cholecystokinin and Huntington-Disease

In recent years, a number of new molecules, particularly peptides, have been identified as putative neurotransmitters. The basal ganglia, is especially rich in a number of classical transmitter molecules, amino acids and neuropeptides considered to function in neurotransmission. These include: the well-described terminal fields in the striatum which originate from the brain stem and contain the monoamines, dopamine and serotonin; amino acid containing axons projecting from the cortex and thalamus; striatal cholinergic and peptide-positive interneurons; and amino acid and peptide containing projection neurons to the globus pallidus and substantia nigra. Two amino acids, glutamate and aspartate, are considered to provide excitatory input to the striatum while gamma aminobutyric acid is thought to mediate inhibitory output. Neuropeptides which are richly concentrated in the basal ganglia include, enkephalin, dynorphin, substance P, somatostatin, neuropeptide Y and cholincystokinease. Changes in many of these peptide levels have recently been associated with a number of basal ganglia disorders.

Topics: Acetylcholine; Amino Acids; Animals; Basal Ganglia; Cholecystokinin; Dopamine; Endorphins; Humans; Huntington Disease; Neuropeptides; Neurotransmitter Agents; Parkinson Disease; Primates; Serotonin

Neuropeptides are sufficiently stable to allow valid radioimmunoassay of peptide concentrations in post-mortem human nervous tissue and in human cerebrospinal fluid. Studies have now documented abnormalities of peptide concentrations in degenerative diseases of the brain. Somatostatin concentration is reduced in the hippocampus and neocortex of patients dying with Alzheimer's type dementia. In Huntington's disease, there are reduced concentrations of substance P, met-enkephalin and cholecystokinin in the basal ganglia; in contrast the concentrations of somatostatin and TRH are increased. Immunocytochemical and experimental lesion studies are underway in an attempt to localize the peptide-containing cells affected by these disorders; and the potential role of alterations in neuropeptide function in the pathogenesis, clinical manifestations and therapy of these illnesses is of great interest. Although alterations of CSF peptide concentrations have been reported in a variety of human diseases, interpretation of these results requires knowledge of the origin and disposition of CSF peptides. Future research into the pathology of peptidergic systems will depend on the development of specific peptide antagonists to probe dynamic aspects of peptide function and on the application of the tools of molecular biology, such as specific mRNA assays, to human material.

Topics: Alzheimer Disease; Animals; Brain; Cholecystokinin; Choline O-Acetyltransferase; Endorphins; Epilepsy; Forecasting; Histocytochemistry; Humans; Huntington Disease; Migraine Disorders; Nerve Tissue Proteins; Nervous System Diseases; Pain; Parkinson Disease; Radioimmunoassay; Somatostatin; Substance P; Thyrotropin-Releasing Hormone; Tissue Distribution; Vasopressins

In Huntington's disease, there is a decrease of the neuropeptides, substance P, enkephalins, and cholecystokinin in the striatonigral system, whereas in Parkinson's disease an increase of substance P is found in the substantia nigra. Several neuropeptides should be involved in Alzheimer's disease: substance P, endorphins, vasopressin, ACTH, somatostatin, vasoactive intestinal peptide, cholecystokinin, neurotensin, delta sleep-inducing peptide. Alterations of substance P, vasoactive intestinal peptide, cholecystokinin, somatostatin, and endorphins may be related to the pathophysiology of schizophrenia. Delta sleep-inducing peptide may interfere in addiction pathology.

Topics: Alzheimer Disease; Brain Mapping; Central Nervous System Diseases; Cholecystokinin; Enkephalins; Humans; Huntington Disease; Limbic System; Nerve Tissue Proteins; Neurotransmitter Agents; Parkinson Disease; Schizophrenia; Substance P; Substance-Related Disorders

Topics: Animals; Anura; Brain; Chemical Phenomena; Chemistry; Cholecystokinin; Humans; Huntington Disease; Intestine, Small; Neurotransmitter Agents; Obesity; Pancreatitis; Species Specificity; Swine

Huntington's disease is a progressive neurodegenerative disease in which the basal ganglia are preferentially affected. Recent evidence, however, suggests involvement of the cerebral cortex as well, with sparing of neurochemically defined subsets of gamma-aminobutyric acid (GABA)-ergic interneurons. In the present study, we examined changes in concentrations of the amino acid neurotransmitters GABA, glutamate, and aspartate in nine cortical regions from 23 patients with advanced Huntington's disease and 12 control brains. GABA concentrations were significantly increased in eight of the nine regions, consistent with a sparing of GABAergic local circuit neurons in the context of progressive cortical atrophy. Small but significant increases in glutamate were found in six of the nine regions, while aspartate levels were generally unaffected. Striate cortex (Brodmann's area 17) showed the most profound increases in GABA and glutamate. We also investigated the effects of powdering the excitotoxins N-methyl-D-aspartate (NMDA) or kainic acid onto the dura of rats. The resulting lesions were examined at 1 week and 6 months. The NMDA-induced lesions showed striking sparing of parvalbumin-positive neurons (a subset of GABAergic interneurons), and this sparing was reflected in neurochemical measurements of GABA; kainic acid lesions failed to display this selectivity. Somatostatin, cholecystokinin, and vasoactive intestinal polypeptide concentrations were spared by the NMDA-induced lesions, and substance P levels were significantly increased. These results provide evidence that NMDA excitotoxic lesions of cerebral cortex can produce a selective pattern of neuronal damage similar to that which occurs in Huntington's disease.

Topics: Age Factors; Aged; Animals; Aspartic Acid; Brain Chemistry; Cholecystokinin; Female; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Glutamine; Humans; Huntington Disease; Male; Middle Aged; N-Methylaspartate; Neurochemistry; Rats; Rats, Sprague-Dawley; Somatostatin; Substance P

Topics: Animals; Basal Ganglia; Brain Chemistry; Cell Survival; Cholecystokinin; Corpus Striatum; Disease Models, Animal; Humans; Huntington Disease; Ibotenic Acid; Rats

Cholecystokinin (CCK) receptor binding was measured in postmortem brain tissue of patients with Alzheimer's dementia, Huntington's chorea, and neurologically healthy matched controls. CCK binding was significantly reduced inthe basal ganglia and cerebral cortex of Huntington's patients, but was normal in the temporal and cingulate cortex of patients with Alzheimer's disease. These findings indicate that CCK receptor loss is unique to specific neurodegenerative disease(s), and that CCK may be involved in the symptoms of Huntington's disease but is not implicated in the neuropathology of Alzheimer's dementia.

Topics: Alzheimer Disease; Basal Ganglia; Brain; Cerebral Cortex; Cholecystokinin; Dementia; Female; Gyrus Cinguli; Humans; Huntington Disease; Male; Receptors, Cell Surface; Receptors, Cholecystokinin; Temporal Lobe

Cholecystokinin (CCK) receptors were found to be significantly reduced in basal ganglia and cerebral cortex of post-mortem from Huntington's patients with matched controls. The magnitude of the reduction in CCK binding (69% in basal ganglia, 43% in cerebral cortex) is consistent with the degree of neuronal degeneration in basal ganglia, but suggests a possibly selective loss of CCK receptor-containing neurons in cerebral cortex of Huntington's patients.

Topics: Basal Ganglia; Cell Membrane; Cerebral Cortex; Cholecystokinin; Humans; Huntington Disease; Kinetics; Organ Specificity; Receptors, Cell Surface; Receptors, Cholecystokinin

Topics: Basal Ganglia; Cholecystokinin; Humans; Huntington Disease; Neurons