Corticotropin-releasing factor: Cerebrospinal fluid studies

Garth Bissett, Charles B. Nemeroff

Research output: Chapter in Book/Report/Conference proceedingChapter


The study of neurochemical alterations in living patients with psychiatric or neurologic disease requires access to a physiologically available tissue that is representative of the CNS environment under scrutiny. In this case, the relevant environment is the extracellular fluid within the synaptic cleft. The presently available tissues for study of this environment are brain biopsy samples, plasma, platelets, or cerebrospinal fluid. Brain biopsy offers the most direct route for assessment of neurochemical status. Unfortunately it is invasive, nonrenewable and, in many cases, the area of interest is not accessable without disruption of overlying structures. Moreover, the anomalous venous supply to the brain renders this technique liable to unexpected morbidity. Plasma has the advantage of being relatively plentiful and renewable, but suffers the serious disadvantages of being on the wrong side of the blood-brain banier, being remote from the site of interest and, due to its large volume, diluting the substance(s) of interest. In addition, many plasma constituents interfere nonspecifically with assay techniques requiring extraction steps with reduced recovery as well as containing contributions from other tissues that may not be involved in the primary pathological process under investigation. Platelets, like brain tissue, are embryologically derived from neural crest. They have some characteristics of neurons, such as receptors, but lack a nucleus. They possess most of the disadvantages of plasma and are not representative of extracellular fluid. Cerebrospinal fluid at present, offers the most direct access to the internal mileau of the central nervous system. While a lumbar or intracisternal tap is technically an invasive procedure, lumbar taps are now performed routinely with few complications and can be performed more than once in an individual. Cerebrospinal fluid is in direct communication with the extracellular fluid of the brain and moderate amounts of CSF are quickly replaced. However, at present, very few studies have shown a correlation between brain tissue concentrations of a neurotransmitter or its metabolite with their respective concentrations in CSF. Stanley et al.1 have shown a direct correlation between brain and CSF concentrations of the acidic serotonin metabolite, 5-hydroxyindole acetic acid (5-HIAA). The contribution of spinal cord sources to the component being measured must also be considered when CSF is obtained from lumbar taps. Rostral-caudal gradients have recently been observed for several neurotransmitters in postmortem studies in which both cisternal and lumbar CSF were sampled and in studies in which 30 rnl of CSF were obtained in patients or normal control subjects. While these confounding factors must be considered, differences have been reported between several diagnostic groups and normal controls for specific neurochemical substances contained in CSF. One of these substances is corticotropin-releasing factor (CRF). This substance was first isolated from sheep hypothalami and as described elsewhere in this volume has been detected in human brain, plasma, and CSF. Human CRF immunoreactivity in CSF has been characterized by Suda et al.2 and is indistinguishable from synthetic CRF or hypothalamic CRF by chromatography or radioimmunoassay dilution curves. Oldfield et al.3 has demonstrated that125 I-CRF is cleared from CSF six times as rapidly as a control substance known to be cleared by bulk flow. Both Garrick et al.4 and Kalin et al.5 have reported a circadian rhythm for CRF in monkey CSF that is 180º out of phase with CSF cortisol. Thus CRF peaks at the beginning of the dark cycle while cortisol values have declined to the lowest point in the 24-h cycle. While there does not seem to be any sex difference in CSF concentrations of CRF, there may be an effect of age. In a collaboration with Jan and Thomas Hedner of the University of Gothenburg in Sweden, we found that measurements of CSF from children aged 6 months to 2 years have revealed an exponential decline in CRF concentrations with age (unpublished). Before the age of 2 years, mean CSF concentrations of CRF were twice as high as the amount found in children after the age of 2 years. In the remainder of this chapter we describe the current literature on CSF CRF in neuropsychiatric disorders.

Original languageEnglish (US)
Title of host publicationCorticotropin-Releasing Factor
Subtitle of host publicationBasic and Clinical Studies of a Neuropeptide
PublisherCRC Press
Number of pages7
ISBN (Electronic)9781351079389
ISBN (Print)0849345502, 9781315891835
StatePublished - Jan 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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