Serum and cerebrospinal fluid concentrations of melatonin:
a pilot study in healthy male volunteers
A. Rousseau1, S. Petrén1, J. Plannthin1, T. Eklundh2, and C. Nordin1
1 Department of Neuroscience and Locomotion, Division of Psychiatry, 2 Department of Clinical Neuroscience and Family Medicine, Psychiatry Section, Huddinge University Hospital, Huddinge, Sweden Received November 17, 1998; accepted April 20, 1999 Summary. Melatonin was determined in serum and cerebrospinal fluid (CSF)
obtained from 13 healthy males lumbar-punctured in the sitting position
without preceding bed rest.
There was a significant correlation between the levels of melatonin in The serum concentration was lower than that in the CSF, a finding that calls in question the theory that melatonin is mainly released from the pinealgland into the bloodstream.
In conclusion, serum levels of melatonin in healthy male volunteers, mir- ror the CSF concentrations when lumbar puncture is carried out using thedescribed technique.
Keywords: Melatonin, cerebrospinal fluid, serum.
The indoleamine melatonin (5-methoxy-N-acetyltryptamine) is a peptide-hormone synthesised and secreted by the pineal gland. Melatonin secretiondisplays a circadian rhythm (Adrendt et al., 1977) and it also exhibits seasonalas well as interindividual variation (Bergiannaki et al., 1996). Various studieshave indicated that melatonin influences sleep (Chase and Gidal, 1997),body temperature (Deacon et al., 1994), the immune system (Hofbauer andHeufelder, 1996) and mental performance (Slotten and Krekling, 1996).
Owing to the inversed relationship between melatonin and cortisol, melatoninis of specific interest in affective disorders (Wetterberg et al., 1979; Brown,1989).
Few studies have compared melatonin concentrations in human cere- brospinal fluid (CSF) and blood. According to current concepts, melatonin levels are higher in blood than in the CSF (Adrendt et al., 1977; Cardinali,1981; Young et al., 1984). However, a single report has shown higher levels inthe CSF (Bruce et al., 1991).
The concentrations of compounds in lumbar CSF have been assumed to mirror the levels in the central nervous system (CNS), an assumption that hasbeen called in question, however (Meltzer and Lowy, 1987; Potter and Manji,1993; Altemus et al., 1994). One major reason is that CSF concentrations areinfluenced by confounding factors such as age, height, body weight, volumeof CSF drawn, diet, site of puncture (Bertilsson and Åsberg, 1984), motility(Post et al., 1980; Bertilsson and Åsberg, 1984), neuraxis distance (Nordinet al., 1993), atmospheric pressure (Nordin et al., 1992; Eklundh et al., 1994)and CSF collection time (tapping-time) (Nordin et al., 1993). If these factorsare of significance for melatonin in the CSF as well as for the other com-pounds, they have to be taken into consideration when interpreting CSF dataon melatonin.
The primary aim of the present study was to investigate whether there is a relationship between the serum and CSF concentrations of melatonin. Fur-thermore, we wanted to elucidate whether the concentration of melatonin inlumbar CSF is influenced by the confounding factors mentioned above. Thestudy is exploratory and hypothesis generating.
Subjects and methods
The subjects comprised 13 healthy males (aged 25.3 Ϯ s.d. 4.5, Table 1) recruited amongmedical students and their friends. Prior to experimentation, the subjects were inter- Table 1. Clinical data on 13 lumbar punctured male volunteers (mean Ϯ SD)
viewed, physically examined and bloodtested based on the following exclusion criteria:having either neurological, cardiovascular, hepatic, renal, haematopoetic, gastrointesti-nal, metabolic or psychiatric dysfunction, receiving medication on a regular basis. Allsubjects participated in the study after giving their informed consent.
Lumbar puncture was performed at the L 4–5 level at 8–9 a.m. after a minimum of 8 hours in the fasting state. There was no restriction concerning rest during the 8 hourspreceding the puncture. With the volunteer in a sitting position, CSF was obtained byallowing it to drip into a test tube using a disposable needle (Becton – Dickinson 0.70 ϫ75 mm). The CSF collection time was recorded. The first two consecutive 6-ml fractions ofCSF were immediately protected from light, centrifuged at 3,500 rpm for 2 minutes andstored at Ϫ70°C until analysed. Immediately after the lumbar puncture, a 6-ml venousblood sample was obtained using a standard venipuncture technique.
Melatonin was analysed using radioimmunoassay technique using [3H] melatonin as a tracer. The intra-assay variability is 7% and the inter-assay variability is 10%(Wetterberg et al., 1978).
Data on atmospheric pressure in Linköping were obtained from a meteorologist at SAAB airport, located less than 10 km from the hospital.
The StatView 4.5 (Abacus Concepts Inc.) program was used for statistical calcula- tions. Parametric statistics were employed according to Kleinbaum et al. (1988). Inrepeated stepwise regression analyses (F-to-Enter set at 4.75), the concentration of mela-tonin in 12 ml of CSF was used as the dependent variable. The serum concentration ofmelatonin, age of the volunteer, body mass index (BMI), CSF collection time, atmo-spheric pressure and neuraxis distance (from the external occipital protuberance to thesite of puncture) in the sitting position were used as regressors. Due to the study design,environmental light conditions were not controlled for.
The Ethics Committee of the University Hospital in Linköping, Sweden, approved Clinical data on the volunteers are presented in Table 1. On using the stepwiseregression technique, we found that the concentration of melatonin in 12 ml ofCSF was influenced by the serum level (r ϭ 0.72, p ϭ 0.0059; Fig. 1), but notby any of the confounding factors.
The concentration of melatonin in 12 ml of CSF was significantly higher than the serum level (paired t-test; t ϭ 2.52, p ϭ 0.0272).
There was no difference between the concentrations of melatonin when comparing the first (0–6 mL) and the second (7–12 mL) CSF fraction (t ϭ 0.73;NS).
The major finding of the study is a correlation between the concentration ofmelatonin in serum and the CSF. This is in line with previous findings in sheep(Shaw et al., 1989) and in a small sample of 4 volunteers (Bruce et al., 1991).
Our findings may be explained by a relatively unrestricted exchange of mela-tonin across the blood-brain barrier, owing to the fact that melatonin is highlylipid-soluble (Reiter et al., 1994). At any rate, the finding of a correlationindicates that serum melatonin can be used to predict the concentration inlumbar CSF, when sampled as described above with the volunteer in thesitting position after 8 hours of fasting.
Fig. 1. Simple regression plot showing the correlation between melatonin in the CSF and
serum (r ϭ 0.72; p ϭ 0.0059; Y ϭ 0.048 ϩ 1.08 * X) The level of melatonin in lumbar CSF was significantly higher than in simultaneously sampled serum. This is an unexpected finding. The route bywhich melatonin reaches its targets is not known, but it has been assumed thatsecretion must be effectuated through venous drainage into the peripheralcirculation because of the pineal morphology (Kappers et al., 1974) andfindings of higher levels of melatonin in the blood than in the CSF (Arendtet al., 1977; Cardinali, 1981; Young et al., 1984). However, animal studies haveshown that intraventricular injections of melatonin elevates plasma melatoninlevels within one minute, while subcutaneous infusion yields three timeshigher melatonin levels in plasma than in CSF (Kanematsu et al., 1989; Vitteet al., 1988), indicating a rapid turnover of CSF melatonin and compatibilitywith the hypothesis of a direct pineal secretion of melatonin into the ventricu-lar system.
Each individual has his own temporal profile of circadian melatonin secretion which varies little intra-individually but widely inter-individually(Coetzee et al., 1989; Bruce et al., 1991). It also seems as if the melatonin CSFprofile lags about 30 minutes compared to plasma levels, e.g. the nocturnalpeak comes 30 minutes earlier in plasma than in CSF (Bruce et al., 1991). Thismy be part of the explanation why CSF levels were higher than plasma levelsas melatonin levels were dropping at the time of sampling.
In previous studies on humans (e.g., Young et al., 1984), nothing was reported on the position of the volunteers at lumbar puncture. When inter- preting data on amine metabolites in the CSF, the position of the subject hasto be taken into account (Bertilsson and Åsberg, 1984). Posture is also ofinterest for plasma melatonin since moving from a supine to a standing posi-tion yields increasing levels (Deacon and Arendt, 1994).
No difference was found on comparing melatonin concentrations in two consecutive CSF fractions. This homogeneity supports findings in earlierstudies (Young et al., 1984), but contrasts with observations regarding neu-rotransmitter metabolites, which usually display concentration gradients inCSF (Siever et al., 1975; Sjöström et al., 1975; Nordin et al., 1982, 1995). Thelack of a melatonin concentration gradient may be explained by a high rate ofexchange across the blood-brain barrier. Another plausible explanation mightbe that no metabolism of the hormone occurs in the lower part of the CSFcompartment.
The presumed confounding factors did not influence CSF melatonin levels in the present study and apparently may not need to be taken into accountwhen following the described puncture procedure.
This study was supported by grants from the Söderström-König Foundation and from theResearch Foundation of the University Hospital in Linköping. We thank our researchnurse, Ms. M. Mansfield, for her invaluable help and assistance.
Altemus M, Swedo S, Leonard H, et al (1994) Changes in cerebrospinal fluid neuro- chemistry during treatment of obsessive-compulsive disorder with clomipramine.
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