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

Hedonistic homeostatic dysregulation (HHD) is a neuropsychiatric disorder recently described in Parkinson's disease (PD), which is characterized by self-medication and addiction to dopaminergic drugs. To understand the prevalence of this disorder, we screened 202 PD patients attending our movement disorder unit for HHD. The clinical features of the patients identified as affected by this syndrome were then compared with those of control PD patients in an attempt to ascertain the possible risk factors for HHD. Results showed 7 subjects who fulfilled the HHD criteria. The analysis of a case-control study showed a significant correlation between HHD and a previous history of mood disorders, and the use of dopamine agonists, either in monotherapy or in combination. The prevalence of HHD in our study is similar to the one reported in the United Kingdom by the authors who first described this syndrome in PD. Of interest, our patients showed a somewhat different pattern of the disorder, suggesting that cultural and environmental factors may play a role in the phenomenology of HHD.
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PMID:Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease. 1603 20

The five subtypes of dopaminergic receptors exhibit different transduction, cerebral localization, regulation, pharmacological, and physiological roles, explaining their multiple pathophysiological implications in different neuropsychiatric conditions which result, at least in part from anomalous dopaminergic neurotransmission: Parkinson's disease, schizophrenia, addiction, migraine, mode disorders, Gilles de la Tourette disease, hyperactivity syndrome with attention deficit. The wide range of pharmacological implications explains the diversity of the therapeutic approaches perspectives for development of new drugs for these neuropsychiatric conditions.
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PMID:[Central dopaminergic receptors (Part II): pathophysiological and therapeutic considerations]. 1549 28

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.
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PMID:L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons. 1553 Jun 53

Trace amines (TAs) are present in the central nervous system in which they up-regulate catecholamine release and are implicated in the pathogenesis of addiction, attention-deficit/hyper-activity disorder, Parkinson's disease, and schizophrenia. By using intracellular and patch-clamp recordings from dopaminergic cells in the rat midbrain slices, we report a depressant postsynaptic action of two TAs, beta-phenylethylamine (beta-PEA) and tyramine (TYR) on the GABA(B)-mediated slow inhibitory postsynaptic potential and baclofen-activated outward currents. beta-PEA and TYR activated G-proteins, interfering with the coupling between GABA(B) receptors and G-betagamma-gated inwardly rectifying potassium channels. This is the first demonstration that beta-PEA and TYR depress inhibitory synaptic potentials in neurons of the central nervous system, supporting their emerging role as neuromodulators.
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PMID:Trace amines depress GABA B response in dopaminergic neurons by inhibiting G-betagamma-gated inwardly rectifying potassium channels. 1564 97

Dopaminergic neurons of the midbrain are the main source of dopamine (DA) in the mammalian central nervous system. Their loss is associated with one of the most prominent human neurological disorders, Parkinson's disease (PD). Dopaminergic neurons are found in a 'harsh' region of the brain, the substantia nigra pars compacta, which is DA-rich and contains both redox available neuromelanin and a high iron content. Although their numbers are few, these dopaminergic neurons play an important role in the control of multiple brain functions including voluntary movement and a broad array of behavioral processes such as mood, reward, addiction, and stress. Studies into the developmental pathways which are involved in the generation of dopaminergic neurons in the brain have led to the identification of several specific transcription factors including Nurr1, Lmx1b and Pitx3, all shown to be important in the development of the mesencephalic dopaminergic system. The selective degeneration of these dopaminergic neurons in the substantia nigra pars compacta leads to PD but the exact cause for this nigral cell loss is still unknown.
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PMID:Dopaminergic neurons. 1574 69

In Parkinson's disease, dopamine dysregulation syndrome (DDS) is characterized by severe dopamine addiction and behavioral disorders such as manic psychosis, hypersexuality, pathological gambling, and mood swings. Here, we describe the case of 2 young parkinsonian patients suffering from disabling motor fluctuations and dyskinesia associated with severe DDS. In addition to alleviating the motor disability in both patients, subthalamic nucleus (STN) deep brain stimulation greatly reduced the behavioral disorders as well as completely abolished the addiction to dopaminergic treatment. Dopaminergic addiction in patients with Parkinson's disease, therefore, does not constitute an obstacle to high-frequency STN stimulation, and this treatment may even cure the addiction.
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PMID:Addiction in Parkinson's disease: impact of subthalamic nucleus deep brain stimulation. 1585 3

Neurotensin (NT) is a 13 amino acid neuropeptide that is found in the central nervous system and in the gastrointestinal tract. In brain, this peptide is prominently associated anatomically with dopaminergic, as well as other neurotransmitter systems. Based on animal studies, already decades old, researchers have hypothesised that NT receptor agonists will have antipsychotic properties in patients. However, to date no one has obtained a non-peptide NT receptor agonist. Therefore, there has been great interest in obtaining peptide analogues of NT, that, unlike NT resist degradation by peptidases and cross the blood-brain barrier, yet have the pharmacological characteristics of native NT, for therapeutic use in the treatment of schizophrenia, as well as other neuropsychiatric diseases such as Parkinson's disease and addiction to psychostimulants. In this review, we present the rationale for development of NT receptor agonists for treatment of certain central nervous system diseases, as well as a review of those peptide agonists that are in early stages of development.
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PMID:Neurotensin agonists as an alternative to antipsychotics. 1588 13

Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3'-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3'-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine in humans would be one of the causal factors for the interindividual differences in nicotine metabolism. This review mainly summarizes recent results from our studies.
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PMID:Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. 1614 2

Compelling evidence suggests a monoaminergic dysfunction in the aetiology of various neuro-psychiatric diseases such as depression, attention deficit hyperactivity disorder (ADHD), schizophrenia, addiction and Parkinson's disease. The efficiency of monoaminergic neurotransmission is controlled by rapid and efficient reuptake of dopamine out of the synaptic cleft by specific transporters for dopamine, serotonin and noradrenaline. In case of the serotonin transporter, many investigators have determined its function and expression also on peripheral cells such as blood platelets under the assumption that changes in protein expression in these cells might reflect neuronal changes. No comparable studies have so far been performed with respect to the dopamine transporter due to the lack of information about the existence of this protein in platelets. Here, we present pharmacological, immunological as well as microarray and PCR data that human blood platelets express the dopamine transporter protein (DAT), which is identical to that first identified in neurons. Because DAT expression is modulated also in non-neuronal cells independently of gene transcription, platelets may well serve as an easy accessible peripheral system to study DAT regulation in mental diseases or during drug treatment or drug abuse.
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PMID:Characterization of the neuronal dopamine transporter DAT in human blood platelets. 1649 Mar 14

Dysfunction of dopamine neurons has been implicated in several neuropsychiatric disorders, including Parkinson's disease, addiction, bipolar disorder and depression. Recent elucidation of gene expression profiles in dopamine neuron subpopulations has shed light on the function of different groups of dopamine neurons in the CNS and on their dysfunction in disease states. In particular, concerted differences in gene expression appear to underlie the unique properties of distinct dopamine neurons. Specifically, dopamine neurons in the substantia nigra (SN), which are prone to degenerate in Parkinson's disease, express high levels of transcripts related to energy metabolism, mitochondria and phosphate signalling pathways. In contrast, ventral tegmental area (VTA) dopamine neurons prominently express genes related to synaptic plasticity and neuropeptides, suggesting intriguing mechanisms for the involvement of VTA dysfunction in addiction and mood disorders. As new functions of dopaminergic neurotransmission become clearer, continued exploration of the transcriptional neuroanatomy of these unique neurons will be vital for producing targeted, selective, and effective therapeutic agents.
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PMID:Gene expression profiles of brain dopamine neurons and relevance to neuropsychiatric disease. 1674 Jun 10


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