cholecystokinin and Bipolar-Disorder

Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.

Topics: Animals; Behavior, Animal; Bipolar Disorder; Cholecystokinin; CLOCK Proteins; Gene Knockdown Techniques; Histone-Lysine N-Methyltransferase; Humans; Lithium Chloride; Male; Mice; Mutation; Myeloid-Lymphoid Leukemia Protein; Ventral Tegmental Area

Suicidal behaviour is a phenotype widely associated with psychiatric disorders such as major depressive disorder and bipolar disorder. However, recent evidence indicates that part of the heritability of suicidal behaviour is independent of the heritability of individual psychiatric disorders. This allows investigation into genetic risk factors for suicidal behaviour within a disorder using a candidate gene association approach.. We used family-based association testing in a cohort of 130 multiplex bipolar pedigrees, comprising 795 individuals, to look for associations between suicidal behaviour and 32 single nucleotide polymorphisms (SNPs) from across the genes brain-derived neurotrophic factor (BDNF), cholecystokinin (CCK) and the cholecystokinin beta-receptor (CCKBR).. We found associations (p≤0.05) between suicide attempt and 12 SNPs of CCKBR and five SNPs of BDNF. After correction for multiple testing, seven SNPs of CCKBR remained significantly associated. No association was found between CCK and suicidal behaviour.. The study relied on retrospective self-reporting by individuals to determine phenotype, and the sample size was relatively small.. The results of the study support the hypothesis that some CCKBR polymorphisms may contribute to an underlying predisposition towards suicidal behaviour in bipolar disorder.

Topics: Bipolar Disorder; Brain-Derived Neurotrophic Factor; Cholecystokinin; Female; Genotype; Humans; Male; Polymorphism, Single Nucleotide; Receptor, Cholecystokinin B; Retrospective Studies; Suicide

The evidence for a significant genetic contribution to the functional psychoses (schizophrenia and bipolar disorder) is now well established. However, in both cases, the non-mendelian mode of inheritance has made the identification of susceptibility loci particularly challenging. The neuropeptide cholecystokinin (CCK) is present both in the gut and the CNS. Studies of CCK-like immunoreactivity and CCK mRNA levels in human brains have revealed high concentrations in numerous loci and shown colocalisation of CCK with, for example, dopamine and tyrosine hydroxylase. Furthermore, antagonists of CCK-B receptors, which are found most frequently in the brain, inhibit the activity of brain dopamine neurons. Such findings suggest that, with respect to neuropsychiatric disorders, CCK is a suitable candidate for analysis using methods to detect gene variations which have the potential to affect protein structure or expression. In the present study, mutation analyses were carried out on the human CCK gene. Linked polymorphisms were found in the promoter region and in intron 1 close to the 3' mRNA splice acceptor site. However, the allele frequencies of these polymorphisms in samples of individuals affected with either schizophrenia (n=117) or bipolar disorder (n=124) did not differ from those of control subjects (n=234), suggesting that these variations do not confer a predisposition to either of the functional psychoses.

Topics: Alleles; Alternative Splicing; Base Sequence; Bipolar Disorder; Cholecystokinin; Consensus Sequence; Disease Susceptibility; Exons; Genetic Linkage; Genotype; Humans; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Reference Values; Schizophrenia

Vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK) and gastrin in the cerebrospinal fluid (CSF) were studied in patients with endogenous depression, non-endogenous depression, mania, schizophrenia and a control group. All patients were classified according to ICD-9 and the group of depressions was further classified according to the Newcastle Rating Scales for depression (Carney et al. 1965) (N-I). In the group of non-endogenously depressed patients, CSF-VIP levels (median 16 pmol/l) were found to be significantly lower than those of controls (median = 32 pmol/l) and endogenous depressives (36 pmol/l). In the non-endogenous group, it appeared that the low CSF-VIP was due to a group of patients who, during a past or present depressive episode, had been diagnosed as suffering from endogenous depression. Moreover, this group was clinically characterized by 'dysphoric/hysterical features', 'reversed diurnal variation' (i.e. worse in the evening), and 'lack of clearly circumscribed episodes'. In many aspects this group seems similar to the atypical depressives described as monoamine oxidase inhibitor responders. Concerning CSF-CCK and CSF-gastrin, no significant differences between the examined groups were demonstrated.

Topics: Adult; Aged; Bipolar Disorder; Cholecystokinin; Depressive Disorder; Female; Gastrins; Humans; Male; Middle Aged; Psychological Tests; Psychotic Disorders; Schizophrenia; Vasoactive Intestinal Peptide

The close relationship of cholecystokinin peptides with some of the dopamine pathways and the limbic system suggests a putative role for these peptides in the pathophysiology of neuropsychiatric disorders such as Parkinson's disease, manic-depression and schizophrenia. By use of radioimmunoassay, we report a significant decrease in cholecystokinin-immunoreactivity in the cerebrospinal fluid of patients with bipolar manic-depression and untreated schizophrenia in comparison to control subjects.

Topics: Adult; Bipolar Disorder; Cholecystokinin; Depressive Disorder; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Schizophrenia

Immunoreactive somatostatin, bombesin, and cholecystokinin were measured in cerebrospinal fluid of normal subjects and patients with anorexia nervosa, depression, mania, and schizophrenia. Somatostatin-like immunoreactivity was decreased in anorexic and depressed patients. Bombesin-like immunoreactivity tended to be decreased in schizophrenics. Cholecystokinin-like immunoreactivity did not differ between groups. These data suggest a possible function for neuropeptides in regulation of human behavior.

Topics: Adult; Anorexia Nervosa; Bipolar Disorder; Bombesin; Cholecystokinin; Depressive Disorder; Female; Humans; Male; Mental Disorders; Peptides; Schizophrenia; Somatostatin