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Menstrual cycle affects plasma HVA
169
Psgchiatr.v Research, 17, 169-l 7 I Elsevier
Letter Menstrual
Cycle Affects
Plasma
HVA
To the Editor: Recent studies suggest that peripheral levels of homovanillic acid (HVA), as measured in plasma, may be a neurochemical correlate of psychosis (Pickar et al., 1984; Davis et al., 1985) and therefore may be a potential biological marker for schizophrenia. HVA is a metabolite of dopamine (DA), a neurotransmitter implicated in the neurochemistry of psychosis. All antipsychotic drugs are DA antagonists. and their relative degree of DA antagonism tends to correlate with their clinical antipsychotic potency. A measure of neurotransmitter activity is its turnover, which determines tissue levels of neurotransmitter metabolites. Levels of DA metabolites, specifically HVA and dihydroxyphenylacetic acid (DOPAC), in regions of rat brain correlate well with other estimates of DA turnover or activity in these regions. Recently. altered plasma levels of HVA in schizophrenics have been reported, with a positive correlation noted between HVA levels and severity of psychosis (Pickar et al.. 1984; Davis et al., 1985). Although the ultimate origin of plasma HVA is unknown, it is reasonable to suppose that about half may originate in the central nervous system (Bacopoulos et al., 1978. 1979; Kendler et al.. 1981. 1982). If so, it must exit the arachnoid villi. and therefore be an imperfect measure of cerebrospinal fluid (CSF) HVA, let alone regional brain dopamine activity. One prior study of peripheral factors in plasma HVA research (Kendler et al., 1983) found no significant effects of diet, so long as the diet did not include large amounts of monoamines. This study also associated increased plasma HVA with vigorous exercise, but this result was confounded by circadian fluctuations of baseline HVA. In the present study, we have examined effects of menstrual cycle. moderate exercise. and diet on plasma HVA.
Methods Subjects. Subjects were recruited from clinical personnel at the Psychiatry Service of the Dallas Veterans Administration (VAMC) and from patients referred to the gastroenterology laboratory of the Dallas VAMC for colonoscopy. All subjects denied personal or family history of psychiatric illness. To control for possible circadian variations, plasma HVA samples were taken at a fixed time of day for each study: (I) between 0800h and 0900h, after an overnight fast, for studies on menstrual cycle and exercise; (2) between 1030h and I230h for the diet study. Assay. Blood specimens were obtained in heparinized vacutainers and centrifuged within 15 minutes. Plasma was then decanted with plastic pipets into plastic storage tubes, which were then frozen at -7O’C until analysis. Frozen plasma samples were thawed, deproteinized with I / 10th volume of 3 M HC104. and centrifuged (I 5,600g) for IO minutes. An aliquot of the supernatant was injected onto a high performance liquid chromatograph. Electrochemical detection was used, with external standards for reference (Changet al.. 1983). All assays were run in one batch, for exercise and menstrual cycle studies. The intra-assay coefficient of variation was 7.471 Exercise. Six normal control plasma HVA determined before brisk l-mile walk (20 minutes).
males had and after a
Menstrual Cycle. Eight normally menstruating females, taking no oral contraceptives, were studied. Plasma for HVA determination was obtained at 0800h on day 7 and day 2 I of the menstrual cycle. All women in this study had normal, regular menstrual cycles, of 27 to
0165-1781/86/$03.50 0 1986 Elsevier Science Publishers B.V.
170
31 days’ duration. obtained reflects activity.
Thus, the plasma HVA pre- and post-ovulatory
Results Exercise. Mean (+ SD) plasma HVA levels in normal control males did not change after brief moderate exericse(pre-exercise HVA 7. I + 3.0; post-exercise HVA 6.9 + 3. I). Menstrual Cycle. A significant drop in plasma HVA was noted after presumed ovulation in all women studied (Fig. I). Fig. 1. Plasma HVA levels in normally menstruating women on day 7 and day 21 of the cycle, before and after ovulation
Discussion The menstrual cycle appears to be an important factor to consider in plasma HVA research, since normally menstruating women in the present study had a drop in their plasma HVA after ovulation. To what extent this finding is related to psychological changes in women during the menstrual cycle remains to be investigated. The finding is not readily accounted for, since the ovary does not appear to contain either a very large number of DA receptors or a high concentration of DA. On the other hand, brain dopaminergic influences on hormonal function are well known. Acknowledgment. The authors thank the Veterans Administration for support. Judith Moss capably assisted in preparation of the manuscript. References Bacopoulos. N.G., Hattox, S.E., and Roth, R.H. 3,4_Dihydroxyphenylacetic acid and homovanillic acid in rat plasma: Possible indicators of central dopaminergic activity. European
Journal
of Pharmacology,
56, 225
( 1979). Bacopoulos, N.G., Heninger. G.R., and Roth. R.H. Effects of haloperidol and probenecid on plasma and CSF dopamine metabolites in the rhesus monkey (Macacca mularta).
2
t PRE
POST
Mean + SD: pre-ovulation 6.4 + 2.3 ng/ml; ovulation 6.6 t 2.1 ng/ml. p < 0.005. Student’s
post-
t test.
Life Sciences,
23, 1805 (1978).
Chang, W.H., Scheinin, M., Burns, R.S., and Linnoila, M. Rapid and simple determination of homovanillic acid in plasma using high performance liquid chromatography with electrochemical detection. Acta Pharmacologica et Toxicologica. 53,275 (1983). Davis, K.L., Davidson, M.. Mohs, R.C.. Kendler. K.S.. Davis, B.M., Johns, C.A.. DeNigris. Y.. and Horvath, T.B. Plasma homovanillic acid concentration and the severity of schizophrenic illness. Science, 227, 1601 (1985).
171 Kendler, K.S., Heninger, G.R., and Roth, R.H. Brain contribution to the haloperidolinduced increase in plasma homovanillic acid.
Frederick Petty, Ph.D., Gerald Kramer, B.A. John Weed, P.A.-C.
European (1981).
Veterans Administration Medical Center and Department of Psychiatry Southwestern Medical School Dallas, TX
Journal
of Pharmacology,
71, 321
Kendler, K.S., Heninger, G.R., and Roth, R.H. Influence of dopamine agonists on plasma and brain levels of homovanillic acid. Life Sciences,
30, 2063 (1982).
Kendler, K.S., Mohs, R.C., and Davis, K.L. The effects of diet and physical activity on plasma homovanillic acid in normal human subjects. Psychiatry Research, 8, 215 (1983).
Pickar, D.. Labarca. R., Linnoila, M., Roy, A., Hommer, D.. Everett, D., and Paul, S.M. Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science. 225, 954 ( 1984).
November
M.D.1
20. 1985
I. Reprint requests to Dr. F. Petty, Psychiatry Service (I 16A). VAMC, 4500 S. Lancaster Rd., Dallas. TX 75216. USA.
Psgchiatr.v Research, 17, 169-l 7 I Elsevier
Letter Menstrual
Cycle Affects
Plasma
HVA
To the Editor: Recent studies suggest that peripheral levels of homovanillic acid (HVA), as measured in plasma, may be a neurochemical correlate of psychosis (Pickar et al., 1984; Davis et al., 1985) and therefore may be a potential biological marker for schizophrenia. HVA is a metabolite of dopamine (DA), a neurotransmitter implicated in the neurochemistry of psychosis. All antipsychotic drugs are DA antagonists. and their relative degree of DA antagonism tends to correlate with their clinical antipsychotic potency. A measure of neurotransmitter activity is its turnover, which determines tissue levels of neurotransmitter metabolites. Levels of DA metabolites, specifically HVA and dihydroxyphenylacetic acid (DOPAC), in regions of rat brain correlate well with other estimates of DA turnover or activity in these regions. Recently. altered plasma levels of HVA in schizophrenics have been reported, with a positive correlation noted between HVA levels and severity of psychosis (Pickar et al.. 1984; Davis et al., 1985). Although the ultimate origin of plasma HVA is unknown, it is reasonable to suppose that about half may originate in the central nervous system (Bacopoulos et al., 1978. 1979; Kendler et al.. 1981. 1982). If so, it must exit the arachnoid villi. and therefore be an imperfect measure of cerebrospinal fluid (CSF) HVA, let alone regional brain dopamine activity. One prior study of peripheral factors in plasma HVA research (Kendler et al., 1983) found no significant effects of diet, so long as the diet did not include large amounts of monoamines. This study also associated increased plasma HVA with vigorous exercise, but this result was confounded by circadian fluctuations of baseline HVA. In the present study, we have examined effects of menstrual cycle. moderate exercise. and diet on plasma HVA.
Methods Subjects. Subjects were recruited from clinical personnel at the Psychiatry Service of the Dallas Veterans Administration (VAMC) and from patients referred to the gastroenterology laboratory of the Dallas VAMC for colonoscopy. All subjects denied personal or family history of psychiatric illness. To control for possible circadian variations, plasma HVA samples were taken at a fixed time of day for each study: (I) between 0800h and 0900h, after an overnight fast, for studies on menstrual cycle and exercise; (2) between 1030h and I230h for the diet study. Assay. Blood specimens were obtained in heparinized vacutainers and centrifuged within 15 minutes. Plasma was then decanted with plastic pipets into plastic storage tubes, which were then frozen at -7O’C until analysis. Frozen plasma samples were thawed, deproteinized with I / 10th volume of 3 M HC104. and centrifuged (I 5,600g) for IO minutes. An aliquot of the supernatant was injected onto a high performance liquid chromatograph. Electrochemical detection was used, with external standards for reference (Changet al.. 1983). All assays were run in one batch, for exercise and menstrual cycle studies. The intra-assay coefficient of variation was 7.471 Exercise. Six normal control plasma HVA determined before brisk l-mile walk (20 minutes).
males had and after a
Menstrual Cycle. Eight normally menstruating females, taking no oral contraceptives, were studied. Plasma for HVA determination was obtained at 0800h on day 7 and day 2 I of the menstrual cycle. All women in this study had normal, regular menstrual cycles, of 27 to
0165-1781/86/$03.50 0 1986 Elsevier Science Publishers B.V.
170
31 days’ duration. obtained reflects activity.
Thus, the plasma HVA pre- and post-ovulatory
Results Exercise. Mean (+ SD) plasma HVA levels in normal control males did not change after brief moderate exericse(pre-exercise HVA 7. I + 3.0; post-exercise HVA 6.9 + 3. I). Menstrual Cycle. A significant drop in plasma HVA was noted after presumed ovulation in all women studied (Fig. I). Fig. 1. Plasma HVA levels in normally menstruating women on day 7 and day 21 of the cycle, before and after ovulation
Discussion The menstrual cycle appears to be an important factor to consider in plasma HVA research, since normally menstruating women in the present study had a drop in their plasma HVA after ovulation. To what extent this finding is related to psychological changes in women during the menstrual cycle remains to be investigated. The finding is not readily accounted for, since the ovary does not appear to contain either a very large number of DA receptors or a high concentration of DA. On the other hand, brain dopaminergic influences on hormonal function are well known. Acknowledgment. The authors thank the Veterans Administration for support. Judith Moss capably assisted in preparation of the manuscript. References Bacopoulos. N.G., Hattox, S.E., and Roth, R.H. 3,4_Dihydroxyphenylacetic acid and homovanillic acid in rat plasma: Possible indicators of central dopaminergic activity. European
Journal
of Pharmacology,
56, 225
( 1979). Bacopoulos, N.G., Heninger. G.R., and Roth. R.H. Effects of haloperidol and probenecid on plasma and CSF dopamine metabolites in the rhesus monkey (Macacca mularta).
2
t PRE
POST
Mean + SD: pre-ovulation 6.4 + 2.3 ng/ml; ovulation 6.6 t 2.1 ng/ml. p < 0.005. Student’s
post-
t test.
Life Sciences,
23, 1805 (1978).
Chang, W.H., Scheinin, M., Burns, R.S., and Linnoila, M. Rapid and simple determination of homovanillic acid in plasma using high performance liquid chromatography with electrochemical detection. Acta Pharmacologica et Toxicologica. 53,275 (1983). Davis, K.L., Davidson, M.. Mohs, R.C.. Kendler. K.S.. Davis, B.M., Johns, C.A.. DeNigris. Y.. and Horvath, T.B. Plasma homovanillic acid concentration and the severity of schizophrenic illness. Science, 227, 1601 (1985).
171 Kendler, K.S., Heninger, G.R., and Roth, R.H. Brain contribution to the haloperidolinduced increase in plasma homovanillic acid.
Frederick Petty, Ph.D., Gerald Kramer, B.A. John Weed, P.A.-C.
European (1981).
Veterans Administration Medical Center and Department of Psychiatry Southwestern Medical School Dallas, TX
Journal
of Pharmacology,
71, 321
Kendler, K.S., Heninger, G.R., and Roth, R.H. Influence of dopamine agonists on plasma and brain levels of homovanillic acid. Life Sciences,
30, 2063 (1982).
Kendler, K.S., Mohs, R.C., and Davis, K.L. The effects of diet and physical activity on plasma homovanillic acid in normal human subjects. Psychiatry Research, 8, 215 (1983).
Pickar, D.. Labarca. R., Linnoila, M., Roy, A., Hommer, D.. Everett, D., and Paul, S.M. Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science. 225, 954 ( 1984).
November
M.D.1
20. 1985
I. Reprint requests to Dr. F. Petty, Psychiatry Service (I 16A). VAMC, 4500 S. Lancaster Rd., Dallas. TX 75216. USA.