Cerebrospinal fluid and plasma leptin measurements: covariability with dopamine and cortisol in fasting humans.

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

Continuous covariability of dopamine and serotonin metabolites in human cerebrospinal fluid.

BACKGROUND: Experiments in lower animals and humans have demonstrated the existence of functional interactions between serotonin and dopamine in neuronal tissue. However, the relationship between parameters of serotonin and dopamine neuronal activity over time within the central nervous system (CNS) of the individual human has not yet been established. METHODS: We used continuous cerebrospinal fluid (CSF) sampling over 6 hours to test the hypothesis that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the dopamine metabolite homovanillic acid (HVA) significantly covary in concentration over time. Two groups of normal volunteers (total n = 16) were studied at separate hospitals and CSF was assayed for 5-HIAA and HVA by high-performance liquid chromatography (HPLC). Three subjects underwent repeat CSF-withdrawal procedures after a 6-week interval. RESULTS: Strong and sustained positive covariability in concentrations of HVA and 5-HIAA was observed in the CSF of individual humans. High intraindividual correlation coefficients were +0.897 and +0.871 in the two normal volunteer groups. The HVA to 5-HIAA concentration ratio in CSF was 2.2 +/- 0.7 with very little variability over intervals ranging from minutes to weeks. CONCLUSIONS: The balance between CSF dopamine and serotonin metabolite concentrations remains relatively constant over time in healthy humans. Serial measures of CSF dopamine and serotonin metabolites within the same person could be an effective model in which to explore the interrelationships between these systems in various psychiatric syndromes, in response to drug treatment, and during provactive testing.

Low CSF concentration of a dopamine metabolite in tobacco smokers.

OBJECTIVE: To screen for dopaminergic abnormalities in tobacco smokers and patients with posttraumatic stress disorder (PTSD), the authors determined serial CSF and plasma concentrations of the dopamine metabolite homovanillic acid (HVA). METHOD: Continuous subarachnoid sampling was used to obtain 37 serial CSF samples over 6 hours in 13 normal volunteers and 11 patients with combat-related PTSD; 10 smoked and 14 had never smoked. The smokers were abstinent from tobacco for 1 1 to 17 hours. RESULTS: The smokers had markedly lower CSF, but not plasma, HVA levels. Their CSF HVA concentrations averaged only 54% of the concentrations of the nonsmokers, independent of diagnosis. CONCLUSIONS: Smokers' low CSF concentrations of HVA may be associated either with chronic inhalation of nicotine or other constituents of tobacco smoke or with acute abstinence. Any possible basal dopaminergic abnormalities in patients with PTSD are small relative to the abnormalities associated with smoking.

Cerebrospinal fluid and plasma beta-endorphin in combat veterans with post-traumatic stress disorder.

Opioid-mediated analgesia develops in experimental animals following traumatic stress and increased opioid-mediated analgesia has been observed in combat veterans with post-traumatic stress disorder (PTSD). These observations have led to the hypothesis that increased central nervous system (CNS) opioidergic activity exists in patients with PTSD. However, direct CNS data on opioid peptide concentrations and dynamics in patients with PTSD are lacking. We withdrew cerebrospinal fluid (CSF) via a flexible, indwelling subarachnoid catheter over a 6-h period and determined hourly CSF concentrations of immunoreactive beta-endorphin (ir beta END) in 10 well-characterized combat veterans with PTSD and nine matched normal volunteers. Blood was simultaneously withdrawn to obtain plasma for ir beta END. PTSD symptom clusters, as measured by the CAPS, were correlated with neuroendocrine data. Mean CSF ir beta END was significantly greater in patients with PTSD compared with normals and there was a negative correlation between the ir beta END and PTSD intrusive and avoidant symptoms of PTSD. No intergroup difference between plasma ir beta END was found, nor was there a significant correlation between CSF and plasma ir beta END. Immunoreactive beta-lipotropin (ir beta LPH) and pro-opiomelanocortin (irPOMC), both precursors of beta END, were much more plentiful in human CSF than was beta-endorphin itself, as has been previously reported. It remains to be determined whether the increased CNS opioid concentrations predate traumatic stress, thereby conferring a vulnerability to dissociative states and PTSD itself, or result from the trauma. The negative correlation between CSF ir beta END and avoidant and intrusive symptoms suggests that CNS hypersecretion of opioids might constitute an adaptive response to traumatic experience. Poor correlation between CSF and plasma ir beta END limits use of plasma measures to assess CNS opioid activity.

The effect of lumbar puncture stress on dopamine and serotonin metabolites in human cerebrospinal fluid.

In order to examine concentrations of cerebrospinal fluid (CSF) neurochemicals, the technique of lumbar puncture is typically used. However, the effect of the intrinsic stress of undergoing a lumbar puncture on CSF monoamine concentrations in humans has not yet been established. We used lumbar puncture followed 3 h later by continuous CSF sampling to examine the effect of lumbar puncture on levels of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively. Additionally, we examined the effect of lumbar puncture on the CSF HVA to 5-HIAA ratio. Immediately post lumbar puncture, CSF concentrations of HVA and 5-HIAA were, respectively, only 51 and 54% of the mean levels detected hours later. However, the HVA to 5-HIAA ratio remained stable during lumbar puncture. While HVA and 5-HIAA levels in CSF obtained via lumbar puncture reflect highly variable responses to the stress of the procedure, the ratio of these metabolites is unaffected.

Activity of body energy regulatory pathways in inflammation-induced anorexia.

Previous research has shown that reductions in body weight prior to induction of acute inflammation can attenuate inflammation-induced anorexia in male rats. In the current study, potential mechanisms responsible for this observation were examined. Specifically, the effect of a 12% prior reduction in body weight on serum leptin, insulin, and corticosterone; levels of interleukin-1 (IL-1), interleukin-6 (IL-6) in the serum, liver, and spleen; neuropeptide Y (NPY) and POMC mRNA levels in the arcuate nucleus (ARC) of the hypothalamus were examined 8 h after induction of acute inflammation. Rats with prior weight reduction had significantly lower serum leptin levels and gene expression of POMC in the ARC than normal-weight rats. In contrast, prior weight reduction altered neither NPY mRNA in the ARC, nor IL-1alpha, IL-1beta, and IL-6 levels in the serum, liver, and spleen. These results suggest that the attenuation of inflammation-induced anorexia by prior weight reduction is not due to altered cytokine activity, but rather to changes in energy regulatory systems that moderate the anorexic actions of IL-1beta and IL-6. One potential change may be reduced activity of the CNS melanocortin system induced by decreased circulating leptin.