Kearns-Sayre syndrome: Cerebral folate deficiency,MRI findings and new cerebrospinal fluid biochemical features

We evaluated cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF), biogenic amines, and white matter status in six Kearns-Sayre syndrome (KSS) patients. They presented severe 5-MTHF deficiency. A significant negative correlation was observed between CSF 5-MTHF and protein concentration. CSF homovanillic acid was clearly high. Regarding neuroimaging, the main feature was hyperintensity in the basal ganglia, brainstem, and cerebral/cerebellar white matter. The severity of hemispheric white matter disturbances appeared to be qualitatively associated with 5-MTHF values. The negative correlation between 5-MTHF and proteins supports the hypothesis of impaired choroid plexus function. Interestingly, despite very low 5-MTHF, clearly high neurotransmitter metabolites were found.     

In-use stability of monoamine metabolites in human cerebrospinal fluid

Cerebrospinal fluid (CSF) concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) are commonly used to provide information about central nervous system (CNS) dopaminergic and serotonergic activity. However, little attention has been given to the effects of sample handling on the concentrations of these compounds in human CSF. Using high-performance liquid chromatography (HPLC) with electrochemical detection, we observed that, in CSF stored at −80°C, concentrations of the serotonin metabolite 5-HIAA and the dopamine metabolite HVA remained unchanged through six 1-h and six 24-h freeze–thaw cycles. Exposure to bright room light (3 h, 1230 lux) resulted in a 5-HIAA concentration that was 96.3±2.0% of the initial and an HVA concentration that was 98.8±1.03% of initial. The pH of the CSF significantly increased during both freeze–thaw series and while maintained on ice (4°C). These results demonstrate the in-use stability of 5-HIAA and HVA in human CSF under commonly-encountered laboratory conditions.     

Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity

The proton-coupled oligopeptide transporter PEPT2 (or SLC15A2 ) is the major protein involved in the reclamation of peptide-bound amino acids and peptide-like drugs in kidney. PEPT2 is also important in effluxing peptides and peptidomimetics from CSF at the choroid plexus, thereby limiting their exposure in brain. In this study, we report a neuroprotective role for PEPT2 in modulating the toxicity of a heme precursor, 5-aminolevulinic acid (5-ALA). Our findings demonstrate that in PEPT2-deficient mice, 5-ALA administration results in reduced survivability, a worsening of neuromuscular dysfunction, and CSF concentrations of substrate that are 8–30 times higher than that in wild-type control animals. The ability of PEPT2 to limit 5-ALA exposure in CSF suggests that it may also have relevance as a secondary genetic modifier of conditions (such as acute hepatic porphyrias and lead poisoning) in which 5-ALA metabolism is altered and in which 5-ALA toxicity is important.     

Selenium Concentration in Cerebrospinal Fluid Samples from a Paediatric Population

Selenium is an important trace element for brain function. Our objective was to analyse cerebrospinal fluid (CSF) selenium (Se) in 89 paediatric patients. We also studied correlations between Se and other biochemical variables (age, CSF protein concentrations and glutathione peroxidase activity and plasma Se values). Cerebrospinal fluid Se values showed a significant negative correlation with the age of patients (r = −0.476; p < 0.0001), and positive with CSF total protein concentrations and GPX activity (r = 0.446, p < 0.001; r = 0.431; p = 0.001, respectively). No association was observed between plasma and CSF Se concentrations. Median CSF Se values were 32 times lower when compared with those for plasma. In conclusion, CSF Se concentrations depend on age and total CSF protein values. The association observed between CSF Se and GPX activity suggests that Se quantification might be a reflection of some Se-dependent protein function. Cerebrospinal fluid Se values were independent of serum Se concentrations.     

Cerebrospinal Fluid Parameters in Healthy Volunteers During Serial Lumbar Punctures

Lumbar punctures were performed on four occasions over a 5-day period (8:30 a.m. on days 1, 3, and 5; 2:30 p.m. on day 2) on 10 normal volunteers (five of each sex; mean age, 27.7 years) to assess, with repeated sampling, the day-to-day variation of selected CSF parameters. Two subjects abstained from the lumbar puncture on day 5 due to headache after the third puncture. Lumbar CSF was analyzed for concentrations of free and total gamma-aminobutyric acid (GABA), homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), total protein, albumin, and immunoglobulin (Ig)G. No significant concentration differences were found between the afternoon and next morning samples. No differences were found in concentrations of free GABA, total GABA, homocarnosine, 5-HIAA, or albumin across the study. In contrast, HVA concentrations significantly increased by day 5, whereas total protein and IgG decreased during the study. The most likely explanation for these changes involves the known concentration gradients in the CSF column.     

Increased Cerebrospinal Fluid Dopamine and 3,4-Dihydroxyphenylacetic Acid Levels in Huntington''s Disease: Evidence for an Overactive Dopaminergic Brain Transmission

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of patients with Huntington's disease (HD) were measured by HPLC. CSF DA, DOPAC, and MHPG levels were found to be increased in HD patients. Levels of HVA, 5-HIAA, and NA in the CSF of HD patients did not differ from those of controls. Changes in CSF DA and DOPAC levels were consistent with previous findings of increased DA tissue content in some brain areas of patients with HD. These results suggest that CSF DOPAC levels could be a more reliable index of overactive dopaminergic brain systems in HD than CSF HVA levels.     

Enhancement of Brain Dopamine Metabolism by Tyrosine During Immobilisation: An In Vivo Study Using Repeated Cerebrospinal Fluid Sampling in Conscious Rats

Central dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism was monitored in conscious, freely moving rats by determination of levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF samples withdrawn repeatedly from the cisterna magna and treated with acid to hydrolyse DOPAC and HVA conjugates. The effect of tyrosine on DA metabolism was investigated. Time courses of metabolite concentrations in individual rats in a quiet room showed that tyrosine (20, 50, or 200 mg/kg i.p.) was without significant effect; brain changes were essentially in agreement. However, the increases of CSF DOPAC and HVA levels that occurred on immobilisation for 2 h were further enhanced by tyrosine (200 mg/kg). The associated increases of 5-HIAA level were unaffected. The corresponding increases of DA metabolite concentrations in the brains of immobilised rats given tyrosine were less marked than the CSF changes and only reached significance for "rest of brain" DOPAC. The CSF studies revealed large interindividual variation in the magnitude and duration of the effects of immobilisation on transmitter amine metabolism. These results may help toward the elucidation of possible relationships between the neurochemical and behavioural effects of stress.     

3,4-Dihydroxyphenylethylamine and 5-Hydroxytryptamine Metabolism in the Rat: Acidic Metabolites in Cisternal Cerebrospinal Fluid Before and After Giving Probenecid

3,4-Dihydroxyphenylethylamine (DA, dopamine) and 5-hydroxytryptamine (5-HT) turnover values were determined in freely moving male rats by measuring the rates of accumulation of the acidic metabolites of the above transmitters, i.e., 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (CSF) samples after probenecid (200 mg/kg i.p.) administration. Determinations on samples before and after acid hydrolysis showed that the latter procedure was necessary for DA turnover determination. Thus whereas total (DOPAC + HVA) increased linearly with time after probenecid, free (DOPAC + HVA) did not. This was because the percentage of DOPAC + HVA in conjugated form increased with time. Determinations on a group of 28 rats during the dark (red light) period showed that cisternal amine metabolite concentrations before probenecid injection did not parallel turnover values. This was probably because individual differences in metabolite egress strongly affect the pre-probenecid values. The poor correlations between CSF tryptophan and 5-HT turnover suggested that differences of brain tryptophan concentration were not major determinants of differences of brain 5-HT metabolism within this group of normal rats. Considering that the rats were of similar weight and that the turnover values were all determined at approximately the same time of day, the three- to fourfold ranges of the turnover values are remarkable. The positive correlation between the DA and 5-HT turnovers of individual rats suggests the existence of common effects on DA and 5-HT turnover in normal rats.     

Melatonin content of cat cerebrospinal fluid and blood following intravenous injection of melatonin as measured by Xenopus laevis skin melanophore test.

Melatonin content of the cerebrospinal fluid (CSF), serum and choroid plexus was measured in untreated and melatonin-injected cats using the Xenopus laevis melanophore-contracting bioassay. CSF and choroid plexus had a considerable melanophore contracting activity in the untreated animals. Intravenously injected melatonin considerably enhanced the melanophore-contracting activity of the CSF and choroid plexus. Two hours later, melatonin was still present at high concentrations in these tissues, whereas it had considerably diminished in the blood. It is concluded that the choroid plexus concentrates and secretes melatonin into the CSF in a bioactive form.     

Production and Secretion of Adrenomedullin by Cultured Choroid Plexus Carcinoma Cells

Abstract: Adrenomedullin is a potent vasodilator peptide that was originally isolated from pheochromocytoma. The production and secretion of adrenomedullin by cultured choroid plexus carcinoma cells were studied by radioimmunoassay and northern blot hybridization. Choroid plexus carcinoma is a rare malignant tumor derived from the epithelium of the choroid plexus. Immunoreactive adrenomedullin was detected in the conditioned medium of choroid plexus carcinoma cells (40.8 ± 7.5 fmol/10⁵ cells/24 h; mean ± SEM, n = 5). Reverse-phase HPLC of the conditioned medium showed one major peak of the immunoreactive peptide eluting in the position of synthetic human adrenomedullin and two smaller peaks eluting earlier. Addition of interleukin-1β (10 ng/ml) alone or in combination with three cytokines, interferon-γ (100 U/ml), tumor necrosis factor-α (20 ng/ml), and interleukin-1β (10 ng/ml), caused significant increases in the immunoreactive adrenomedullin concentrations in the medium (∼175 and 293% of the control level, respectively). Northern blot analysis showed the expression of 1.6-kb adrenomedullin mRNA in the total RNA sample prepared from cultured choroid plexus carcinoma cells. Treatment with either interleukin-1β or the combination of three cytokines caused significant increases in levels of adrenomedullin mRNA in parallel with those in immunoreactive adrenomedullin concentrations in the conditioned medium. These findings raise a possibility that adrenomedullin is secreted from the choroid plexus and has physiological roles in the CNS via the CSF. In addition, adrenomedullin secreted from choroid plexus carcinoma may be related to the pathophysiology of the tumor.     

The contribution from the choroid plexus and the periventricular CNS to amino acids and proteins in the human CSF

During neurosurgery the freshly secreted extracellular fluid (ECF) from the choroid plexus was sampled with small pieces of application paper in three patients with intractable epilepsy. The samples were analyzed for free amino acids and for soluble proteins. The results were compared with corresponding data on extracellular fluid from the brain surface obtained with dialysis-perfusion as well as with the cerebrospinal fluid (CSF) acquired by lumbar punction. The dialysis data were calibrated against the paper results. The choroid plexus secretion had a high concentration of transthyretin as well as of an unidentified protein with an isoelectric point of 7.4. The cortical ECF exhibited high concentrations of tau-globulin and gamma-trace protein. Among the amino acids, glutamine had lower concentration in the choroid plexus secretion and higher concentrations in the ECF of the brain compared to the CSF. The amino acid derivative ethanolamine exhibited a similar pattern. This was interpreted to demonstrate that these compounds enter the CSF from the brain tissue. In contrast, alanine, serine, and taurine had a lower concentration in the CSF than in the plexus secretion which suggests that they are removed from the CSF by brain tissue.     

5-Hydroxyindoleacetic acid and homovanillic acid concentrations in cerebrospinal fluid in patients with Alzheimer's disease, depression and mild cognitive impairment

In this study we investigated the cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in Alzheimer (AD) patients (n=75), patients with mild cognitive impairment (MCI, n=9) and patients with depression (n=7). CSF HVA was significantly elevated in AD with depression (Geriatric Depression Scale, 15 point version GDS>5) in comparison to AD without depression (p<0.05, ANOVA) and CSF HVA showed a significant positive correlation with the GDS score of AD-patients (p=0.03, Spearman Rho: 0.38, Spearman Rank Correlation). In the group of AD patients CSF 5-HIAA was positively correlated with cerebrospinal fluid beta-amyloid 1-42 (Abeta42), p<0.05, Spearman Rho: 0.3, Spearman Rank Correlation, but not with CSF tau. Additionally, there was a significant positive correlation between cerebrospinal fluid 5-HIAA and HVA in the group of AD patients (p<0.0001, Rho: 0.47, Spearman Rank correlation). Neither 5-HIAA nor HVA in CSF could differentiate between mild cognitive impairment, depression and AD. The results of this study support the hypothesis that the serotonergic system plays a role in the course of AD. They further suggest an important role of dopamine metabolism in depression within AD patients.     

Choroid plexus protects cerebrospinal fluid against toxic metals.

Although heavy metal ions are known to be toxic to the central nervous system (CNS), the mechanisms by which the CNS may protect itself from initial challenges of such toxic ions is unknown. The choroid plexus is the principal site of formation of the cerebrospinal fluid (CSF) which bathes the brain. We have determined in rats and rabbits that after intraperitoneal administration of lead, cadmium, mercury, and arsenic compounds, these toxic metal ions accumulated in the lateral choroid plexus at concentrations of Pb, Hg, and As that were 70-, 95-, and 40-fold higher, respectively, than those found in the CSF. Cd was not detected in the CSF. In addition, concentrations of these heavy metal ions were found to be many fold greater in the choroid plexus than in the brain or blood. The accumulation of Pb in the choroid plexus was dose-dependent and time-related. When the choroid plexus was preincubated, in vitro, with ouabain (1.5 mM), the uptake of Cd from the CSF side of the choroid plexus was inhibited 57%. Cadmium metallothionein was not found in the choroid plexus. Whereas the concentration of reduced glutathione in the choroid plexus was less than that in the brain cortex, the concentration of cystine was fourfold greater. The lateral choroid plexus sequesters Pb, Cd, As, and Hg. It appears to be one of the important mechanisms that protects the CSF and the brain from the fluxes of toxic heavy metals in the blood.     

Characterization of cerebrospinal fluid monoamine metabolites in peripubertal chimpanzees (Pan troglodytes)

Background  Assessment of cerebrospinal (CSF) monoamine metabolites 5-hydroxyindoeacetic acid (5-HIAA) and homovanillic acid (HVA), and the serotonin precursor tryptophan (TRP), in chimpanzees may help in understanding the neurobiology underlying aggressive, impulsive behavior in humans and non-human primates.
Methods  Two CSF samples were obtained from 11 peripubertal chimpanzees 8 months apart and were assayed for monoamine metabolite and TRP concentrations.
Results  Substantial inter-individual stability was observed for 5-HIAA (n = 11; r = 0.83, P  <   0.001) and HVA (r = 0.91, P  <   0.001). Females had significantly higher concentrations of 5-HIAA compared to males (F_1,8 = 7.31; P  <   0.05). Levels of 5-HIAA (r = −0.62, P  <   0.05), HVA (r = −0.86, P  <   0.001) and TRP levels (r = −0.67; P  <   0.05) decreased with age.
Conclusion  Close parallels were observed between chimpanzees and humans with respect to absolute levels, sex effects, ontogeny, and 5-HIAA-HVA correlations, supporting the potential utility of the measures in understanding relationships between monoamine functioning and behavior in chimpanzees and humans.     

EFFECTS OF POTASSIUM AND LITHIUM ON SODIUM TRANSPORT FROM BLOOD TO CEREBROSPINAL FLUID

Abstract— The relationship between isotopic sodium entry into cerebrospinal fluid (CSF) from blood and cisternal potassium concentration was studied using ventriculo-cisternal perfusion in the rabbit. The entry of sodium into CSF was separated into 2 components. The fast component was significantly correlated with cisternal potassium concentration during perfusions with a potassium-free artificial CSF. ATPase activity in the homogenised choroid plexus was shown to be sensitive to potassium over a range of concentrations similar to that in the perfusion studies. The results are interpreted as showing a potassium-sensitive entry of ²⁴Na across the choroid plexus due to a sodium-pump situated in the apical membrane of the choroid plexus. The effects of low concentrations of lithium (0.6–1.2 mm) on ²⁴Na entry into CSF and brain and on CSF secretion were studied. When applied via the ventricles lithium caused a 30–39% stimulation of the fast component of sodium entry and a 28% stimulation of CSF secretion. When given via the blood lithium inhibited the fast component of sodium entry and CSF secretion by 43% and 40% respectively. No effects of lithium were found on the slow component of sodium entry into CSF or sodium entry into brain. The results suggest that lithium at low (0.6–1.2 mM) concentrations can stimulate the choroid plexus sodium-pump at the potassium-sensitive side and inhibit it at the sodium-sensitive side.     

Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model

Reduced derivatives of folic acid (folates) play a critical role in the development, function and repair of the CNS. However, the molecular systems regulating folate uptake and homeostasis in the central nervous system remain incompletely defined. Choroid plexus epithelial cells express high levels of folate receptor α (FRα) suggesting that the choroid plays an important role in CNS folate trafficking and maintenance of CSF folate levels. We have characterized 5-methyltetrahydrofolate (5-MTHF) uptake and metabolism by primary rat choroid plexus epithelial cells in vitro . Two distinct processes are apparent; one that is FRα dependent and one that is independent of the receptor. FRα binds 5-MTHF with high affinity and facilitates efficient uptake of 5-MTHF at low extracellular folate concentrations; a lower affinity FRα independent system accounts for increased folate uptake at higher concentrations. Cellular metabolism of 5-MTHF depends on the route of folate entry into the cell. 5-MTHF taken up via a non-FRα -mediated process is rapidly metabolized to folylpolyglutamates, whereas 5-MTHF that accumulates via FRα remains non-metabolized, supporting the hypothesis that FRα may be part of a pathway for transcellular movement of the vitamin. The proton-coupled folate transporter, proton-coupled folate transporter (PCFT), mRNA was also shown to be expressed in choroid plexus epithelial cells. This is consistent with the role we have proposed for proton-coupled folate transporter in FRα-mediated transport as the mechanism of export of folates from the endocytic compartment containing FRα.     

Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Effects of octanoic acid on monoamines and their acidic metabolites in the rat brain were analyzed by HPLC. Octanoic acid (1,000 mg/kg i.p.) elevated homovanillic acid levels by 54% in the caudate and 338% in the hypothalamus but increased 5-hydroxyindoleacetic acid (5-HIAA) levels in both the caudate and the hypothalamus by approximately 50% compared with the control. A lower dose of octanoic acid (500 mg/kg) increased 5-HIAA levels by 29% in the caudate and 20% in the hypothalamus. However, it did not produce any changes in the concentration of homovanillic acid in either the caudate or the hypothalamus. Treatment with octanoic acid also failed to change the level of dopamine, serotonin, and 3,4-dihydroxyphenylacetic acid in the caudate and the hypothalamus. The role of carrier-mediated transport in the clearance of 5-HIAA from the rabbit CSF was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced in the presence of octanoic acid. Because this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of encephalopathy in children with medium-chain acyl-CoA dehydrogenase deficiency who have elevated levels of octanoic acid systematically.     

Specificity and sodium dependence of the active nucleoside transport system in choroid plexus

The transport of [3H]deoxyuridine by the active nucleoside transport system into the isolated rabbit choroid plexus was measured in vitro under various conditions. Choroid plexuses were incubated in artificial CSF containing 1 microM [3H]deoxyuridine and 1 microM nitrobenzylthioinosine for 5 min under 95% O2-5% CO2 at 37 degrees C and the accumulation of [3H]deoxyuridine measured. Nitrobenzylthioinosine was added to the artificial CSF at a concentration (1 microM) that did not inhibit the active nucleoside transport system but did inhibit the separate, saturable nucleoside efflux system. The active transport of deoxyuridine into the choroid plexus depended on Na+ in the medium, as ouabain, substitution of Li+ and choline for Na+, and poly-L-lysine all inhibited deoxyuridine transport. Thiocyanate in place of chloride and penetrating sulfhydryl reagents also inhibited the active transport of deoxyuridine into choroid plexus. The active transport of deoxyuridine into choroid plexus, which is inhibited by naturally occurring ribo- and deoxyribonucleosides (IC50 = 7-21 microM), was not inhibited (IC50 much greater than 150 microM) by nucleosides with certain alterations on the 2', 3', or 5' positions in D-ribose or 2-deoxy-D-ribose (e.g., adenine arabinoside, 3'-deoxyadenosine, xylosyladenosine); or the pyrimidine or purine rings (e.g., 6-azauridine, xanthosine, 7-methylinosine, or 8-bromoadenosine). Other analogues were effective (IC50 = 8-26 microM; e.g., 5-substituted pyrimidine nucleosides, 7-deazaadenosine, 6-mercaptoguanosine) or less effective (IC50 = 46-145 microM; e.g., 5-azacytidine, 3-deazauridine) inhibitors of deoxyuridine transport into the isolated choroid plexus.     

Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection

An improved high-performance liquid chromatographic method with electrochemical detection (HPLC-EC) for the simultaneous determination of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in cerebrospinal fluid (CSF) of humans and nonhuman primates is described. Quantitation is based on the use of an internal standard, 5-fluoro-HVA. Sample preparation consists of mixing an aliquot of CSF with a solution of the internal standard followed by ultrafiltration. The precision of the method is high, with within-run and between-run coefficients of variation of 2-6% and less than 10%, respectively, in the concentration ranges of the metabolites encountered in human lumbar CSF. Accuracy was tested by comparing the present HPLC method with specific gas chromatographic-mass spectrometric (GS-MS) assays for MHPG and HVA and a GC-MS-validated HPLC assay for 5-HIAA: the correlations obtained were 0.968 for MHPG, 0.989 for 5-HIAA, and 0.999 for HVA, with no systematic bias between the methods. The use of ascorbate as a preserving agent for monoamine metabolites in CSF was not found to be necessary when proper care was exercised in sample handling and storage. The analysis of samples with up to 2% ascorbic acid was possible as well, but MHPG had to be assayed separately using an extraction procedure and an alternative internal standard, 3-ethoxy-4-hydroxyphenylglycol.     

Motor Activity Increases Tryptophan, 5-Hydroxyindoleacetic Acid, and Homovanillic Acid in Ventricular Cerebrospinal Fluid of the Conscious Rat

An investigation was made into the effects of running (1 h at 20 m/min) on central serotonergic and dopaminergic metabolism in trained rats. Methodology involved continuous withdrawal of cerebrospinal fluid (CSF) from the third ventricle of conscious rats and measurements of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels during a 2 h post-exercise period. All three compounds were increased during the hour following exercise and returned to their basal values within an hour later. CSF flow rate was stable when metabolite levels were elevated. Brain determinations indicated that CSF metabolite variations only qualitatively paralleled brain changes. Indeed, post-exercise TRP, 5-HIAA, and HVA levels were increased to a greater extent in brain when compared to CSF. It is suggested that increased serotonergic and dopaminergic metabolism, caused by motor activity, may be involved in the behavioral effects of exercise.