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)

Histamine H(3) receptors were first described in the eighties but finally cloned four years ago. They are G-protein coupled, mostly presynaptic, and are involved in the control of the synthesis and/or release of different neurotransmitters both in the central nervous system and the periphery. The availabiliy of specific ligands has permitted the study of potential therapeutic applications of either stimulating or blocking the function of these receptors. There is experimental evidence that drugs targeted at histamine H(3) receptors could be beneficial for neurodegenerative diseases such as Alzheimer and Parkinson's disease, epilepsy, drug abuse and several affective, appetite and sleeping disorders, among others. This review presents recent advances in this field.
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PMID:Histamine H3 receptor: a potential drug target for the treatment of central nervous system disorders. 1452 62

The search for the underlying pathophysiology of schizophrenia has been an active avenue of investigation since the disease was first recognized more than 100 years ago. Although a great deal of the research has been driven by the known pharmacology of effective antipsychotic drugs, i.e., overactivity of the dopamine system, recent advances in neurobiology provide evidence that reduced synaptic connectivity/neurotransmission may play a substantial role in this disorder. One neuropeptide long posited to play a role in the biology of schizophrenia is neurotensin (NT). Central nervous system administration of NT has been shown to produce a wide variety of effects. Because of its close association with the dopamine (DA) system, the role of the NT system in clinical disorders hypothesized to involve DA circuits such as schizophrenia, Parkinson's disease, and drug abuse has been closely scrutinized. In addition, NT neurotransmission has been implicated in regulation of the stress response, stress-induced gastric ulcers, temperature regulation, food consumption, and analgesia. NT also acts as a growth factor in a variety of human cancer cell lines derived from lung, colon, prostate, and pancreas. This review first provides a background of the NT system. Second, data indicating that NT may mediate the effects of antipsychotic drugs are summarized. Third, data implicating NT in the pathophysiology of schizophrenia are described. Finally, evidence suggesting the use of NTergic compounds as novel antipsychotic drugs are presented.
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PMID:Neurotensin, schizophrenia, and antipsychotic drug action. 1500 94

The neurotoxic properties of the amphetamines such as methamphetamine (METH) were originally described about the time of the National Institute on Drug Abuse's organization, in the early 1970s. It required more than 20 years to confirm these neurotoxic properties in humans. Much like Parkinson's disease, multiple high-dose administration of METH somewhat selectively damages the nigrostriatal dopamine (DA) projection of the brain. This effect appears to be related to the intracellular accumulation of cytosolic DA and its ability to oxidize into reactive oxygen species. Both the dopamine plasmalemmal transporter and the vesicular monoamine transporter-2 seem to play critical roles in this neurotoxicity. METH and related analogs such as methylenedioxymethamphetamine (MDMA) can also damage selective CNS serotonin neurons. The mechanism of the serotonergic neurotoxicity is not as well characterized, but also appears to be related to the formation of reactive oxygen species and monoamine transporters. Studies examining the pharmacological and neurotoxicological properties of the amphetamines have helped to elucidate some critical features of monoamine regulations as well as helped to improve our understanding of the processes associated with degenerative disorders such as Parkinson's disease.
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PMID:The methamphetamine experience: a NIDA partnership. 1546 28

Striatal medium spiny neurons are principal players in the basal ganglia macrocircuits implicated in an astonishing array of psychomotor disorders, including Parkinson's disease, schizophrenia, Huntington's disease, and drug abuse. Using an elegant combination of 2-photon laser scanning microscopy and 2-photon uncaging of glutamate, Carter and Sabatini (this issue of Neuron) provide our first glimpse into the dendrites and spines of striatal medium spiny neurons. The results offer new insights into the workings of these clinically important yet mysterious neurons.
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PMID:Peering into the dendritic machinery of striatal medium spiny neurons. 1550 19

Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates.
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PMID:Mapping dopamine function in primates using pharmacologic magnetic resonance imaging. 1550 42

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.
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PMID:Modulation of dopamine release by striatal 5-HT2C receptors. 1566 11

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

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

We have recently reported hexahydropyrazinoquinolines as a new class of dopamine 3 (D(3)) receptor ligands with high-affinity to the D(3) receptor and excellent selectivity over the closely related D(1)-like and D(2)-like receptors. However, our previously reported most potent and selective D(3) ligands have poor aqueous solubility, which greatly hinders our in vivo studies aimed at evaluation of their therapeutic potential in animal models. In this study, we wish to report the design, synthesis, and evaluation of a series of new hexahydropyrazinoquinolines as D(3) ligands with improved solubility. Among them, compound 4g has a K(i) value of 9.7 nM for the D(3) receptor and displays a selectivity of >5000 and 466 times over the D(1)-like and D(2)-like receptors, respectively. Importantly, the hydrochloride salt form of compound 4g has a good aqueous solubility (>50 mg/mL) and represents a promising D(3) ligand for further in vivo evaluations of its therapeutic potential for the treatment of drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease, and depression.
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PMID:Design of novel hexahydropyrazinoquinolines as potent and selective dopamine D3 receptor ligands with improved solubility. 1629 Jan 42

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


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