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)

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common disorder thought to arise, in part, from alterations in dopamine function. NR4A2, or Nurr1, is an orphan nuclear receptor implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN). Dopaminergic cells of the VTA provide innervation to the prefrontal cortex, believed to be of major importance in the etiology of ADHD, suggesting that NR4A2 is a potential candidate gene for ADHD susceptibility. This study aimed to identify polymorphisms in NR4A2 and test their association to ADHD. Database analysis revealed a CA repeat polymorphism in the 3' UTR of NR4A2 that was confirmed by PCR. SSCP screening revealed a common DeltaC polymorphism, 254 bp 5' to the transcriptional start site. These polymorphisms were tested for an association with ADHD in both a case control study of individuals from the Milwaukee Longitudinal Study of ADHD (103 cases and 66 controls), and in 35 families composed of trios or affected sib pairs (ASP) with ADHD. Functional effects of the promoter polymorphism were tested in vitro. The non-deleted allele was significantly more active in undifferentiated SK-N-MC cells compared to differentiated SK-N-MC and HeLa cells while a trend for increased activity for the DeltaC allele was observed in undifferentiated SK-N-MC cells. Identification of these polymorphisms may aid future candidate gene studies in disorders with altered dopamine signaling, such as schizophrenia Parkinson's disease and ADHD.
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PMID:Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder. 1563 1

The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD).
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PMID:The dopamine transporter: role in neurotoxicity and human disease. 1584 24

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

Membrane and vesicular monoaminergic transporters, responsible for the homeostasis of neurotransmitter pools at nerve endings, are very involved in the physiology and diseases of central nervous system. Recent progresses of cerebral molecular imaging using SPECT and PET methods allow the extend of in vivo exploration of these transporters. For this aim, an increasing number of radiopharmaceuticals labelled with [123I], [99mTc], [11C] or [18F] have been developed such as cocaine derivatives for the DAT, compounds from the diphenyl sulfide family for the SERT, and dihydrotetrabenazine derivatives for the VMAT2. These functional imaging methods can be very useful in several neurological and psychiatric disorders which involve the monoaminergic neurotransmission systems such as Parkinson's disease, ADHD, depression and autism. For example, the DAT is a specific index of the density of dopaminergic endings which progressively degenerate in Parkinson's disease. In vivo exploration of this transporter can therefore be a relevant way (i) to realize an early detection of the loss of dopaminergic neurons, (ii) to assess the progression of the disease, (iii) to validate and improve the efficacy of new therapeutic strategies such as neuroprotection and neuroreparation. In all, the extend of in vivo exploration of monoamine transporters will allow great progress for (1) knowledge of physiopathological mechanisms of brain disorders, (2) early diagnosis of cerebral dysfunctions, allowing early use of new therapies, (3) selection of homogenous classes of subjects for therapeutic assays, (4) objectiveness of drug-molecular target interaction, (5) follow-up of disease evolution and treatment.
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PMID:PET and SPECT exploration of central monoaminergic transporters for the development of new drugs and treatments in brain disorders. 1625 Aug 52

Dopamine has moved from being an insignificant intermediary in the formation of noradrenaline in 1957 to its present-day position as a major neurotransmitter in the brain. This neurotransmitter is involved in the control of movement and Parkinson's disease, the neurobiology and symptoms of schizophrenia and attention deficit hyperactivity disorder. It is also considered an essential element in the brain reward system and in the action of many drugs of abuse. This evolution reflects the ability of several famous names in neuropharmacology, neurology and psychiatry to apply new techniques to ask and answer the right questions. There is now excellent knowledge about the metabolism of dopamine, dopamine receptor systems and the structural organisation of dopamine pathways in the brain. Less is known about the function of the different receptors and how the various dopamine pathways are organised to produce normal behaviour, which exhibits disruption in the disease states mentioned. In particular, we have very limited information as to why and how the dopamine system dies or becomes abnormal in Parkinson's disease or a neurodevelopmental disorder such as schizophrenia. Dopamine neurones account for less than 1% of the total neuronal population of the brain, but have a profound effect on function. The future challenge is to understand how dopamine is involved in the integration of information to produce a relevant response rather than to study dopamine in isolation from other transmission systems. This integrated approach should lead to greater understanding and improved treatment of diseases involving dopamine.
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PMID:Dopamine: the rewarding years. 1640 97

Evidence supports the hypothesis that normalization of cholinergic tone by selective antagonism of neuronal nicotinic acetylcholine receptors (NNRs) may ameliorate the core symptoms of autism. As often is the case, epidemiology has provided the first important clues. It is well recognized that psychiatric patients are significantly more often smokers than the general population. The only known exceptions are obsessive-compulsive disorder (OCD), catatonic schizophrenia and interestingly, autism. In this regard, clinical studies with nicotine have demonstrated amelioration of symptoms of a number of diseases and disorders, including Alzheimer's disease, Parkinson's disease, ADHD and Tourette's syndrome. Nicotine's agonist properties at CNS NNRs have been implicated in these effects and support the concept of self-medication as a strong motivation for smoking in cognitively compromised individuals. On the other hand, the inverse correlation between autism and smoking suggests that smoking does not provide symptomatic relief and may actually be indicative of an active avoidance of nicotine's agonist effects in this disorder. Neuroanatomical evidence is consistent with this idea based on the presence of hypercholinergic architecture in the autistic brain, particularly during the first few years of development, making the avoidance of further stimulation of an already hyperactive cholinergic system plausible. This may also explain why stimulants (known to increase dopamine levels as do NNR agonists) appear to aggravate autistic symptoms and why studies with cholinesterase inhibitors that increase acetylcholine levels in the brain have yielded variable effects in autism. Taken together, the evidence suggests the possibility that nicotinic cholinergic antagonism may in fact be palliative. Pharmacological evidence supports this hypothesis. For example, antidepressants, many of which are now known to be non-competitive NNR antagonists, have been used successfully to treat a number of autistic symptoms. More specifically, there is anecdotal evidence from at least one medical practitioner that mecamylamine, a non-selective NNR antagonist, is effective in treating many autistic symptoms, particularly those that are refractory to most other treatments. Clearly there is a need for carefully controlled clinical studies with novel selective NNR antagonists to explore their potential as a new and exciting approach for the treatment of autism.
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PMID:Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. 1640 87

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

The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as well as normal aging. Considerable effort continues to be devoted to the development of new ligands for the DAT. In this review, we present some of the more interesting ligands developed during the last few years from the 3-phenytropane, 1,4-dialkylpiperazine, phenylpiperidine, and benztropine classes of DAT uptake inhibitors as well as a few less studied miscellaneous DAT uptake inhibitors. Studies related to the therapeutic potential of some of the more studied compounds are presented. A few of the compounds have been studied as pharmacotherapies for Parkinson's disease, ADHD, and obesity. However, most of the drug discovery studies have been directed toward pharmacotherapies for stimulant abuse (mainly cocaine). A number of the compounds showed decreased cocaine maintained responding in rhesus monkeys trained to self-administer cocaine. One compound, GBR 12,909, was evaluated in a Phase 1 clinical trial.
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PMID:Dopamine transporter ligands: recent developments and therapeutic potential. 1701 60

Braak and co-workers have recently shown that movement disorders such as Parkinson's disease develop progressively over years with early neuronal losses in brainstem regions caudal to the substantia nigra. The relevance of this finding to notions of comorbidity between movement disorders and psychiatric symptoms was recognised at the recent meeting concerning, "Implications of Comorbidity for the Etiology and Treatment of Neuropsychiatric Disorders" held in Oct. 2005 in Mazagon, Spain. The identification of stages in the early development of neurodegenerative disorders appeared to unify multiple, diverse findings. These included: novel therapeutic innovations for Parkinson's disease, Alzheimer's disease and depression in the aged; the neurochemical ontogeny of drug-induced oral dyskinesias; the types of chemical agents abused in neuropsychiatric states; postnatal iron overload effects upon the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expression of movement disorders; and the spectrum of motor symptoms expressed in schizophrenia and attention deficit hyperactivity disorder and the eventual treatment of these disorders. A continued focus on a number of neuropsychiatric diseases as progressive disorders may lead to further advances in understanding their etiology and in developing better therapeutics.
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PMID:Movement disorders: neurodevelopment and neurobehavioural expression. 1702 25

The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, the design and biological evaluation of several radioligands for imaging the brain NET system with PET are discussed. Based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[(11)C]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge, (S, S)-[(11)C]MRB remains by far the most promising NET ligand for PET studies.
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PMID:PET imaging of norepinephrine transporters. 1707 82


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