell, Neuropharmacology 10, 25 (1971).
264. K . E. Moore, J. Pharm. Pharmacol. 20, 656 (1968).
265. T . H . Svensson and B. Waldeck, Psychopharmacologia 18, 357 (1970).
266. J. A . Rosecrans, Physiol. & Behav. 5, 453 (1970).
2. AMINO ACID HYDROXYLASE INHIBITORS 99
267. P. Bedard, L. Larochelle, L. J. Poirier, and T. L. Sourkes, Can. J. Physiol.
Pharmacol. 48, 82 (1970).
268. J. Mouret, J. L. Froment, and P. Bobillier, J. Physiol. (Paris) 59, Suppl., 463 (1967).
269. F. Delorme, J. L. Froment, and M . Jouvet, C. R. Soc. Biol. 160, 2347 (1966).
270. J. F. Pujol, P. Bobillier, A. Buguet, B. Jones, and M . Jouvet, C. R. Acad.
Sci. 268, 100 (1969).
271. W . P. Koella, A . Feldstein, and J. S. Czicman, Electroencephalogr. Clin. Neuro-physiol. 25, 481 (1968).
272. J. Mouret, P. Bobillier, and M . Jouvet, C. R. Soc. Biol. 161, 1600 (1967).
273. J. A. Wada and A. Terao, Exp. Neurol. 28, 501 (1970).
274. C. Torda, Brain Res. 6, 375 (1967).
275. E . D . Weitzman, M . M . Rapport, P. McGregor, and J. Jacoby, Science 160, 1361 (1968).
276. W . C. Dement, in "Sleep, Physiology and Pathology: A Symposium" (A.
Kales, ed.), p. 245. Lippincott, Philadelphia, Pennsylvania, 1969.
277. V. J. Hoyland, E. E. Shillito, and M . Vogt, Brit. J. Pharmacol. 40, 659 (1970).
278. T . J. Crowley, G. V. Pegram, and E. Smith, "Primate Electrophysiology, Particularly Related to Sleep," Aeromed. Res. Lab. R e p . A R L TR-65-5 Rep./65 1969. Holloman Air Force Base, N M 5761 St.
279. M . Jouvet, Science 163, 32 (1969).
280. R . J. Wyatt, K . Engelman, D . J. Kupfer, J. Scott, A. Sjoerdsma and F.
Snyder, Electroencephalagr. Clin. Neurophysiol. 27, 529 (1969).
281. A . Sjoerdsma, W . Lovenberg, K . Engelman, W . T . Carpenter, Jr., R . J. Wyatt, and G. L. Gessa, Ann. Intern. Med. 73, 607 (1970).
282. H . B. Cohen, J. M . Ferguson, S. J. Henriksen, J. M . Stolk, V . J. Zarcone, J. D . Barchas, and W . C. Dement, Proc. 78th Annu. Conv., APA, 1970 p . 831.
283. J. M . van Rossum, Psychopharmacologia 4, 271 (1963).
284. I. Geller and K. Blum, Eur. J. Pharmacol. 9, 319 (1970).
285. R. C. Robichaud and K . Sledge, Life Sci. 8 (pt 1), 965 (1969).
286. A. S. Welch and B. L. Welch, Biochem. Pharmacol. 17, 699 (1968).
287. M . Dominguez and V. G. Longo, Physiol. Behav. 4, 1031 (1969).
288. M . H . Sheard, Brain Res. 15, 524 (1969).
289. P. Karli, M . Verrgnes, and F. Didiergeorges, in "Aggressive Behavior" (S.
Garattini and E. B. Sigg, eds.), p. 47. Wiley, New York, 1969.
290. J. Ferguson, S. Henriksen, H. Cohen, G. Mitchell, J. Barchas, and W . Dement, Science 168, 499 (1970).
291. M . H. Sheard, Commun. Behav. Biol. 5, 71 (1970).
292. J. C. de la Torre and S. Mullan, / . Pharm. Pharmacol. 22, 858 (1970).
293. G. Chen, C. R. Ensor, and P. Bohner, Life Sci. 7 (pt 1), 1063 (1968).
294. K . Schlesinger, W . O. Boggan, and D . X . Freedman, Life Sci. 9 (pt 1), 721 (1970).
295. G. J. Alexander and L. M . Kopeloff, Brain Res. 22, 231 (1970).
296. J. C. de la Torre, H . M . Kawanaga, and S. Mullan, Arch. Int. Pharmacodyn.
Ther. 188, 298 (1970).
297. R . E. Whalen and W . G. Luttge, Science 169, 1000 (1970).
298. G. L. Gessa, A. Tagliamonte, P. Tagliamonte, and B. B. Brodie, Nature (Lon
don) 227, 616 (1970).
100 E. G. MCGEER AND P. L. MCGEER 299. A. Tagliamonte, P. Tagliamonte, and G. L. Gessa, Science 166, 1433 (1969).
300. E. E. Shillito, Brit. J. Pharmacol. 38, 305 (1970).
301. P. S. Brown, N euro endocrinology 7, 183 (1971).
302. D . S. Segal and R . E. Whalen, Psychopharmacologia 16, 434 (1970).
303. P. S. Brown, Nature {London) 214, 1268 (1967).
304. A. B. Fajer, D . Hoffman, and E. Shillito, J. Reprod. Pert. 22, 379 (1970).
305. R. D . Myers and W . L. Veale, Science 160, 1469 (1968).
306. W . L. Veale and R . D . Myers, Neuropharmacology 9, 317 (1970).
307. T. J. Cicero and S. Y . Hill, Physiol, & Behav. 5, 787 (1970).
308. H.-H. Frey and M . P. Magnussen, Biochem. Pharmacol 17, 1299 (1968).
309. F. Sulser, M . L. Owens, M . R . Norvich, and J. V . Dingell, Psychopharmacologia 12, 322 (1968).
310. B. L. Welch and A. S. Welch, J. Pharm. Pharmacol. 19, 841 (1967).
311. J. M . Stolk and R . H . Rech, Neuropharmacology 9, 249 (1970).
312. O. A. Orsingher and S. Fulginiti, Psychopharmacologia 19, 231 (1970).
313. O. Strubelt, W . Vogelberg, and G. Zetler, Arzneim.-Forsch. 20, 32 (1970).
314. H. L. Evans, Diss. Abstr. B 31, 1752 (1970).
315. H . L. Evans, / . Pharmacol. Exp. Ther. 176, 244 (1971).
316. J. Knoll and E. S. Vizi, Pharmacol. Res. Commun. 2, 67 (1970).
317. I. Marshall and D . G. Grahame-Smith, Nature (London) 228, 1206 (1970).
318. E. L. Way, H . H. Loh, and F.-H. Shen, Science 162, 1290 (1968).
319. M . J. Mattila, E. Alhava, and R . Mansner, Arzneim.-Forsch. 18, 1163 (1968).
320. E. Eidelberg and A. S. Schwartz, Nature (London) 225, 1152 (1970).
320a. D . L. Cheney and A. Goldstein, / . Pharmacol Exp. Ther. 177, 309 (1971).
321. R . Alonso Verri, F. G. Graeff, and A. P. Corrado, Int. J. Neuropharmacol.
7, 283 (1968).
322. S. S. Tenen, Psychopharmacologia 12, 278 (1968).
322a. A. S. Schwartz and E. Eidelberg, Life Sci. 9 (pt 1 ) , 613 (1970).
323. W . L. Dewey, L. S. Harris, J. F. Howes, and J. A. Nuite, J. Pharmacol.
Exp. Ther. 175, 435 (1970).
324. J. B. Appel, R . A. Lovell, and D . X . Freedman, Psychopharmacologia 18, 387 (1970).
325. A. Horita and A. E. Hamilton, Science 164, 78 (1969).
326. J. S. Bapna and P. C. Dandiya, Psychopharmacologia 17, 361 (1970).
326. J. S. Bapna and P. C. Dandiya, Psychopharmacologia 17, 361 (1970).