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Concentrations of free 3-methoxy-4-hydroxyphenylglycol in the plasma and cerebrospinal fluid are highly correlated, but concentrations in the cerebrospinal fluid are always higher than those in plasma, even when large amounts of the catecholamine metabolite are derived from a tumor of the adrenal medulla. This is explained by considering the plasma and cerebrospinal fluid as a two-compartment system in which the rate constants for entry into and exit from the cerebrospinal fluid compartment are similar. 3-Methoxy-4-hydroxyphenylglycol that is synthesized, but not catabolized, in the central nervous system maintains cerebrospinal fluid levels at an increment over those in plasma. This increment can be used to provide the best available index of formation of 3-methoxy-4-hydroxyphenylglycol in the central nervous system.

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Concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl glycol in cerebrospinal fluid were measured by a gas chromatographic method in 34 patients with affective illness and in 44 controls. Concentrations of this metabolite in spinal fluid were significantly lower in depressed patients than in controls or manic patients. These low values may occur secondary to depressive phenomena such as reduced psychomotor activity, or they may reflect a primary change in norepinephrine metabolism in depressive illness.

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Patients with spinal cord transection had normal concentrations of 5-hydroxyindoleacetic acid and low concentrations of 3-methoxy-4-hydroxyphenyl glycol in lumbar cerebrospinal fluid. The presence or absence of spinal fluid block in these patients did not affect concentrations of either amine metabolite. However, the concentration of homovanillic acid was lower in patients with spinal fluid block than in those without block. The results suggest that the spinal cord contributes to concentrations of 3-methoxy-4-hydroxyphenyl glycol and possibly 5-hydroxyindoleacetic acid, but contributes little to that of homovanillic acid in the lumbar spinal fluid of man.

Levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a major metabolite of norepinephrine, were measured in human CSF by gas-liquid chromatography. MHPG concentrations were similar in both ventricular and lumbar CSF samples ; about 30 per cent of the MHPG from either source occurred as the sulphate conjugate. There was relatively little entry of intravenously infused [14C]MHPG into lumbar spinal fluid. Both a-methylparatyrosine, an inhibitor of tyrosine hydroxylase, and fusaric acid, an inhibitor of dopamine-,%hydroxylase, significantly diminished MHPG values. On the other hand, doses of L-DOPA or probenecid, sufficient to substantially elevate CSF levels of the dopamine metabolite, hornovanillic acid, failed to alter the spinal fluid content of MHPG. CSF concentrations of MHPG in patients with Parkinson's disease or the other central nervous system disorders studied did not differ significantly from control levels. The results suggest that MHPG values in CSF may provide an index to norepinephrine metabolism in the central nervous system of man.CEREBROSPINAL fluid (CSF) levels of monoamine metabolites have been used extensively to estimate dopamine and serotonin metabolism in the human CNS. The rationale for this approach derives from observations suggesting that the CSF content of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), the principal degradation products of these monoamines, reflect levels in CNS tissues (GULDBERG and YATES, 1968; ECCLESTON et al., 1968). Recently a sensitive and specific method has been developed to measure CSF concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) (WILK, DAVIS and THACKER, 1971 ; GORDON and OLIVER, 1971), a major product of norepinephrine metabolism (SCHANBERG et al., 1968; MAAS and LANDIS, 1968; BREESE et d., 1969; SUGDEN and ECCLESTON, 1972). Here we report the application of this technique to the study of noradrenergic function in patients with various CNS disorders and during the administration of centrally active drugs. MATERIALS A N D M E T H O D SLumbar CSF samples were obtained from 67 patients (29 males and 38 females, ages 8-67 yr). Included were 13 with idiopathic parkinsonism, five with dystonia musculorum deformans, three with acquired dystonia, seven with Huntington's chorea, six with Down's syndrome, eight with diseases involving the spinal cord, 14 with miscellaneous central or peripheral nervous system disorders and 11 control subjects who were free of nervous system disease. In addition, ventricular CSF samples were obtained from nine patients with various CNS disorders via chronically indwelling, subcutaneous reservours (RATCHESON and OMMAYA, 1968).Lumbar punctures were ordinarily performed at 0900 hours with the patients kept fasting and recumbent in bed during the preceding 10-12 h. CSF samples from individuals receiving orally Abbreviations used: HVA, homovanillic acid; MHPG, 3-methoxy-4hydroxyphenylethylene glycol ; 581 5-HIAA, 5-hydroxyindoleacetic acid.

The short- and long-term effects of neuroleptic drugs differ both clinically and biochemically. Short-term treatment with such a drug causes a kinetic activation of striatal tyrosine hydroxylase. Long-term treatment causes a prompt activation of the enzyme which is followed by a delayed, compensatory deactivation below control levels. Tolerance also develops to the stimulating effect of haloperidol on striatal dopamine turnover.