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On the cerebrospinal fluid disposition and neurobiological role of cholecystokinin in man
Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cholecystokinin (CCK) is the most abundant neuropeptide in the brain, where it acts as a neurotransmitter and neuromodulator. The tetrapeptide CCK-4 and the octapeptide CCK-8 have been implicated in various behavioural and physiological functions, such as anxiety, pain and satiety. Analyses of the levels of CCK in plasma, CSF and brain tissue have been used in studies aimed at elucidating the pathophysiological mechanisms in psychiatric disorders, but the results have been inconsistent.

Cerebrospinal fluid (CSF) levels of CCK-4 and CCK-8S were analysed in three groups of healthy subjects lumbar-punctured under different conditions, with the aim to provide reference values for studies on patients, and to investigate putative confounding factors. It was found that the concentrations of CCK-4 and CCK-8S were influenced by age, bedrest or not prior to lumbar puncture, neuraxis distance, position during lumbar puncture, height, atmospheric pressure and storage time. For a correct interpretation of data, these factors should be taken into account in future CSF studies in volunteers and patients.

Hypothyroidism is associated with depression. Thyroid hormones have been assumed to affect neuronal functions in the CNS, and animal experiments have indicated a relationship between thyroid hormones and CCK. Depressive symptoms were assessed in hypothyroid patients who were also lumbar-punctured before and during L-thyroxine treatment. Thyroid stimulating hormone, tri-iodothyronine and thyroxine in serum correlated with both CCK peptides in the CSF. A negative correlation between CCK-4 and inner tension (anxiety) was found.

Various studies implicate the involvement of brain-stem structures in the aetiology of panic attacks. Brain-stem auditory evoked potentials were recorded in healthy subjects before and during infusion with the panic-provoking agent CCK-4 or placebo. CCK-4 delayed the latencies of peak I, III and V, and decreased peak III amplitude. This suggests that exogenous CCK-4 affects stimulus processing in the brain stem.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2000. , 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 643
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-28039Local ID: 12800ISBN: 91-7219-744-7 (print)OAI: oai:DiVA.org:liu-28039DiVA: diva2:248590
Public defence
2000-10-20, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-14Bibliographically approved
List of papers
1. Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects
Open this publication in new window or tab >>Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects
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1997 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 68, no 1, 57-61 p.Article in journal (Refereed) Published
Abstract [en]

The clinical reliability of measuring cholecystokinin (CCK) peptides in the cerebrospinal fluid (CSF) has not been fully elucidated. Therefore, we have assayed CCK-8S and CCK-4 in CSF obtained from 14 healthy male subjects, lumbar-punctured at the L4–5 level following a strictly standardised procedure. CSF concentrations of free CCK-8S and free CCK-4 were used as dependent variables while age, height, body weight, atmospheric pressure and some other factors served as independent variables. It was shown that the CCK-8S ratio between the second (7–12 ml) and first (0–6 ml) CSF fractions, correlated significantly with the atmospheric pressure at the time of puncture. Neither CCK-8S nor CCK-4 displayed concentration gradients in CSF. The CCK-4 levels, expressed as pmol l−1 in the total amount of CSF were found to be positively correlated with the neuraxis distance in the lying position and negatively with the neuraxis distance in the sitting position. Furthermore, CCK-4, expressed as pmol l−1 per min of tapping-time (pmol l−1 min−1), showed a negative correlation with storage time, presumably mirroring a proteolytic process. CCK-8S and CCK-4 intercorrelated positively independently of whether expressed as pmol l−1 or pmol l−1 min−1. In conclusion, the results of this exploratory study indicate that the neuraxis distance (in the sitting and lying positions) and storage-time have to be accounted for when interpreting data on CSF levels of CCK-4. Attention has to be paid to the potential influence of atmospheric pressure on the concentration ratio of CCK-8S.

Keyword
CCK-4, CCK-8S, Atmospheric pressure, Storage-time, Tapping-time
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79854 (URN)10.1016/S0167-0115(96)02104-0 (DOI)
Available from: 2012-08-14 Created: 2012-08-14 Last updated: 2017-12-07Bibliographically approved
2. Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects lumbar-punctured without preceding strict bed-rest
Open this publication in new window or tab >>Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects lumbar-punctured without preceding strict bed-rest
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1999 (English)In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 106, no 3-4, 275-282 p.Article in journal (Refereed) Published
Abstract [en]

In a recent study we analysed the concentrations of two forms of cholecystokinin (CCK), CCK-8S (sulphated) and CCK-4 in cerebrospinal fluid (CSF) obtained from 14 healthy male volunteers lumbar-punctured after a minimum of eight hours of strict bed-rest.

We have now lumbar-punctured another group of 14 healthy males, using the same procedure except for the requirement of strict bed-rest prior to puncture.

In contrast to our previous study, the concentration of CCK-4 (but not CCK-8S) was significantly higher in the second CSF fraction (7–12 ml) than in the first one (0–6 ml). On using the concentration ratio between the second and first fraction, CCK-8S (but not CCK-4) correlated positively with the atmospheric pressure, which is in contrast to our previous study in which a significant negative correlation was found.

When the lumbar CSF concentrations were expressed as the concentration per minute of tapping-time (an estimate of the mass flow), atmospheric pressure, age and the neuraxis distance in the lying position made significant contributions to the variance in CCK-8S. A significant positive correlation with atmospheric pressure was found for CCK-4.

In conclusion, the results indicate that the question of strict bed-rest or not prior to lumbar puncture may have to be considered when interpreting data on lumbar CSF concentrations of CCK. A controlled study is warranted.

Keyword
CCK-4, CCK-8, cerebrospinal fluid, atmospheric pressure
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27799 (URN)10.1007/s007020050157 (DOI)12546 (Local ID)12546 (Archive number)12546 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Cerebrospinal fluid levels of monoamine compounds and cholecystokinin peptides after exposure to standardized barometric pressure
Open this publication in new window or tab >>Cerebrospinal fluid levels of monoamine compounds and cholecystokinin peptides after exposure to standardized barometric pressure
2000 (English)In: Aviation, Space and Environmental Medicine, ISSN 0095-6562, E-ISSN 1943-4448, Vol. 71, no 11, 1131-1136 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Connections between mood changes and weather have been described throughout the ages, and in more recent years, there have been reports on a relationship between atmospheric pressure and neurotransmitter levels in cerebrospinal fluid.

METHODS: To further investigate this issue under strictly standardized conditions, we have lumbar-punctured 8 healthy males under low (963 hPa) and high (1064 hPa) barometric pressure, using a pressure chamber.

RESULTS: Under high pressure, the tyrosine concentrations in the cerebrospinal fluid (CSF) were lower, while the cholecystokinin tetrapeptide (CCK-4) levels were higher. No differences between low and high pressure were found for tryptophan, 5-hydroxyindolacetic acid (5-HIAA), dopamine (DA), and sulphated cholecystokinin octapeptide (CCK-8S). The serum level of CCK-8S was higher under high pressure. On comparing concentration ratios between the second and the first CSF fraction, we found significantly increased ratios for homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylglycol (HMPG), but a decreased ratio for tyrosine under high pressure. The difference in the concentration ratios of HVA between low and high pressure correlated negatively with age. Intraspinal pressure correlated negatively with tapping time at low pressure.

CONCLUSION: Our results are in line with the hypothesis that atmospheric pressure influences CSF levels of monoamine compounds and cholecystokinin peptides.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27801 (URN)11086668 (PubMedID)12548 (Local ID)12548 (Archive number)12548 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Cholecystokinin peptides in cerebrospinal fluid: a pilot study in hypothyroid patients
Open this publication in new window or tab >>Cholecystokinin peptides in cerebrospinal fluid: a pilot study in hypothyroid patients
1999 (English)In: Human Psychopharmacology: Clinical and Experimental, ISSN 0885-6222, E-ISSN 1099-1077, Vol. 14, no 2, 113-117 p.Article in journal (Refereed) Published
Abstract [en]

The cholecystokinin tetrapeptide (CCK-4) and the sulphated octapeptide (CCK-8) were measured in cerebrospinal fluid obtained from nine hypothyroid patients before and during L-thyroxine treatment. Before treatment, CCK-4 and CCK-8S correlated negatively with S-TSH, whereas CCK-8S also showed a positive correlation with S-T3. During treatment, S-T4 correlated negatively with CCK-8S. CSF collection time was significantly shorter during treatment than prior to treatment for the first (0–6 ml) CSF fraction. On taking CSF collection time into account, the levels of both CCK-4 and CCK-8S in the first CSF fraction were significantly increased during medication. Our results are consistent with an impact of the hypothyroid disorder and L-thyroxine treatment on the disposition of CCK compounds in CSF. This might be due to an altered CSF circulation, but other mechanisms (e.g. metabolism or elimination) cannot be ruled out.

Keyword
hypothyroidism, cholecystokinin, cerebrospinal fluid, CSF collection time, atmospheric pressure
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27798 (URN)10.1002/(SICI)1099-1077(199903)14:2<113::AID-HUP76>3.0.CO;2-A (DOI)12545 (Local ID)12545 (Archive number)12545 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
5. Depressive Symptoms in Hypothyroid Disorder with some Observations on Biochemical Correlates
Open this publication in new window or tab >>Depressive Symptoms in Hypothyroid Disorder with some Observations on Biochemical Correlates
2001 (English)In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 43, no 2, 70-74 p.Article in journal (Refereed) Published
Abstract [en]

Lumbar punctures and ratings of depressive symptoms were done in hypothyroid patients before and during L-thyroxine therapy. Before treatment, the most prominent symptoms were concentration difficulties, lassitude, and reduced sexual interest. All patients suffered from sleep disturbances. Suicidal thoughts did not occur at all. Inner tension was negatively correlated with the anxiogenic cholecystokinin tetrapeptide (CCK-4) in the cerebrospinal fluid (CSF), while reduced sexual interest was negatively correlated with CSF tryptophan. Furthermore, failing memory correlated negatively with T3 as well as T4 in serum. A positive correlation was found between failing memory and serum TSH. All patients improved significantly during treatment. No biochemical correlates were found. In conclusion, hypothyroidism is associated with major depressive symptoms. CSF CCK-4 and tryptophan, as well as serum thyroid hormones, may constitute biochemical correlates for some of these symptoms.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27797 (URN)10.1159/000054869 (DOI)12544 (Local ID)12544 (Archive number)12544 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
6. Acute Effects of Cholecystokinin Tetrapeptide on Brain Stem Auditory Evoked Potentials in Healthy Volunteers
Open this publication in new window or tab >>Acute Effects of Cholecystokinin Tetrapeptide on Brain Stem Auditory Evoked Potentials in Healthy Volunteers
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2003 (English)In: Pharmacopsychiatry, ISSN 0176-3679, E-ISSN 1439-0795, Vol. 36, no 5, 181-186 p.Article in journal (Refereed) Published
Abstract [en]

This study investigated the effects of continuous slow intravenous infusion of cholecystokinin tetrapeptide (CCK-4) on brain stem auditory evoked potentials (BSAEP) in healthy subjects. Twenty-four subjects, 15 females and 9males, were assigned to infusion with either placebo or CCK-4 in a randomized, double-blind, parallel group design. BSAEPs, mood, physical symptoms, and vital signs were assessed once before infusion and at 10 min and 40 min after the onset of infusion. In the 16 subjects (N = 8, CCK-4; N = 8, placebo) CCK-4, compared to placebo, delayed peak I latency during early infusion, slowed the latencies of peaks III and V, and decreased the amplitude of peak III throughout the infusion. No significant treatment differences were observed with respect to symptoms, mood, or cardiovascular measures. These preliminary findings suggest that CCK-4 may interfere with information processing in the brain stem auditory pathways and that prolonged intravenous CCK-4 administration may be a useful challenge paradigm for investigating CCK's modulatory role on brain stem mechanisms mediating anxiety and panic in humans.

Keyword
Cholecystokinin, CCK-4, brain stem auditory evoked potentials, anxiety, panic
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27796 (URN)10.1055/s-2003-43047 (DOI)12543 (Local ID)12543 (Archive number)12543 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved

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