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Stein and wise theory of schizophrenia: A possible mechanism for 6-hydroxydopamine formation In Vivo
BEHAVIORAL BIOLOGY, 7, 861-866 (1972), Abstract No. 1-129R
Stein and Wise Theory of Schizophrenia: A Possible M e c h a n i s m f o r 6 - H y d r o x y d o p a m i n e
F o r m a t i o n In Vivo 1
RALPH N. ADAMS
Department of Chemistry, University o f Kansas, Lawrence, Kansas 66044
An already established alternate pathway in the dopamine-/3-hydroxylase reaction is suggested as a source of in vivo production of small amounts of 6-hydroxydopamine. This hypothesis is highly consistent with all of the postulates of the Stein and Wise theory of schizophrenia which involves 6-hydroxydopamine damage of norepinephrine nerve terminals in the medial forebrain bundle.
Stein and Wise (1971) have recently proposed a new biochemical etiology for schizophrenia. The postulate is based on aberrant formation of 6-hydroxydopamine (6-OHDA). Long-term uptake of 6-OHDA damages norepinephrine (NE) nerve terminals of the so-called reward system and the resultant damage manifests itself in the complex psychopathology known as schizophrenia. In the Stein and Wise theory, the formation of 6-OHDA is assumed to result from a lowered activity of dopamine-/3-hydroxylase, the enzyme which converts dopamine to norepinephrine. The accumulating "'excess" dopamine then could be converted by autoxidation or other means to 6-OHDA. We propose herein a more concrete pathway for formation of endogenous 6-OHDA based on an established enzymatic reaction and supported by recent electrochemical studies of the conversion of dopamine to 6-OHDA. It was shown i n 1959 that 6-OHDA was formed not only by a variety of in vitro oxidations, but also to a small, but real, extent in vivo in rats 1The support of this work by the National Institutes of Health Grant RO1 NS08740 is gratefully acknowledged. 861 Copyright © 1972 by Academic Press, Inc. All rights of reproduction in any form reserved.
862
ADAMS
(Senoh, Witkop, Creveling, and Undenfriend, 1959a, 1959b). Daly, Benigni, Minnis, Kanaoka, and Witkop, (1965) synthesized a number of 6-hydroxylated compounds to study their possible involvement in CNS metabolism. However, the great interest in 6-OHDA (some 80 publications in the past 2-3 years) has centered on its administration as a drug to produce chemical sympathectomy of noradrenergic nerve terminals. Except for the generalization that it arises from "autoxidation of dopamine," there is no detailed explanation of possible in vivo formation of 6-OHDA. The electrochemical oxidation of catecholamines and related substances, including 6-OHDA, has been under investigation in our laboratory for some time (Adams, Murrill, McCreery, Blank, and Karolczak, 1972). The anodic hydroxylation of substituted hydroquinones and catechols at low redox potentials in aqueous solution has been reported (Papouchado, Petrie, Sharp and Adams, 1968). Recent studies show that oxidation of dopamine to the o-quinone, under conditions which preclude intracyclization of the side chain to the aminochrome, leads to 6-OHDA. This can be illustrated in two ways: (a)by oxidizing dopamine in strong acid where protonation of the amine prevents cyclization; or (b) oxidizing a N-substituted dopamine like the N-carbobenzyloxy derivative. Electrochemical oxidation of 10-4M dopamine in 0.1-1M perchloric acid yields 60-70% 6-OHDA. Air oxidation of N-carbobenzyloxy dopamine at high pH produces the 6-hydroxy derivative. This can be verified by the EPR spectrum of its semiquinone anion radical (Adams et al., 1972). There is absolutely no evidence for 6-hydroxylation of dopamine itself-it must first be oxidized to the o-quinone to undergo hydroxylation. Dopamine-o-quinone also undergoes another reaction of pharmacological significance if the side chain is blocked. Nucleophiles such as amino acids attack the reactive 6-position. The rates of the amino acid substitutions are rapid at physiological pH. For example, the triglycine derivative forms within a few seconds. We have recently shown that injected 6-aminodopamine is about equally as effective as 6-OHDA in producing severe and long-lasting NE depletion in mouse brain (Blank et al., 1972a). Some 6-amino acid dopamine derivatives are undergoing in vivo testing for NE depletion at present. The Stein and Wise hypothesis should undoubtedly be extended to include aberrant production of these 6-amino acid derivatives. In the body, aminochrome formation is a negligible fraction of the overall metabolism of catecholamines. This has been demonstrated amply by Axelrod and coworkers (Kopin, Axelrod, and Gordon, 1961). Since aminochrome formation is somehow blocked, the electrochemical evidence, in accord with previous chemical and autoxidation studies (Senoh et al., 1959a, 1959b), suggests strongly that dopamine-o-quinone, in vivo, may undergo slow but significant hydroxylation. Thus, aberrant production of 6-hydroxydopamine can be explained if one has a rational, biochemical pathway leading to formation of small
6-HYDROXYDOPAMINEAND SCHIZOPHRENIA
863
amounts of dopamine-o-quinone (DOQ). To be relevant to the Stein and Wise postulate, this DOQ formation should at least satisfy the following four criteria: (1)be localized near NE nerve terminals where 6-OHDA formation has significance; (2)be small in magnitude, since excessive formation of 6-OHDA 'would lead to severe destruction of NE nerve terminals; (3)be capable of sustaining itself over lengthy periods, yet probably more active under highly stressful conditions, consistent with the general clinical time pattern of schizophrenic illness (Bellak and Loeb, 1969; Himwich, 1970; Stein and Wise, 1971); (4) be intimately associated with dysfunction of the dopamine-/3-hydroxylase step envisaged by Stein and Wise, thus maintaining the concept of genetic predisposition to the biochemical aberration. Such a mechanism for DOQ production is indeed already well established in the literature. Kaufman and coworkers (Kaufman and Friedman, 1965) showed that dopamine-/~-hydroxylase operates as a typical mixed-function oxidase and the normal hydroxylation of dopamine to NE is coupled to a stoichiometric oxidation of ascorbic acid as in the equation Dopamine + Ascorbic Acid + 02 enzymatic NE + DehydroascorbicAcid + H20. Levin and Kaufman (1961) showed that in the absence of ascorbate as electron donor, a small but significant conversion of dopamine to NE still occurred. They demonstrated clearly that in this case an "extra" molecule of dopamine served as reducing agent in place of ascorbate according to the reactions 2 Dopamine + 02 enzymatic NE + DOQ + H20. The DOQ formed is rereduced by a nonenzymatic reaction with DPNH: DOQ + DPNH + H +
~- Dopamine + DPN + ,
giving the net reaction Dopamine + 02 + DPNH + H +
~ NE + DPN + + H20.
Actual s p e c t r a l e v i d e n c e consistent with the enzyme-catalyzed dopamine-o-quinone formation in the absence of ascorbate and DPNH was obtained by Levin and Kaufman (1961). Kaufman and Friedman (1965) reviewed the details of these reactions. There is little question but that DOQ will be formed in the dopamine-to-norepinephrine conversion if ascorbate is absent or very low in concentration. The DOQ production would be small and it should be recycled back to dopamine. However, depending on ascorbate/DPNH balance and rates
864
ADAMS
of reactions, some DOQ could be available over a time scale consistent with further minimal conversion to 6-OHDA. The process would be in intimate contact with NE nerve endings since it is well established that ~ e dopamine-~-hydroxylase conversion takes place in the vesicles near the site of synaptic release of NE (Axelrod, 1971). It could be operative over long times if the localized ascorbate concentration was deficient or not utilized properly. Furthermore, whenever higher rates of NE production are required, the dopamine-/3-hydroxylase dysfunction, if present, would presumably produce increased levels of aberrant product. Although somewhat dependent on how one defines behavioral stress, it seems generally agreed that NE synaptic activity is greater during periods of excessive stress. Hence, it seems quite significant that increased DOQ and possible 6-OHDA formation could be consonant with the increased conversion of dopamine to NE demanded by the synaptic activity of stressful situations. The present arguments in no way invalidate previous ideas that a peculiarity in dopamine-/3-hydroxylase is responsible for 6-OHDA formation. Rather, they suggest a particular mode of this enzymatic abnormality to look for. In addition, they suggest a possibly important dysfunction in the same enzymatic process, namely, "improper" endogenous ascorbate levels in the microenvironment of NE nerve terminals. It is not clear how chemical manipulation of the dopamine-/3-hydroxylase reaction can be accomplished via ascorbic acid. Izquierdo and coworkers (Izquierdo, Jofre, and Acevedo, 1968) showed that dopamine decreased and NE increased in cerebral hemispheres, cerebellum, diencephalon, and other brain structures of the rat with intraperitoneal injection of ascorbic acid. On the other hand, Sj6strand (1970) found no change in brain catecholamines after intravenous injection of either ascorbic or dehydroascorbic acids. However, after blockage of catecholamine synthesis, dehydroascorbic acid (but not ascorbic acid) caused marked depletion of NE in brain and heart (Sj6strand, 1970). Few, if any, studies and intraventricular injection of ascorbic or dehydroascorbic acids have been made. Further effects of administered ascorbic acid on evoked potentials in dorsal hippocampus linked to NE changeshave been studied (Laguzzi, Acevedo, and Izquierdo, 1970). The mode of formation of 6-OHDA and its relationship to schizophrenia suggested herein is not without some clinical background. Although most urinary ascorbic acid undoubtedly comes from the adrenal glands, it is interesting that urinary ascorbic acid levels of hospitalized schizophrenics remains an active area of study (Mosher and Feinsilver, 1970; Pitt and Pollitt, 1971). Such data are difficult to interpret due to dietary problems and especially since they so often deal only with chronic patients. Indeed, urinary ascorbic acid levels bear little relationship to CNS localized concentrations, the concern of the present argument. Proof of the present mechanism for 6-OHDA formation will be difficult and time-consuminz. In itself, detection of 6-OHDA (or its metabolites) is a
6-HYDROXYDOPAMINE AND SCHIZOPHRENIA
865
chemically elusive problem. To date no one has been able to inject even large quantities o f 6-OHDA into CNS and recover it or its metabolites in any chemically identifiable forms. We have recently shown that oxidized 6-OHDA is transformed into 5,6-dihydroxyindole in vitro under physiological conditions (Blank, Kissinger, and Adams, 1972). M t h o u g h further oxidation o f the indole to melanins is known to occur, at least now there are known possible degradation products to search for. Ascorbate manipulation in CNS via dietary control in guinea pigs and chemical manipulation in rats are presently under investigation. Experiments in which lowered ascorbate levels can be correlated with catecholamine analyses and behavioral responses are in progress. The present communication is presented in the hope that it will suggest to others a variety of experimental approaches to either validate or reject the hypothesis. REFERENCES Adams, R.N., Murrill, E., McCreery, R., Blank, L., and Karolczak, M. (1972). 6-Hydroxydopamine-a new oxidation mechanism. Eur. J. Pharmacol. 17, 287-292. Axelrod, J. (1971). Brain monoamines-biosynthesis and fate. NeuroscL Res. Program Bull 9, 188. Bellak, L., and Loeb, L. (1969). "The Schizophrenic Syndrome." New York: Grune and Stratton. Blank, C.L., MurriU, E., and Adams, R.N. (1972a) "Central nervous system effects of 6-aminodopamine and 6-hydroxydopamine." Brain Res., in press. Blank, C.L., Kissinger, P.T. and Adams, R.N. (1972b) 5,6-Dihydroxyindole formation from oxidized 6-hydroxydopamine. Eur. J. Pharmacol. In press. Daly, J.W., Benigni, J., Minnis, R., Kanaoka, Y., and Witkop, B. (1965). Synthesis and metabolism of 6-hydroxycatecholamine. Biochemistry 4, 2513-2525. Himwich, H. E. (Ed.) (1970). "Biochemistry, Schizophrenias and Affective Illnesses." Baltimore: Williams and Wilkins. Izquierdo, J.A., Jofre, I.J., and Acevedo, C. (1968). The effect of aseorbic acid on the cerebral and adrenal catecholamine content in the male rat. J. Pharm. Pharmacol. 20, 210-214. Kaufman, S., and Friedman, S. (1965). Dopamine-#-hydroxylase. Pharmacol. Rev. 17, 71-100. Kopin, I.J., Axelrod, J., and Gordon, E.K. (1961). The metabolic fate of H3-epinephrine and C14-metanephrine in the rat. J. Biol. Chem. 236, 2109-2113. Laguzzi, R. F., Acevedo, C., and Izquierdo, J.A. (1970). The effect of ascorbic acid on evoked potentials in the dorsal hippocampus by stimulation of the fornix. Arzeim. Forsch, 20, 1270-1271. Levin, E.Y., and Kaufman, S. (1961). Studies on the enzyme catalyzing the conversion of 3,4-dihydroxyphenethylamine to norepinephrine. J. Biol. Chem. 236, 2043-2049. Mosher, L.R., and Feinsilver, D. (1970). "Special Report on Schizophrenia." Washington, D.C.: Nat. Inst. Mental Health. Papouchado, L., Petrie, G., Sharp, J.H., and Adams R.N. (1968) Anodichydroxylationof aromatic compounds. J; Amer. Chem. Soc. 90, 5620-5621. Pitt, B., and Pollitt, N. (1971). Ascorbic acid and chronic schizophrenia. Brit. Z Psychiat. 118~ 227~228.
866
ADAMS
Senoh, S., Witkop, B., Creveling, C.R., and Udenfriend, S. (1959a). 2,4,5-Trihydroxyphenethylamine, a new metabolite of 3,4-dihydroxyphenethylamine. J. Amer. Chem. Soc., 81, 1768-1769. Senoh, S., Creveling, C.R., Udenfriend, S., and Witkop, B. (1959b). Chemica 1, enzymatic and metabolic studies on the mechanism of oxidation of dopamine. J. Amer. Chem. Soc., 81, 6236-6240. Sjostrand, S.E. (1970). Pharmacological properties of dehydroascorbic acid and ascorbic acid. Effects on the central and peripheral nervous systems in experimental animals. Acta Physiol. Scand. Suppl. 356, 1-79. Stein, L., and Wise, C.D. (1971). Possible etiology of schizophrenia: progressive damage to the noradrenergic reward system by 6-OHDA. Science 171, 1032-1036.
Stein and Wise Theory of Schizophrenia: A Possible M e c h a n i s m f o r 6 - H y d r o x y d o p a m i n e
F o r m a t i o n In Vivo 1
RALPH N. ADAMS
Department of Chemistry, University o f Kansas, Lawrence, Kansas 66044
An already established alternate pathway in the dopamine-/3-hydroxylase reaction is suggested as a source of in vivo production of small amounts of 6-hydroxydopamine. This hypothesis is highly consistent with all of the postulates of the Stein and Wise theory of schizophrenia which involves 6-hydroxydopamine damage of norepinephrine nerve terminals in the medial forebrain bundle.
Stein and Wise (1971) have recently proposed a new biochemical etiology for schizophrenia. The postulate is based on aberrant formation of 6-hydroxydopamine (6-OHDA). Long-term uptake of 6-OHDA damages norepinephrine (NE) nerve terminals of the so-called reward system and the resultant damage manifests itself in the complex psychopathology known as schizophrenia. In the Stein and Wise theory, the formation of 6-OHDA is assumed to result from a lowered activity of dopamine-/3-hydroxylase, the enzyme which converts dopamine to norepinephrine. The accumulating "'excess" dopamine then could be converted by autoxidation or other means to 6-OHDA. We propose herein a more concrete pathway for formation of endogenous 6-OHDA based on an established enzymatic reaction and supported by recent electrochemical studies of the conversion of dopamine to 6-OHDA. It was shown i n 1959 that 6-OHDA was formed not only by a variety of in vitro oxidations, but also to a small, but real, extent in vivo in rats 1The support of this work by the National Institutes of Health Grant RO1 NS08740 is gratefully acknowledged. 861 Copyright © 1972 by Academic Press, Inc. All rights of reproduction in any form reserved.
862
ADAMS
(Senoh, Witkop, Creveling, and Undenfriend, 1959a, 1959b). Daly, Benigni, Minnis, Kanaoka, and Witkop, (1965) synthesized a number of 6-hydroxylated compounds to study their possible involvement in CNS metabolism. However, the great interest in 6-OHDA (some 80 publications in the past 2-3 years) has centered on its administration as a drug to produce chemical sympathectomy of noradrenergic nerve terminals. Except for the generalization that it arises from "autoxidation of dopamine," there is no detailed explanation of possible in vivo formation of 6-OHDA. The electrochemical oxidation of catecholamines and related substances, including 6-OHDA, has been under investigation in our laboratory for some time (Adams, Murrill, McCreery, Blank, and Karolczak, 1972). The anodic hydroxylation of substituted hydroquinones and catechols at low redox potentials in aqueous solution has been reported (Papouchado, Petrie, Sharp and Adams, 1968). Recent studies show that oxidation of dopamine to the o-quinone, under conditions which preclude intracyclization of the side chain to the aminochrome, leads to 6-OHDA. This can be illustrated in two ways: (a)by oxidizing dopamine in strong acid where protonation of the amine prevents cyclization; or (b) oxidizing a N-substituted dopamine like the N-carbobenzyloxy derivative. Electrochemical oxidation of 10-4M dopamine in 0.1-1M perchloric acid yields 60-70% 6-OHDA. Air oxidation of N-carbobenzyloxy dopamine at high pH produces the 6-hydroxy derivative. This can be verified by the EPR spectrum of its semiquinone anion radical (Adams et al., 1972). There is absolutely no evidence for 6-hydroxylation of dopamine itself-it must first be oxidized to the o-quinone to undergo hydroxylation. Dopamine-o-quinone also undergoes another reaction of pharmacological significance if the side chain is blocked. Nucleophiles such as amino acids attack the reactive 6-position. The rates of the amino acid substitutions are rapid at physiological pH. For example, the triglycine derivative forms within a few seconds. We have recently shown that injected 6-aminodopamine is about equally as effective as 6-OHDA in producing severe and long-lasting NE depletion in mouse brain (Blank et al., 1972a). Some 6-amino acid dopamine derivatives are undergoing in vivo testing for NE depletion at present. The Stein and Wise hypothesis should undoubtedly be extended to include aberrant production of these 6-amino acid derivatives. In the body, aminochrome formation is a negligible fraction of the overall metabolism of catecholamines. This has been demonstrated amply by Axelrod and coworkers (Kopin, Axelrod, and Gordon, 1961). Since aminochrome formation is somehow blocked, the electrochemical evidence, in accord with previous chemical and autoxidation studies (Senoh et al., 1959a, 1959b), suggests strongly that dopamine-o-quinone, in vivo, may undergo slow but significant hydroxylation. Thus, aberrant production of 6-hydroxydopamine can be explained if one has a rational, biochemical pathway leading to formation of small
6-HYDROXYDOPAMINEAND SCHIZOPHRENIA
863
amounts of dopamine-o-quinone (DOQ). To be relevant to the Stein and Wise postulate, this DOQ formation should at least satisfy the following four criteria: (1)be localized near NE nerve terminals where 6-OHDA formation has significance; (2)be small in magnitude, since excessive formation of 6-OHDA 'would lead to severe destruction of NE nerve terminals; (3)be capable of sustaining itself over lengthy periods, yet probably more active under highly stressful conditions, consistent with the general clinical time pattern of schizophrenic illness (Bellak and Loeb, 1969; Himwich, 1970; Stein and Wise, 1971); (4) be intimately associated with dysfunction of the dopamine-/3-hydroxylase step envisaged by Stein and Wise, thus maintaining the concept of genetic predisposition to the biochemical aberration. Such a mechanism for DOQ production is indeed already well established in the literature. Kaufman and coworkers (Kaufman and Friedman, 1965) showed that dopamine-/~-hydroxylase operates as a typical mixed-function oxidase and the normal hydroxylation of dopamine to NE is coupled to a stoichiometric oxidation of ascorbic acid as in the equation Dopamine + Ascorbic Acid + 02 enzymatic NE + DehydroascorbicAcid + H20. Levin and Kaufman (1961) showed that in the absence of ascorbate as electron donor, a small but significant conversion of dopamine to NE still occurred. They demonstrated clearly that in this case an "extra" molecule of dopamine served as reducing agent in place of ascorbate according to the reactions 2 Dopamine + 02 enzymatic NE + DOQ + H20. The DOQ formed is rereduced by a nonenzymatic reaction with DPNH: DOQ + DPNH + H +
~- Dopamine + DPN + ,
giving the net reaction Dopamine + 02 + DPNH + H +
~ NE + DPN + + H20.
Actual s p e c t r a l e v i d e n c e consistent with the enzyme-catalyzed dopamine-o-quinone formation in the absence of ascorbate and DPNH was obtained by Levin and Kaufman (1961). Kaufman and Friedman (1965) reviewed the details of these reactions. There is little question but that DOQ will be formed in the dopamine-to-norepinephrine conversion if ascorbate is absent or very low in concentration. The DOQ production would be small and it should be recycled back to dopamine. However, depending on ascorbate/DPNH balance and rates
864
ADAMS
of reactions, some DOQ could be available over a time scale consistent with further minimal conversion to 6-OHDA. The process would be in intimate contact with NE nerve endings since it is well established that ~ e dopamine-~-hydroxylase conversion takes place in the vesicles near the site of synaptic release of NE (Axelrod, 1971). It could be operative over long times if the localized ascorbate concentration was deficient or not utilized properly. Furthermore, whenever higher rates of NE production are required, the dopamine-/3-hydroxylase dysfunction, if present, would presumably produce increased levels of aberrant product. Although somewhat dependent on how one defines behavioral stress, it seems generally agreed that NE synaptic activity is greater during periods of excessive stress. Hence, it seems quite significant that increased DOQ and possible 6-OHDA formation could be consonant with the increased conversion of dopamine to NE demanded by the synaptic activity of stressful situations. The present arguments in no way invalidate previous ideas that a peculiarity in dopamine-/3-hydroxylase is responsible for 6-OHDA formation. Rather, they suggest a particular mode of this enzymatic abnormality to look for. In addition, they suggest a possibly important dysfunction in the same enzymatic process, namely, "improper" endogenous ascorbate levels in the microenvironment of NE nerve terminals. It is not clear how chemical manipulation of the dopamine-/3-hydroxylase reaction can be accomplished via ascorbic acid. Izquierdo and coworkers (Izquierdo, Jofre, and Acevedo, 1968) showed that dopamine decreased and NE increased in cerebral hemispheres, cerebellum, diencephalon, and other brain structures of the rat with intraperitoneal injection of ascorbic acid. On the other hand, Sj6strand (1970) found no change in brain catecholamines after intravenous injection of either ascorbic or dehydroascorbic acids. However, after blockage of catecholamine synthesis, dehydroascorbic acid (but not ascorbic acid) caused marked depletion of NE in brain and heart (Sj6strand, 1970). Few, if any, studies and intraventricular injection of ascorbic or dehydroascorbic acids have been made. Further effects of administered ascorbic acid on evoked potentials in dorsal hippocampus linked to NE changeshave been studied (Laguzzi, Acevedo, and Izquierdo, 1970). The mode of formation of 6-OHDA and its relationship to schizophrenia suggested herein is not without some clinical background. Although most urinary ascorbic acid undoubtedly comes from the adrenal glands, it is interesting that urinary ascorbic acid levels of hospitalized schizophrenics remains an active area of study (Mosher and Feinsilver, 1970; Pitt and Pollitt, 1971). Such data are difficult to interpret due to dietary problems and especially since they so often deal only with chronic patients. Indeed, urinary ascorbic acid levels bear little relationship to CNS localized concentrations, the concern of the present argument. Proof of the present mechanism for 6-OHDA formation will be difficult and time-consuminz. In itself, detection of 6-OHDA (or its metabolites) is a
6-HYDROXYDOPAMINE AND SCHIZOPHRENIA
865
chemically elusive problem. To date no one has been able to inject even large quantities o f 6-OHDA into CNS and recover it or its metabolites in any chemically identifiable forms. We have recently shown that oxidized 6-OHDA is transformed into 5,6-dihydroxyindole in vitro under physiological conditions (Blank, Kissinger, and Adams, 1972). M t h o u g h further oxidation o f the indole to melanins is known to occur, at least now there are known possible degradation products to search for. Ascorbate manipulation in CNS via dietary control in guinea pigs and chemical manipulation in rats are presently under investigation. Experiments in which lowered ascorbate levels can be correlated with catecholamine analyses and behavioral responses are in progress. The present communication is presented in the hope that it will suggest to others a variety of experimental approaches to either validate or reject the hypothesis. REFERENCES Adams, R.N., Murrill, E., McCreery, R., Blank, L., and Karolczak, M. (1972). 6-Hydroxydopamine-a new oxidation mechanism. Eur. J. Pharmacol. 17, 287-292. Axelrod, J. (1971). Brain monoamines-biosynthesis and fate. NeuroscL Res. Program Bull 9, 188. Bellak, L., and Loeb, L. (1969). "The Schizophrenic Syndrome." New York: Grune and Stratton. Blank, C.L., MurriU, E., and Adams, R.N. (1972a) "Central nervous system effects of 6-aminodopamine and 6-hydroxydopamine." Brain Res., in press. Blank, C.L., Kissinger, P.T. and Adams, R.N. (1972b) 5,6-Dihydroxyindole formation from oxidized 6-hydroxydopamine. Eur. J. Pharmacol. In press. Daly, J.W., Benigni, J., Minnis, R., Kanaoka, Y., and Witkop, B. (1965). Synthesis and metabolism of 6-hydroxycatecholamine. Biochemistry 4, 2513-2525. Himwich, H. E. (Ed.) (1970). "Biochemistry, Schizophrenias and Affective Illnesses." Baltimore: Williams and Wilkins. Izquierdo, J.A., Jofre, I.J., and Acevedo, C. (1968). The effect of aseorbic acid on the cerebral and adrenal catecholamine content in the male rat. J. Pharm. Pharmacol. 20, 210-214. Kaufman, S., and Friedman, S. (1965). Dopamine-#-hydroxylase. Pharmacol. Rev. 17, 71-100. Kopin, I.J., Axelrod, J., and Gordon, E.K. (1961). The metabolic fate of H3-epinephrine and C14-metanephrine in the rat. J. Biol. Chem. 236, 2109-2113. Laguzzi, R. F., Acevedo, C., and Izquierdo, J.A. (1970). The effect of ascorbic acid on evoked potentials in the dorsal hippocampus by stimulation of the fornix. Arzeim. Forsch, 20, 1270-1271. Levin, E.Y., and Kaufman, S. (1961). Studies on the enzyme catalyzing the conversion of 3,4-dihydroxyphenethylamine to norepinephrine. J. Biol. Chem. 236, 2043-2049. Mosher, L.R., and Feinsilver, D. (1970). "Special Report on Schizophrenia." Washington, D.C.: Nat. Inst. Mental Health. Papouchado, L., Petrie, G., Sharp, J.H., and Adams R.N. (1968) Anodichydroxylationof aromatic compounds. J; Amer. Chem. Soc. 90, 5620-5621. Pitt, B., and Pollitt, N. (1971). Ascorbic acid and chronic schizophrenia. Brit. Z Psychiat. 118~ 227~228.
866
ADAMS
Senoh, S., Witkop, B., Creveling, C.R., and Udenfriend, S. (1959a). 2,4,5-Trihydroxyphenethylamine, a new metabolite of 3,4-dihydroxyphenethylamine. J. Amer. Chem. Soc., 81, 1768-1769. Senoh, S., Creveling, C.R., Udenfriend, S., and Witkop, B. (1959b). Chemica 1, enzymatic and metabolic studies on the mechanism of oxidation of dopamine. J. Amer. Chem. Soc., 81, 6236-6240. Sjostrand, S.E. (1970). Pharmacological properties of dehydroascorbic acid and ascorbic acid. Effects on the central and peripheral nervous systems in experimental animals. Acta Physiol. Scand. Suppl. 356, 1-79. Stein, L., and Wise, C.D. (1971). Possible etiology of schizophrenia: progressive damage to the noradrenergic reward system by 6-OHDA. Science 171, 1032-1036.