CHOLECYSTOKININ IN HUMAN CEREBROSPINAL-FLUID - CONCENTRATIONS, DYNAMICS, MOLECULAR-FORMS AND RELATIONSHIP TO FASTING AND FEEDING IN HEALTH, DEPRESSION AND ALCOHOLISM

Very little is known about the physiologic significance of the gut-brain hormone cholecystokinin (CCK) in the human central nervous system, although the hormone has been hypothesized to be involved in the regulation of both appetite and anxiety. We continuously collected lumbar cerebrospinal fluid (CSF) via indwelling subarachnoid catheters in ten normal volunteers, ten patients with major depression and five abstinent alcoholic humans, while fasting and after eating. Five other healthy subjects were fasted throughout the experiment. We quantified CSF immunoreactive cholecystokinin (IR-CCK) and glucose concentrations at 10-min intervals from 11.00 to 17.00 h. No difference in CSF IR-CCK concentration, half-life or rhythm was observed between normal volunteers and either depressed or alcoholic patients. Fasting CSF IR-CCK concentrations were 1.3+/-0.18, 1.3+/-0.21 and 1.2+/-0.21 fmol/ml (mean+/-S.E.M.) in normal volunteers, depressed patients and alcoholic patients, respectively. After eating, CSF IR-CCK concentrations rose to 1.5+/-0.21, 1.5+/-0.24 and 1.4+/-0.26 fmol/ml, respectively. Normal volunteers who did not eat had similar basal CSF IR-CCK concentrations (1.1+/-0.1 fmol/ml) which similarly rose to 1.4+/-0.13 fmol/ml during the sampling interval. In contrast, CSF glucose concentrations rose only in the subjects who ate, beginning to rise after about 1 h and remaining elevated for at least 3 h after eating. These data suggest the existence of a diurnal rhythm of IR-CCK release into CSF, as opposed to a response to feeding. The disappearance half-time of CCK in human CSF is less than 13 min. The rapid intra-individual concentration transients in CSF IR-CCK concentration observed suggest pulsatile release of CCK into and rapid removal from CSF. Thus, it is likely that the IR-CCK measured in lumbar CSF is principally derived from spinal cord and does not reflect possible changes in hypothalamic IR-CCK after eating. Finally, gel filtration chromatography confirmed that IR-CCK in human CSF is heterogeneous, but, in contrast to previous studies, we found that the majority of activity is associated with a peptide(s) whose molecular weight is 1.66 kDa, corresponding in size to CCK-12 (CCK-[22-331]).