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)

Modulation of the endocannabinoid system might be useful in treating Parkinson's disease. Here, we show that systemic administration of N-(4-hydroxyphenyl)-arachidonamide (AM404), a cannabinoid modulator that enhances anandamide (AEA) availability in the biophase, exerts antiparkinsonian effects in 6-hydroxydopamine-lesioned rats. Local injections of AM404 into denervated striata reduced parkinsonian motor asymmetries, these effects being associated with the reduction of D2 dopamine receptor function together with a positive modulation of 5-HT(1B) serotonin receptor function. Stimulation of striatal 5-HT(1B) receptors alone was observed to ameliorate parkinsonian deficits, supporting the fact that AM404 exerts antiparkinsonian effects likely through stimulation of striatal 5-HT(1B) serotonin receptor function. Hence, modulation of cannabinoid function leading to enhancement of AEA in the biophase might be of therapeutic value in the control of symptoms of Parkinson's disease. On the other hand, reduced levels of N-acyl-transferase (AEA precursor synthesizing enzyme), without changes in fatty acid amidohydrolase (AEA degradative enzyme), were detected in denervated striata in comparison with intact striata. This finding reveals the presence of a homeostatic striatal mechanism emerging after dopaminergic denervation likely tending to enhance low dopamine tone.
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PMID:Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function. 1501 Jun 94

Trace amines are biological compounds that are still awaiting identification of their role in neuronal function. Using intracellular electrophysiological recordings, we investigated the depressant action of two trace amines (beta-phenylethylamine and tyramine) on the firing activity of dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area. This inhibition was due to a membrane hyperpolarisation that was blocked by the D2 dopamine receptor antagonist sulpiride and was not potentiated by the dopamine-uptake blocker, cocaine. Inhibition of the dopamine transporter did not mediate the effects of trace amines, because unlike cocaine, trace amines did not potentiate the inhibitory responses to exogenously applied dopamine. The inhibitory actions of beta-phenylethylamine and tyramine were present in reserpine-treated animals but were abolished when the dopamine-synthesis inhibitor carbidopa was applied. Our data suggest that trace amines cause an indirect activation of dopamine autoreceptors, by an increased efflux of newly synthesised dopamine. The inhibition of dopaminergic activity by trace amines may relate to their involvement in neuronal processes linked to drug addiction, schizophrenia, attention deficit hyperactive disorders and Parkinson's disease.
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PMID:Inhibitory effects of trace amines on rat midbrain dopaminergic neurons. 1503 40

HIV has a propensity to invade subcortical regions of the brain, which may lead to a subcortical dementia termed HIV-cognitive motor complex. Therefore, we aimed to assess whether dopamine (DA) D2 receptors and transporters (DAT) are affected in the basal ganglia of subjects with HIV, and how these changes relate to dementia status. Fifteen HIV subjects (age 44.5 +/- 11 years; CD4 185 +/- 130/mm3)) and 13 seronegative controls (42 +/- 12 years) were evaluated with PET to assess availability of DAT ([11C]cocaine) and DA D2 receptor ([11C]raclopride). HIV patients with associated dementia (HAD), but not those without dementia (ND) had significantly lower DAT availability in putamen (-19.3%, P = 0.009) and ventral striatum (-13.6%, P = 0.03) compared with seronegative controls. Higher plasma viral load in the HIV dementia patients correlated with lower DAT in the caudate (r = -0.7, P = 0.02) and putamen (r = -0.69, P = 0.03). DA D2 receptor availability, however, showed mild and non-significant decreases in HIV patients. These results provide the first evidence of DA terminal injury in HIV dementia patients, and suggest that decreased DAT may contribute to the pathogenesis of HIV dementia. The greater DAT decrease in the putamen than in the caudate parallels that observed in Parkinson's disease. The inverse relationship between viral burden and DAT availability further supports HIV-mediated neurotoxicity to dopaminergic terminals.
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PMID:Decreased brain dopaminergic transporters in HIV-associated dementia patients. 1531 73

The basal ganglia in the brain contains glutamate, dopamine, serotonin, noradrenaline, CCK, adenosine, opioid, cannabinoid, etc. These agents contribute to keep motor control and modulation of the agent may be a cue to the treatment of movement disorders. D1 or D2 dopamine receptor agonists increase locomotor activity in MPTP-treated common marmosets which showed decreased locomotor activity and decreased number of dopamine neurons in the substantia nigra. Using this model of parkinsonism, NMDA receptor antag-onists, antimuscarinic receptor antagonists, 5-HT1A receptor agonists, adenosine receptor antagonists were showed to reverse the impaired movement of the model animals. The results may contribute to the development of new drugs for the treatment of Parkinson's disease.
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PMID:[The pharmacological and rational theory for the drug development of Parkinson's disease]. 1546 80

Compelling evidence indicates that the long (D2L) and the short (D2S) isoform of dopamine (DA) D2 receptors serve distinct physiological functions in vivo. To address the involvement of these isoforms in the control of synaptic transmission in the striatum, we measured the sensitivity to D2 receptor stimulation of glutamate- and GABA-mediated currents recorded from striatal neurons of three mutant mice, in which the expression of D2L and D2S receptors was either ablated or variably altered. Our data indicate that both isoforms participate in the presynaptic inhibition of GABA transmission in the striatum, while the D2-receptor-dependent modulation of glutamate release preferentially involves the D2S receptor. Accordingly, the inhibitory effects of the DA D2 receptor agonist quinpirole (10 microM) on GABA(A)-mediated spontaneous inhibitory postsynaptic currents (IPSCs)correlate with the total number of D2 receptor sites in the striatum, irrespective of the specific receptor isoform expressed. In contrast, glutamate-mediated spontaneous excitatory postsynaptic currents (EPSCs) were significantly inhibited by quinpirole only when the total number of D2 receptor sites, normally composed by both D2L and D2S receptors in a ratio favoring the D2L isoform, was modified to express only the D2S isoform at higher than normal levels. Understanding the physiological roles of DA D2 receptors in the striatum is essential for the treatment of several neuropsychiatric conditions, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and drug addiction.
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PMID:Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum. 1548 38

Receptor priming is a recently discovered phenomenon by which receptor agonists produce abrupt and long-lived supersensitization of receptors. Induction of dopamine (DA) D2 receptor supersensitivity by the agonist quinpirole was discovered approximately 15 years ago, and was found to occur consistently if rats were treated repeatedly at daily or weekly or monthly intervals with low or high doses of quinpirole. In this review we summarize and discuss some of the major studies that underlie DA D2 receptor supersensitivity, describe behavioral processes that are known to be altered by DA D2 receptor supersensitivity, and discuss the importance of DA innervation on expression of enhanced behaviors. DA D2 receptor supersensitivity represents one of the neural mechanisms implicated in psychiatric disorders. Also, DA D2 receptor supersensitivity and increased DA D3 receptor expression are associated with motor dyskinesias, as in L-DOPA-treated Parkinson's disease patients. An understanding of receptor priming, a knowledge of the types of behavioral expression associated with DA D2 receptor supersensitivity, and an understanding of mechanisms associated with receptor supersensitization, can lead to improvements in the treatments of psychiatric and neurological disorders.
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PMID:Dopamine D2 agonist priming in intact and dopamine-lesioned rats. 1563 79

SKF83959, previously described as an antagonist of the D1 dopamine receptor, has been shown to be a potent anti-parkinsonian agent. However, its mechanism of action is unknown. The present communication was designed to study the mechanism by which SKF83959 exerts its pharmacological effects. SKF83959 induced contralateral rotations in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease (PD). The rotations were completely blocked by the D1 dopamine receptor antagonist, SCH23390. The response was not affected by the serotonin receptor antagonist, mesulergine and was transiently attenuated by alpha1 adrenergic or D2 dopamine receptor antagonists, prazosin or spiperone, respectively. Injection of 0.5 and 1 mg/kg SKF83959 elicited significant elevations in IP3 accumulation in lesioned as compared to intact striata. This effect was blocked by SCH23390 at a dose that completely obviated the rotational response to SKF83959, suggesting that activation of the PI-linked D1 dopamine receptor and the PLC/IP3 pathway may be the underlying mechanism for the rotational activity induced by SKF83959. The present data provide the first evidence that the PI-linked D1 dopamine receptor plays a role in regulating motor activity in striatum and that modulation of the D1 dopamine receptor/PLC/IP3 pathway may be a novel target in the discovery of drugs for the treatment of Parkinson's disease.
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PMID:The role of the phosphatidyinositol-linked D1 dopamine receptor in the pharmacology of SKF83959. 1582 May 29

At this large and varied meeting on neuropharmacotherapy, progress was reported on the newer more selective antipsychotics. The selective D(2) dopamine receptor partial agonist, aripiprazole (Otsuka Pharmaceutical Co Ltd) was recently proved effective over the medium term. The atypical antipsychotics generally, such as clozapine, have a good side effect profile and better patient compliance, even in Parkinson's disease (PD). Reboxetine (Pharmacia & Upjohn AB), having a far greater selectivity for norepinephrine reuptake inhibition than for serotonin or dopamine reuptake, is of particular value in treating depression. Paroxetine (Novo Nordisk A/S), a selective serotonin reuptake inhibitor (SSRI), has just completed a multicenter clinical trial, being effective in about 50% of cases of post-traumatic stress disorder. A meta-analysis of trials of other uptake inhibitors showed that ability to block serotonin (rather than norepinephrine) uptake correlated well with efficacy. Bipolar and other disorders were hoped to benefit from more selective agents in the future, the potential for which has been revealed through basic neurobiology, with, for example, only non-alpha7 nicotinic receptor subunits being expressed by those interneurons mediating nicotinic responses. An open label, 30-day study of a pyrrolopyrimidine, the corticotrophin releasing factor (CRF) type 1 receptor inhibitor, NBI-30775 (Neurocrine Biosciences Inc/Janssen Pharmaceutica NV) produced good antidepressant effects, but has had to be abandoned as a product due to indications of potential liver damage. Similarly, although glial-derived neurotrophic factor (GDNF) had proved ineffective in a 1999 trial for PD, due to failure to access the striatum, there was however much evidence to suggest that small molecule agonists of the TRK-B receptor should be effective. Of these, quinones such as L-783281 (Merck Research Laboratories) appear to activate all TRK subtypes by a common intracellular, rather than receptormediated action, which may limit their usefulness. Although such agents would have many potential applications, it is likely that highly selective receptor activation will be needed.
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PMID:CINP 2000 - Collegium Internationale Neuro-Psychopharmacologicum 22nd Congress. 1604 59

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.
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PMID:PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. 1631 Dec 69

Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult-onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa-induced dyskinesia. Carrying the G-allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia (P=0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia (P=0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor.
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PMID:Genotype and smoking history affect risk of levodopa-induced dyskinesias in Parkinson's disease. 1643 2


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