Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Effects of microinjection of cholecystokinin-8 (CCK-8) into the rat ventral tegmental area were studied on dopamine (DA) release from nucleus accumbens (Acb), using fast cyclic voltammetry and carbon fibre microelectrode. 2. DA release was evoked by electrical stimulation of the medial forebrain bundle (MFB). DA release from Acb was increased with increasing intensity or frequency of electrical stimulation in a dose-dependent manner and was inhibited by microinjection of CCK-8 (0.5 microg/kg) into the ventral tegmental area. 3. The release of DA was clearly reduced at all the intensities (0.25, 0.5, 0.75 and 1.0 mA) tested following CCK injection into the VTA, which was statistically significant (P<0.05). But the reduced percentage of DA release did not show significant changes between the data obtained with stimuli of different intensities (P>0.05). 4. While no change could be found with the stimuli of 10Hz, the DA release was significantly suppressed by injection of CCK-8 at the other three frequencies tested (50 Hz, 100 Hz and 250 Hz). Furthermore, although the differences in the reduced amounts of DA release obtained at 50 Hz, 100 Hz and 250 Hz were statistically significant, the reduced percentage seemed to be not closely related to the frequency applied (P>0.05). 5. These results indicate that CCK-8 is involved in the regulation of midbrain DA neurotransmission, and thereby implicated in disorders, such as Parkinson's disease, that involve malfunctions of the basal ganglion DA neuronal systems.
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PMID:Effect of cholecystokinin-8 microinjection into ventral tegmental area on dopamine release in nucleus accumbens of rats: an in vivo voltammetric study. 1129 86

Neuropeptide Y, cholecystokinin (tetra- and octasulphated peptides) and substance P were measured in lumbar cerebrospinal fluid obtained from patients with various neurologic disorders such as Parkinson's disease, cerebrovascular disorders, multiple sclerosis, tuberculous meningitis and aseptic meningitis. These results are statistically compared with healthy results. The results accumulated showed that the data collected can provide the vital information necessary for designing drug therapy.
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PMID:Variation in cerebrospinal fluid levels of neuropeptide Y, cholecystokinin and substance P in patients with neurological disorders. 1145 34

Cholecystokinin modulates the release of dopamine and dopamine-related behaviours in the mesolimbic pathway, where cholecystokinin and dopamine coexist in dopaminergic neurones. Because cholecystokinin and its receptors (A and B) have a functional interaction with dopaminergic neurotransmission, alterations in them may constitute a predisposition for Parkinson's disease. We performed a case-control study to investigate the association between the cholecystokinin system and Parkinson's disease using genetic markers for three genes: cholecystokinin and its two receptors (A and B). One hundred and sixty patients with Parkinson's disease and 160 controls, matched for age, gender, ethnic origin and area of residence, were recruited. Cholecystokinin -45C>T, cholecystokinin-A receptor 779T>C and cholecystokinin-B receptor 1550G>A gene polymorphisms were studied using polymerase chain reaction-restriction fragment length polymorphism analyses. These three gene polymorphisms showed no correlation with risk of Parkinson's disease; however, the cholecystokinin CT/TT genotype was associated with a 4.429-fold increased risk for visual hallucinations in Parkinson's disease. Cholecystokinin-A receptor and B receptor polymorphisms, considered alone, showed no correlation with hallucinations in Parkinson's disease; however, a combined effect was found in patients with hallucinations harboring both the cholecystokinin CT/TT and cholecystokinin-A receptor TC/CC genotypes. Parkinson's disease patients harboring this genotype have a 5.922-fold increased risk for developing visual hallucinations. These results suggest that, in Chinese, visual hallucinations in Parkinson's disease are associated with cholecystokinin -45C>T polymorphism, and this association was still observed in the presence of the cholecystokinin-A receptor TC/CC genotype, indicating a possible interaction of these two genes in the visual hallucinogenesis in Parkinson's disease.
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PMID:Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease. 1277 67

Dyskinesia frequently mars the long-term therapeutic response to levodopa (LD) in Parkinson's disease (PD). New treatment strategies for levodopa-induced dyskinesia (LID) currently being investigated include some that target the nondopaminergic pathways. Indeed, LID in parkinsonism can be modulated by drugs acting on different neurotransmitters including glutamate, gamma-aminobutyric acid, noradrenaline, acetylcholine, serotonin, adenosine, and cholecystokinin. In many cases, the possibility of using specific compounds to counteract LID was raised by the previously shown efficacy of such compounds in the treatment of other types of dyskinesia. More data are now available on drugs that act on the noradrenergic system. Two studies have recently shown how the alpha-2 adrenoreceptor antagonist idazoxan can significantly reduce LID in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate model of parkinsonism and in patients with advanced PD. The experimental paper, which studied the antagonistic action of idazoxan on dyskinesia induced by both LD and apomorphine in marmosets with MPTP-induced parkinsonism, showed that the pharmacologic mechanisms underlying LID and apomorphine-induced dyskinesia in PD are probably distinct. LD, although not apomorphine-induced, dyskinesia was found to be influenced by adrenoreceptor antagonists. Indeed, the action of alpha-2 adrenoreceptor antagonists may involve the blockade of the action of noradrenaline synthesized from LD. The hypothesis is that because dopamine agonists are not metabolized to noradrenaline, alpha-2 adrenoreceptor antagonists do not reduce dyskinesia produced by such agents. This finding is particularly relevant in planning clinical studies in which LD or dopamine agonist challenges are used to assess the potential antidyskinetic properties of new drugs. The clinical study assessed the effects of idazoxan on LID in 18 patients with advanced PD: An improvement in LID, without the reappearance of parkinsonian symptoms, was observed. The practical outcome of this research is that, although the mechanisms underlying the manifestations and the priming process for dyskinesia have yet to be fully elucidated, a nondopaminergic approach to therapy may provide an effective way of preventing, or at least limiting, the expression of involuntary movements in PD.
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PMID:Noradrenergic drugs for levodopa-induced dyskinesia. 1464 9

Mammalian motor activity displays circadian patterns in normal behaviour and in many movement disorders, like levodopa responsive dystonia and Parkinson's disease. Here, we hypothesized that a circadian pattern of dopamine synthesis would trigger rhythms in the expression of genes in regions receiving dopaminergic innervation. Indeed tyrosine hydroxylase and cholecystokinin mRNA were upregulated in the substantia nigra and ventral tegmental area in the course of the day. However, in the caudate putamen, the mRNA levels, for dopamine D2 and adenosine 2A receptor, dynorphin, and substance P were lower during the day than during the night, whereas the expression of dopamine D1 receptor, enkephalin, and somatostatin was stable. In the frontal cortex, a clear midday peak of enkephalin expression was detected, while cholecystokinin and vasoactive intestinal peptide expression did not vary. Clear circadian gene expression patterns can therefore be demonstrated in brain regions involved in motor regulation, but they do not follow a simple dopaminergic drive and more complex regulatory patterns have to be assumed.
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PMID:Circadian patterns of neurotransmitter related gene expression in motor regions of the rat brain. 1501 24

Midbrain dopaminergic (DA) neurones sustain important physiological functions such as control of motricity, signalling of the error in prediction of rewards and modulation of emotions and cognition. Moreover, their degeneration leads to Parkinson's disease and they may be dysfunctional in other pathological states, such as schizophrenia and drug abuse. A subset of DA neurones has been known for many years to contain releasable peptides such as neurotensin and cholecystokinin. However, recent experimental evidence indicates that the phenotype of DA neurones may be much more diverse, since it is suggested that, under certain conditions, they may also release glutamate, cannabinoids and even serotonin.
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PMID:Dopaminergic neurones: much more than dopamine? 1602 40

Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role in motor and cognitive function. However, the impairment of emotional processes in neurologic and psychiatric pathologies involving the dopaminergic system (Parkinson disease, schizophrenia, autism, Attention Deficit Hyperactivity Disorder, Huntington disease, frontal lobe lesions), as well as the influence that administration of dopaminergic agonists/antagonists exert on the processing of emotion, suggest a role for DA in emotional processes. Moreover, emotional processes are dependent upon a variety of structures, the majority of which form part of the limbic system and are subject to DA innervation. In reviewing the literature, the amygdala emerges as a brain structure critical for emotional processing. It may also be implicated in deficits in emotional recognition found in two major disorders where DA's implication is clear: Parkinson disease and schizophrenia. In addition, the amygdala's response to emotional tasks is likely to be altered by the administration of both agonist and antagonist dopaminergic drugs. Experimental studies reinforce the idea of a dopaminergic contribution to emotional response, as suggested by biochemical, pharmacologic, and lesion experiments. Although the implication of the dopaminergic system in emotional processing appears to be clearly documented, the contribution of specific DA receptor subtypes, or of the DA cotransmitters cholecystokinin and neurotensin, or even glutamate, is, however, still unclear. Altogether, these observations suggest that DA has, undoubtedly, a direct and/or indirect role in the full emotional process.
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PMID:Dopaminergic contribution to the regulation of emotional perception. 1623 63

Most patients with Parkinson's disease (PD) have sporadic form of the disease with a multifactorial etiology due to interactions between environmental conditions and the genetic constitution of the individuals. We have analyzed by APEX technology 50 single nucleotide polymorphisms (SNPs) in 19 genes related to cholecystokinin, serotonin, dopamine and opioid neurotransmission. Significant differences in the allele and genotype frequencies between the controls and PD patients were detected for four SNPs from three genes (serotonin 2A receptor (rs6311, P=0.043), Wolfram syndrome 1 (rs1801211, P=0.007), proopiomelanocortin (rs28930368, P=0.026 and rs2071345, P=0.027) genes). Two SNPs in proopiomelanocortin (POMC) gene were also associated with different clinical forms of PD. Our data suggest that at least three genes involved in neurotransmitter systems may have more specific role in genetic predisposition to PD.
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PMID:Association study of sporadic Parkinson's disease genetic risk factors in patients from Russia by APEX technology. 1687 16

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.
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PMID:When words are painful: unraveling the mechanisms of the nocebo effect. 1737 17

The vesicular monoamine transporter type 2 (VMAT2) packages pre-synaptic monoamines into vesicles. Previously, we generated mice hypomorphic for the VMAT2 gene (Slc18a2), which results in a approximately 95% reduction in VMAT2 protein, disrupted vesicular storage, severe depletion of striatal dopamine and mice with moderate motor behaviour deficits. Dopamine released from mid-brain dopamine neurons acts on post-synaptic type 1 (D1) and 2 (D2) receptors located on striatal medium spiny neurons to initiate a signalling cascade that leads to altered transcription factor activity, gene expression and neuronal activity. We investigated striatal gene expression changes in VMAT2hypo mice by quantitative real-time PCR and in situ hybridisation. Despite unaltered expression of D1 and D2 dopamine receptors, there were dramatic alterations in striatal mRNAs encoding the neuropeptides substance P, dynorphin, enkephalin and cholecystokinin. The promoters of these genes are regulated by a combination of transcription factors that includes cAMP responsive element binding protein-1 (CREB) and c-Fos. Indeed, the changes in peptide mRNAs were associated with elevated expression of Creb1 and c-Fos. These data indicate that striatal dopamine depletion, as a consequence of deficient vesicular storage in this mouse, triggers a complex program of gene expression, consistent with this mouse being an excellent model of Parkinson's disease.
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PMID:Differential gene expression in the striatum of mice with very low expression of the vesicular monoamine transporter type 2 gene. 1743 7


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