Neuropsychobiology /: 26-31 (1975)
Effect of Peripheral Decarboxylase Inhibition on HVA and 5HIAA in Cerebrospinal Fluid of Depressed Patients Jean-Michel Gaillard, Jean Constantinidis and René Tissot Clinique psychiatrique universitaire de Bel-Air, Chêne-Bourg
Key Words. Benserazide • HVA • 5HIAA • CSF • Depression Abstract. The effects of benserazide on the level of homovanillic acid and 5-hydroxyindoleacetic acid in CSF have been investigated in 1 manic and 11 depressed patients. Benserazide induced no change on both metabolites. This negative result supports the view that monoamine metabolites in CSF, in the absence of loading with an exogenous precursor, originate mostly from brain parenchyma, without significant contribution of the metabo lism in capillary walls.
Introduction
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Several lines of evidence favour the involvement of monoamine metabolism disturbances in affective disorders (Coppen, \961\Schildkraut, 1973). Catechol amine as well as indolamine hypothesis are supported by experimental results. Metabolites of monoamines, especially homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA), can be measured in CSF and seem to originate, at least partly, from the nervous tissue (Papeschi etal., 1971 \Garelis et al., 1974). They have been used as a tool for the investigation of possible disturbances in the metabolism of cerebral monoamines in affective diseases. Peripheral administration of L-dopa in man brings about a rise of HVA in CSF. If a decarboxylase inhibitor (DCI), acting preferentially in periphery, is given prior to L-dopa, this rise of HVA is almost completely abolished (Tissot, 1970). However, it is known that in the rat, the enhancement of cerebral dopa mine after L-dopa is much greater if the animal has previously received a DCI {Bartholini et al., 1967). On the other hand, Bartholini et al. (1966) have shown that in the cat, at least part of the HVA appearing in CSF after peripheral loading with L-dopa and without DCI is not derived as such from the blood.
Gaillard/Constantinidis/Tissot
27
¿-dopa injected intraperitoneally in rat brings about a strong green fluores cence of brain capillary walls. This fluorescence does not appear if the animal is previously given low doses of DCI {Bertler et al., 1966; Constantinidis et al., 1967). This observation is interpreted as due to the presence of decarboxylase in capillary walls; ¿-dopa is taken up by endothelial cells and decarboxylated into dopamine, mainly responsible for the green fluorescence. During an infusion of ¿-dopa in man, more dopa is found in the jugular vein than in arterial blood. However, the arteriovenous difference is reversed if subjects have been pre treated with a DCI. In the last case, a certain amount of dopa leaves the blood compartment in cerebral region (Geissbuhler etal., 1972). These observations taken together might indicate that in man, as in rats, exogenous ¿-dopa could be decarboxylated in brain capillary walls, leading to an enhancement of HVA in CSF. When the endothelial decarboxylase in inhibited, ¿-dopa can pass freely in brain parenchyma where it is transformed into dopa mine. Direct evidence in favour of this mechanism is lacking, and the problem is further complicated by the fact that fluorescence of brain capillary walls, after peripheral loading with ¿-dopa, is not a general phenomenon among species; it is not found in the cat, monkey (Langelier et al., 1972), rabbit, or guinea pig (Constantinidis, unpublished data). It is not yet known with certainty if man is closer to the rat or to the monkey in this respect, but preliminary results from indirect experiments with postmortem human brain indicate that in the presence of ¿-dopa, brain capillary walls do not exhibit any green fluorescence (Constantinidis et al., in prepara tion). This would speak against a decarboxylation of ¿-dopa in the capillary endothelium to a significant extent. Considering the rise of HVA in CSF after administration of ¿-dopa, and the suppression of this enhancement after pretreatment by a DCI, it remains to be seen if endogenous metabolites of monoamines behave in the same way. We are reporting here the results of the administration of DCI without ¿-dopa in de pressed patients.
Methods
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Twelve patients hospitalized at the psychiatric clinic participated in this study. Their ages, sex and diagnosis are indicated in table I. Diagnosis is established according to Ey et al. (1974). Most of them were without medication upon admission in the clinic, and drugs were withdrawn in the others. All along the experiment, all patients were given the same amount of diazepam (0.5 mg/kg); this was necessary due to the marked symptomatology they presented. All patients were in good physical condition and without evidence of neurological symptomatology. They were having a standardized diet throughout the experiment. On the 4th and 6th day of hospitalization, a cisternal puncture was performed at 8 a.m. One of
28
Gaillard/Constantinidis/Tissot
Table I. Individual values of HVA and 5HIAA (ng/ml) in the CSF of 1 manic and 11 de pressed patients Patients
Age
Sex
Diagnosis
+ DCI
-DCI
+ DCI
unipolar melancholy unipolar melancholy unipolar melancholy unipolar melancholy unipolar melancholy bipolar melancholy
98 24 59 25 156 102
93 19 14 65 113 110
44 45 31 5 56 32
28 45 18 25 37 45
reactive depression reactive depression reactive depression
98 80 104
88 96 45
40 37 50
50 43 50
33 110
111 106
44 42
56 28
24
24
35
35
52 62 64 43 63 52
d d
7 8 9
50 54 62
d
10 11
65 40
9 9
involutional depression depressive syndrome with paranoia
12
66
d
mania
9 9
5HIAA
-DCI 1 2 3 4 5 6
d 9 9 9
HVA
these punctures, the first or the second in a balanced cross-over design, was preceded by administration of benserazide, a peripheral decarboxylase inhibitor, 250 mg at 6 p.m., 10 p.m. and 2 a.m., and 500 mg at 6 a.m. before the puncture. Patients were fasted and confined in bed since the evening before the day of puncture. CSF was withdrawn on 0.2 cm3 of 5 N HCL, put on ice and stored for less than 1 week at -3 0 °C . Dosage of HVA and 5HIAA was performed by fluorometry with classical tech niques (Anden and Ross, 1963 \Maickel, 1972). Remaining fractions of CSF from punctures with and without DCI, respectively, were pooled for assay of dopa and O-methyl-dopa (OMD).
The values for HVA and 5HIAA in our patients are given in table I. The following factors have been tested and yielded no significant differences: pres ence of DCI or not (t = 0.22 for HVA, 0.022 for 5HIAA; NS), sex, age and diagnosis (table II). Since motor activity has been shown to affect the level of CSF metabolites, this factor was assessed by clinical observation of the patient and rated as inhibited, normal or increased. In fact, the manic patient was the only one who displayed an increased motor activity, and the level of HVA and 5HIAA was not different in retarded patients with respect to non-retarded.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Results
Depression: HVA and 5HIAA in CSF
29
Table //. Two-tailed t tests for unrelated means for the various factors tested. All values are far below the significance level of 0.05; df = 9; the data of the manic patient are not included in this calculation HVA
Sex Age Diagnosis Motor actvity
5HIAA
-DCI
+ DCI
-DCI
+ DCI
0.65 0.39 0.41 0.40
1.88 1.56 0.90 0.65
0.23 1.58 0.87 0.27
0.67 0.61 1.87 1.86
Without DCI, levels of dopa and OMD were below the sensitivity threshold of the technique: 5 ng/ml for dopa and 13 ng/ml for OMD. After DCI, the level of dopa was 10 ng/ml and the level of OMD, 40 ng/ml.
Numerous evidences show that HVA and 5HIAA found in CSF come most ly, or perhaps totally, from the nervous parenchyma where they are produced by the metabolism of corresponding amines, i.e. dopamine and serotonine (Garelis and Sourkes, 1973; Goodwin et al, 1973\Sourkes, 1973; Young et al., 1974). Extracerebral inhibition of decarboxylase leads to a decrease of dopamine metabolism in periphery; the present experiment in man shows that this decrease is not reflected by a parallel diminution of the level of HVA in CSF; this fact can be understood if HVA originates mostly from brain parenchyma, where the metabolism of dopamine would probably not be influenced to a significant extent by DCI. An identical mechanism can be postulated for 5HT and 5HIAA. Thus, a significant contribution of the metabolism of amines in capillary endo thelium seems to be ruled out, at least in the absence of loading with an exoge nous precursor. This is the most likely explanation of our findings. However, two other possibilities may be raised. First, one might suppose an inhibitory effect of benserazide on the transport of aromatic acids in or out of CSF: this effect has never been demonstrated. Second, if, in spite of appear ances, dopamine is metabolized in brain capillary walls in man as in the rat, a decrease of this metabolism could be compensated for by an increase of HVA formation in brain tissue. It appears unlikely that these two mechanisms, acting in an opposite direction, compensate for each other so precisely, if one looks at the mean changes of HVA and 5HIAA, 2 ± 37 and 0.1 ± 13 ng/ml, respectively. It has been shown that dosable levels of dopa appear in plasma when periph
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Discussion
Gaillard/Constantinidis/Tissot
30
eral decarboxylase is inhibited (Geissbuhler etal., 1974). We have demonstrated here that this is the case in CSF also. Although the dosage of DCI in this study is relatively low, a slight diminution of decarboxylase activity in the brain could account for the appearance of parenchymatous dopa, leading in turn to an enhancement of methylation into OMD, and to a diffusion of these two amino acids in CSF.
Anden, N. and Ross, E.: On the occurence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sci. 7: 448 (1963). Bartholini, G.; Bates, H.M.; Burkard, W.P., and Pletscher, A.: Increase of cerebral catechol amines caused by 3,4-dihydroxyphenylalanine after inhibition of peripheral decarbox ylase. Nature, Lond. 215: 853-853 (1967). Bartholini, G.; Pletscher, A., and Tissot, R.: On the origin of homovanillic acid in the cerebrospinal fluid. Experimentia 22: 609 (1966). Bertler, A.: Falck, B.; Owman, C., and Rosengreen, E.: The localization of monoaminergic blood-brain barrier mechanisms. Pharmac. Rev. 18: 369-385 (1966). Costantinidis, J.; Bartholini, G.; Tissot, R. und Pletscher, A.: Elektive Anreichung von Dopamin im Parenchym des Ratten-hirns. Helv. physiol, pharmac. Acta 25: 411-413 (1967). Coppen, A.: The biochemistry of affective disorders. Br. J. Psychiat. 113: 1237-1264 (1967). Ey, H.: Bernard, P. et Brisset, Ch.: Manuel de Psychiatrie; 4e éd. (Masson, Paris 1974). Garelis, £. and Sourkes, T.L.: Sites of origin in the central nervous system of monoamine metabolites measures in human cerebrospinal fluid. J. Neurol. Neurosurg. Psychiat. 36: 625-629 (1973). Garelis, E.; Young, S.N.; Lai, S., and Sourkes, T.L.: Monoamine metabolites in lumbar CSF: the question of their origin in relation to clinical studies. Brain Res., Osaka 79: 1-8 (1974). Geissbuhler, F.; Constantinidis, J.; Gaillard, J.-M.; Jacot des Combes, N. et Tissot, R.: Effet d’un inhibiteur de la decarboxylase sur la dopa plasmatique endogène chez l’homme. Biomédecine 21: 297-298(1974). Geissbuhler, F.; Eisenring, J.J.; Friedli, P.: Bartholini, G. et Tissot, R.: Consommation cérébrale et pérophérique de ¿-dopa chez des patients atteints de syndromes parkin soniens, dépressifs ou maniaques sous ¿-dopa en perfusion combinée ou non à un inhibiteur de la décarboxylase. Effets pharmacologiques. Encéphale 2: 127-148 (1972) . Goodwin, F.K.; Post, R.M.; Dunner, D.L., and Gordon, E.K.: Cerebrospinal fluid amine metabolites in affective illness: the probenecid technique. Am. J. Psychiat. 130: 73-79 (1973) . Langelier, P.; Parent, A., and Poirier, L.-J.: Decarboxylase activity of the brain capillary walls and parenchyma in the rat, cat and monkey. Brain Res., Osaka 45: 622-629 (1972). Maickel, R.P.: Fluorometric analysis of 5-hydroxy try ptamine and related compounds. Meth. Neurochem. 2: 101-129 (1972). Papeschi, R.; Sourkes, T.L.: Poirier, J., and Boucher, R.: On the intracerebral origin of
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
References
Depression: HVA and 5H1AA in CSF
31
Dr. J.M. Gaillard, Clinique psychiatrique universitaire de Bel-Air, C H -1225 Chêne-Bourg (Switzerland)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
homovanillic acid of the cerebrospinal fluid of experimental animals. Brain Res., Osaka 28: 527-533 (1971). Schildkraut, J.J.: Neuropharmacology of the affective disorders. A. Rev. Pharmac. 13: 427-454 (1973). Sourkes, T.L.: On the origin of homovanillic acid (HVA) in the cerebrospinal fluid. J. neural Transmission 34: 153-157 (1973). Tissot, R.: ¿-dopa and decarboxylase inhibitor (DCI): biochemical and clinical implications; in Barbeau and McDowell ¿-dopa and Parkinsonism, pp. 80-86 (Davis, Philadelphia 1970). Young, S.N.; Garelis, E.; Lai, S.; Martin, J.B.: Molina-Negro, P.; Ethier, R., and Sourkes, T.L.: Tryptophan and 5-hydroxyindoleacetic acid in human cerebrospinal fluid. J. Neurochem. 22: 777-779 (1974).
Effect of Peripheral Decarboxylase Inhibition on HVA and 5HIAA in Cerebrospinal Fluid of Depressed Patients Jean-Michel Gaillard, Jean Constantinidis and René Tissot Clinique psychiatrique universitaire de Bel-Air, Chêne-Bourg
Key Words. Benserazide • HVA • 5HIAA • CSF • Depression Abstract. The effects of benserazide on the level of homovanillic acid and 5-hydroxyindoleacetic acid in CSF have been investigated in 1 manic and 11 depressed patients. Benserazide induced no change on both metabolites. This negative result supports the view that monoamine metabolites in CSF, in the absence of loading with an exogenous precursor, originate mostly from brain parenchyma, without significant contribution of the metabo lism in capillary walls.
Introduction
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Several lines of evidence favour the involvement of monoamine metabolism disturbances in affective disorders (Coppen, \961\Schildkraut, 1973). Catechol amine as well as indolamine hypothesis are supported by experimental results. Metabolites of monoamines, especially homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA), can be measured in CSF and seem to originate, at least partly, from the nervous tissue (Papeschi etal., 1971 \Garelis et al., 1974). They have been used as a tool for the investigation of possible disturbances in the metabolism of cerebral monoamines in affective diseases. Peripheral administration of L-dopa in man brings about a rise of HVA in CSF. If a decarboxylase inhibitor (DCI), acting preferentially in periphery, is given prior to L-dopa, this rise of HVA is almost completely abolished (Tissot, 1970). However, it is known that in the rat, the enhancement of cerebral dopa mine after L-dopa is much greater if the animal has previously received a DCI {Bartholini et al., 1967). On the other hand, Bartholini et al. (1966) have shown that in the cat, at least part of the HVA appearing in CSF after peripheral loading with L-dopa and without DCI is not derived as such from the blood.
Gaillard/Constantinidis/Tissot
27
¿-dopa injected intraperitoneally in rat brings about a strong green fluores cence of brain capillary walls. This fluorescence does not appear if the animal is previously given low doses of DCI {Bertler et al., 1966; Constantinidis et al., 1967). This observation is interpreted as due to the presence of decarboxylase in capillary walls; ¿-dopa is taken up by endothelial cells and decarboxylated into dopamine, mainly responsible for the green fluorescence. During an infusion of ¿-dopa in man, more dopa is found in the jugular vein than in arterial blood. However, the arteriovenous difference is reversed if subjects have been pre treated with a DCI. In the last case, a certain amount of dopa leaves the blood compartment in cerebral region (Geissbuhler etal., 1972). These observations taken together might indicate that in man, as in rats, exogenous ¿-dopa could be decarboxylated in brain capillary walls, leading to an enhancement of HVA in CSF. When the endothelial decarboxylase in inhibited, ¿-dopa can pass freely in brain parenchyma where it is transformed into dopa mine. Direct evidence in favour of this mechanism is lacking, and the problem is further complicated by the fact that fluorescence of brain capillary walls, after peripheral loading with ¿-dopa, is not a general phenomenon among species; it is not found in the cat, monkey (Langelier et al., 1972), rabbit, or guinea pig (Constantinidis, unpublished data). It is not yet known with certainty if man is closer to the rat or to the monkey in this respect, but preliminary results from indirect experiments with postmortem human brain indicate that in the presence of ¿-dopa, brain capillary walls do not exhibit any green fluorescence (Constantinidis et al., in prepara tion). This would speak against a decarboxylation of ¿-dopa in the capillary endothelium to a significant extent. Considering the rise of HVA in CSF after administration of ¿-dopa, and the suppression of this enhancement after pretreatment by a DCI, it remains to be seen if endogenous metabolites of monoamines behave in the same way. We are reporting here the results of the administration of DCI without ¿-dopa in de pressed patients.
Methods
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Twelve patients hospitalized at the psychiatric clinic participated in this study. Their ages, sex and diagnosis are indicated in table I. Diagnosis is established according to Ey et al. (1974). Most of them were without medication upon admission in the clinic, and drugs were withdrawn in the others. All along the experiment, all patients were given the same amount of diazepam (0.5 mg/kg); this was necessary due to the marked symptomatology they presented. All patients were in good physical condition and without evidence of neurological symptomatology. They were having a standardized diet throughout the experiment. On the 4th and 6th day of hospitalization, a cisternal puncture was performed at 8 a.m. One of
28
Gaillard/Constantinidis/Tissot
Table I. Individual values of HVA and 5HIAA (ng/ml) in the CSF of 1 manic and 11 de pressed patients Patients
Age
Sex
Diagnosis
+ DCI
-DCI
+ DCI
unipolar melancholy unipolar melancholy unipolar melancholy unipolar melancholy unipolar melancholy bipolar melancholy
98 24 59 25 156 102
93 19 14 65 113 110
44 45 31 5 56 32
28 45 18 25 37 45
reactive depression reactive depression reactive depression
98 80 104
88 96 45
40 37 50
50 43 50
33 110
111 106
44 42
56 28
24
24
35
35
52 62 64 43 63 52
d d
7 8 9
50 54 62
d
10 11
65 40
9 9
involutional depression depressive syndrome with paranoia
12
66
d
mania
9 9
5HIAA
-DCI 1 2 3 4 5 6
d 9 9 9
HVA
these punctures, the first or the second in a balanced cross-over design, was preceded by administration of benserazide, a peripheral decarboxylase inhibitor, 250 mg at 6 p.m., 10 p.m. and 2 a.m., and 500 mg at 6 a.m. before the puncture. Patients were fasted and confined in bed since the evening before the day of puncture. CSF was withdrawn on 0.2 cm3 of 5 N HCL, put on ice and stored for less than 1 week at -3 0 °C . Dosage of HVA and 5HIAA was performed by fluorometry with classical tech niques (Anden and Ross, 1963 \Maickel, 1972). Remaining fractions of CSF from punctures with and without DCI, respectively, were pooled for assay of dopa and O-methyl-dopa (OMD).
The values for HVA and 5HIAA in our patients are given in table I. The following factors have been tested and yielded no significant differences: pres ence of DCI or not (t = 0.22 for HVA, 0.022 for 5HIAA; NS), sex, age and diagnosis (table II). Since motor activity has been shown to affect the level of CSF metabolites, this factor was assessed by clinical observation of the patient and rated as inhibited, normal or increased. In fact, the manic patient was the only one who displayed an increased motor activity, and the level of HVA and 5HIAA was not different in retarded patients with respect to non-retarded.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Results
Depression: HVA and 5HIAA in CSF
29
Table //. Two-tailed t tests for unrelated means for the various factors tested. All values are far below the significance level of 0.05; df = 9; the data of the manic patient are not included in this calculation HVA
Sex Age Diagnosis Motor actvity
5HIAA
-DCI
+ DCI
-DCI
+ DCI
0.65 0.39 0.41 0.40
1.88 1.56 0.90 0.65
0.23 1.58 0.87 0.27
0.67 0.61 1.87 1.86
Without DCI, levels of dopa and OMD were below the sensitivity threshold of the technique: 5 ng/ml for dopa and 13 ng/ml for OMD. After DCI, the level of dopa was 10 ng/ml and the level of OMD, 40 ng/ml.
Numerous evidences show that HVA and 5HIAA found in CSF come most ly, or perhaps totally, from the nervous parenchyma where they are produced by the metabolism of corresponding amines, i.e. dopamine and serotonine (Garelis and Sourkes, 1973; Goodwin et al, 1973\Sourkes, 1973; Young et al., 1974). Extracerebral inhibition of decarboxylase leads to a decrease of dopamine metabolism in periphery; the present experiment in man shows that this decrease is not reflected by a parallel diminution of the level of HVA in CSF; this fact can be understood if HVA originates mostly from brain parenchyma, where the metabolism of dopamine would probably not be influenced to a significant extent by DCI. An identical mechanism can be postulated for 5HT and 5HIAA. Thus, a significant contribution of the metabolism of amines in capillary endo thelium seems to be ruled out, at least in the absence of loading with an exoge nous precursor. This is the most likely explanation of our findings. However, two other possibilities may be raised. First, one might suppose an inhibitory effect of benserazide on the transport of aromatic acids in or out of CSF: this effect has never been demonstrated. Second, if, in spite of appear ances, dopamine is metabolized in brain capillary walls in man as in the rat, a decrease of this metabolism could be compensated for by an increase of HVA formation in brain tissue. It appears unlikely that these two mechanisms, acting in an opposite direction, compensate for each other so precisely, if one looks at the mean changes of HVA and 5HIAA, 2 ± 37 and 0.1 ± 13 ng/ml, respectively. It has been shown that dosable levels of dopa appear in plasma when periph
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
Discussion
Gaillard/Constantinidis/Tissot
30
eral decarboxylase is inhibited (Geissbuhler etal., 1974). We have demonstrated here that this is the case in CSF also. Although the dosage of DCI in this study is relatively low, a slight diminution of decarboxylase activity in the brain could account for the appearance of parenchymatous dopa, leading in turn to an enhancement of methylation into OMD, and to a diffusion of these two amino acids in CSF.
Anden, N. and Ross, E.: On the occurence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sci. 7: 448 (1963). Bartholini, G.; Bates, H.M.; Burkard, W.P., and Pletscher, A.: Increase of cerebral catechol amines caused by 3,4-dihydroxyphenylalanine after inhibition of peripheral decarbox ylase. Nature, Lond. 215: 853-853 (1967). Bartholini, G.; Pletscher, A., and Tissot, R.: On the origin of homovanillic acid in the cerebrospinal fluid. Experimentia 22: 609 (1966). Bertler, A.: Falck, B.; Owman, C., and Rosengreen, E.: The localization of monoaminergic blood-brain barrier mechanisms. Pharmac. Rev. 18: 369-385 (1966). Costantinidis, J.; Bartholini, G.; Tissot, R. und Pletscher, A.: Elektive Anreichung von Dopamin im Parenchym des Ratten-hirns. Helv. physiol, pharmac. Acta 25: 411-413 (1967). Coppen, A.: The biochemistry of affective disorders. Br. J. Psychiat. 113: 1237-1264 (1967). Ey, H.: Bernard, P. et Brisset, Ch.: Manuel de Psychiatrie; 4e éd. (Masson, Paris 1974). Garelis, £. and Sourkes, T.L.: Sites of origin in the central nervous system of monoamine metabolites measures in human cerebrospinal fluid. J. Neurol. Neurosurg. Psychiat. 36: 625-629 (1973). Garelis, E.; Young, S.N.; Lai, S., and Sourkes, T.L.: Monoamine metabolites in lumbar CSF: the question of their origin in relation to clinical studies. Brain Res., Osaka 79: 1-8 (1974). Geissbuhler, F.; Constantinidis, J.; Gaillard, J.-M.; Jacot des Combes, N. et Tissot, R.: Effet d’un inhibiteur de la decarboxylase sur la dopa plasmatique endogène chez l’homme. Biomédecine 21: 297-298(1974). Geissbuhler, F.; Eisenring, J.J.; Friedli, P.: Bartholini, G. et Tissot, R.: Consommation cérébrale et pérophérique de ¿-dopa chez des patients atteints de syndromes parkin soniens, dépressifs ou maniaques sous ¿-dopa en perfusion combinée ou non à un inhibiteur de la décarboxylase. Effets pharmacologiques. Encéphale 2: 127-148 (1972) . Goodwin, F.K.; Post, R.M.; Dunner, D.L., and Gordon, E.K.: Cerebrospinal fluid amine metabolites in affective illness: the probenecid technique. Am. J. Psychiat. 130: 73-79 (1973) . Langelier, P.; Parent, A., and Poirier, L.-J.: Decarboxylase activity of the brain capillary walls and parenchyma in the rat, cat and monkey. Brain Res., Osaka 45: 622-629 (1972). Maickel, R.P.: Fluorometric analysis of 5-hydroxy try ptamine and related compounds. Meth. Neurochem. 2: 101-129 (1972). Papeschi, R.; Sourkes, T.L.: Poirier, J., and Boucher, R.: On the intracerebral origin of
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
References
Depression: HVA and 5H1AA in CSF
31
Dr. J.M. Gaillard, Clinique psychiatrique universitaire de Bel-Air, C H -1225 Chêne-Bourg (Switzerland)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/19/2018 2:59:56 AM
homovanillic acid of the cerebrospinal fluid of experimental animals. Brain Res., Osaka 28: 527-533 (1971). Schildkraut, J.J.: Neuropharmacology of the affective disorders. A. Rev. Pharmac. 13: 427-454 (1973). Sourkes, T.L.: On the origin of homovanillic acid (HVA) in the cerebrospinal fluid. J. neural Transmission 34: 153-157 (1973). Tissot, R.: ¿-dopa and decarboxylase inhibitor (DCI): biochemical and clinical implications; in Barbeau and McDowell ¿-dopa and Parkinsonism, pp. 80-86 (Davis, Philadelphia 1970). Young, S.N.; Garelis, E.; Lai, S.; Martin, J.B.: Molina-Negro, P.; Ethier, R., and Sourkes, T.L.: Tryptophan and 5-hydroxyindoleacetic acid in human cerebrospinal fluid. J. Neurochem. 22: 777-779 (1974).
