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)

We investigated the dopamine receptor (DAR) mRNA expression in peripheral blood lymphocytes from 45 patients with Parkinson's disease (PD) and 21 age-matched controls using the quantitative reverse transcription and polymerase chain reaction method. Beta-actin mRNA was used as an internal control to evaluate the relative expression level of the DAR mRNA. There was a statistically significant decrease of the D3 dopamine receptor (D3R) mRNA expression in PD patients compared with that in controls. There was no change in expression of the D5 dopamine reception mRNA in PD patients. A further binding study showed reduction of the D3R binding sites in PD lymphocytes. The decrease of the D3R mRNA expression correlated with the degree of clinical severity in PD patients.
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PMID:Decrease of the D3 dopamine receptor mRNA expression in lymphocytes from patients with Parkinson's disease. 861 85

The D3 receptor is recognized with high affinity by all antipsychotics and selectively expressed in limbic brain areas participating in the central of emotions, motivation and reward. In transfected cultured cells, stimulation of the D3 receptor inhibits cAMP formation and increases mitogenesis, which, in turn, is potentiated by activation of the cAMP cascade. This suggests that both opposite and synergistic interactions occur between the D3 receptor and the cydic AMP pathway, possibly underlying D1/D3 receptor interactions. In fact, D1 and D3 receptors colocalize in the islands of Calleja, in which they interact in opposition on c-fos mRNA expression, and in the shell of nucleus accumbens, in which they interact in synergy on substance P mRNA expression. The expression of the D3 receptor is highly dependent of the dopamine innervation: lesion of ascending dopamine neurons reduces D3 receptor mRNA and binding in the shell of nudeus accumbens, by deprivation of an unknown factor of dopamine neurons, distinct form dopamine and its cotransmitters. In agreement, expression of the D3 receptor in neurons during rat brain development starts after the settlement of dopamine innervation during the first postnatal week. However, in adult rats with a unilateral lesion of dopamine neurons, repeated treatment with levodopa rescues D3 receptor expression in the shell of nudeus accumbens and induces this expression in the dorsal striatum, a region controlling movements in which the D3 receptor is normally absent. This induction seems responsible for the behavioral sensitisation, i.e. increased responsiveness to levodopa. These observations suggest a role of the D3 receptor in the progressive increase in the therapeutic efficacy of levodopa in the initial treatment of Parkinson's disease, and/or its adversive motor and psychopathological effects during long-term treatment. Finally, various pharmacological and genetic data suggest a role of the D3 receptor in drug addiction and schizophrenia, the treatment of which could benefit from selective D3R agents.
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PMID:[Function and therapeutic potential of the dopamine D3 receptor]. 1010 7

L-DOPA-induced dyskinesias are one of the main problems encountered in treating patients with Parkinson's disease (PD). They are induced by the antiparkinsonian medications and primarily related to the degree of dopaminergic depletion, as shown by the fact that they tend to appear several years after the onset of the disease. Do the initial therapeutic decisions taken in treating a PD patient influence the point at which dyskinesias first occur? This question is raised in view of the apparent priming phenomenon that occurs in first exposure to L-DOPA. L-DOPA administrated to an MPTP intoxicated monkey rapidly corrects the animals' motor symptoms but generate dyskinesias. In contrast, the administration of dopaminergic agonists with a long half-life has a similar therapeutic effect but without inducing dyskinesias. However, a parkinsonian monkey that had received L-DOPA and developed dyskinesias, which were subsequently abolished when the treatment was withdrawn for several months, proceeded to develop dyskinesias when treatment with dopaminergic agonists with long half-life was introduced. The monkeys' previous exposure to L-DOPA (i.e. priming) thus increased its susceptibility to develop dyskinesias after exposure to drugs which would not otherwise have had this effect. Pulsatile activation of type D2 dopamine receptors is reported to be the principal factor in the triggering of dyskinesias and may well be involved in the priming phenomenon. While the pathophysiological basis of priming is not yet known, the phenomenon would not appear to be related to a hyperexpression of dopamine receptors (types D1 and D2) in the sensorimotor striatum. The results of recent experiments have given rise to several different hypothesis for the mechanisms involved in priming: the role of internalization of dopamine receptors after administration of dopaminergic drugs; change in the distribution of D3 dopamine receptor; changes in the expression of peptides (substance P, enkephalin) in efferent neurons of the striatum; and reorganization of connections at the level of the dopaminergic neurons and their target tissue. While many questions remain unanswered, it may well be that the initial therapeutic decisions taken when treating de novo patient are crucial in trying to delay the onset of dyskinesias.
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PMID:[Development of dyskinesias induced by treatment for Parkinson's disease: potential role of first exposure to L-DOPA (or phenomenon of priming)]. 1074 93

Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are highly concentrated in the striatum, where they are co-localized and exert reciprocal antagonistic interactions. It has been suggested that the A2R/D2R interactions might provide a therapeutic approach for basal ganglia disorders, such as Parkinson's disease, and schizophrenia. In the present work evidence is presented for the existence of an A2AR/D2R interaction in human brain by using quantitative autoradi- ography. The areas analyzed were the dorsal caudate nucleus and putamen. Parallel studies were performed in rat striatal sections. The A2AR agonist CGS 21680 was found to significantly increase IC50 values of competitive inhibition curves of the D2R/D3R antagonist [125I]iodosulpiride vs dopamine both in rat striatal and human striatal brain sections.
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PMID:Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum. 1143 7

Dopamine by itself has not up to now been reported to activate T cell function. We show here that dopamine interacts directly with dopaminergic receptors on normal human T cells and triggers beta1 integrin-mediated T cell adhesion to a major extracellular matrix component, fibronectin (FN). Such adhesion is a characteristic feature of activated T cells, and is critical for trafficking and extravasation of T cells across blood vessels and tissue barriers. Seven dopamine D2/D3 receptor agonists and antagonists were used to identify the receptor subtypes with which dopamine specifically interacts to activate T cells. The D3 dopamine receptor agonist, 7-hydroxy-DPAT (DPAT), mimics the effects of dopamine, and the effects of both dopamine and DPAT are blocked by a specific D3 receptor antagonist, U-maleate. The dopamine receptor agonists bromocriptine and pergolide mimic the direct effect of dopamine on the beta1 integrin function, while the dopamine receptor antagonists butaclamol and haloperidol suppress it, suggesting additional signaling via the dopamine D2 receptor subtype. Our study shows, for the first time, that dopamine can directly activate T cells via ist specific receptors and suggests a possible role for dopamine in integrin-mediated cellular trafficking and extravasation of T cells in the central nervous system and possibly also in the periphery. Finally, we suggest that the reported changes in the D3 and D2 receptor RNA levels in peripheral blood lymphocytes of individuals with schizophrenia, Parkinson's disease, Alzheimer's disease and migraine can serve not only as a 'passive' diagnostic marker, but primarily reflect the dynamic functional dopamine-T cell interactions in these diseases.
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PMID:Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta1 integrin function. 1174 70

While levodopa-induced neurochemical changes have been studied in animal models of Parkinson's disease, very little is known regarding the effects of levodopa administration in normal animals. The present study investigates the effects normal and MPTP-lesioned mice chronically treated with two different doses of levodopa. We assess changes in striatal dopamine (DA) receptor binding, striatal DA receptor mRNA levels and striatal neuropeptide precursor levels (preproenkephalin-A [PPE-A]; preprotachykinin [PPT]; preproenkephalin-B [PPE-B]). The extent of the lesion was measured by striatal DA transporter binding and stereological estimation of the number of tyrosine hydroxylase immunoreactive neurones in the substantia nigra pars compacta (SNc). In non-lesioned animals, chronic levodopa treatment induced an increase in PPE-A mRNA, whereas both D3R binding and PPE-B mRNA levels were dramatically increased in the lesioned animals in a dose dependent manner. The present results show that chronic levodopa administration may induce pathophysiological changes, even in the absence of a lesion of the nigro-striatal pathway, suggesting that the sensitization process involves predominantly the indirect striatofugal pathway in non-lesioned animals, whereas the direct pathway is primarily involved in lesioned animals.
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PMID:Pattern of levodopa-induced striatal changes is different in normal and MPTP-lesioned mice. 1261 25

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), remains the most common treatment for Parkinson's disease. However, following long-term treatment, disabling side effects, particularly L-DOPA-induced dyskinesias, are encountered. Conversely, D2/D3 dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect while eliciting less dyskinesia when administered de novo in Parkinson's disease patients. Parkinson's disease and L-DOPA-induced dyskinesia are both associated with changes in mRNA and peptide levels of the opioid peptide precursors preproenkephalin-A (PPE-A) and preproenkephalin-B (PPE-B). Furthermore, a potential role of abnormal opioid peptide transmission in dyskinesia is suggested due to the ability of opioid receptor antagonists to reduce the L-DOPA-induced dyskinesia in animal models of Parkinson's disease. In this study, the behavioural response, striatal topography and levels of expression of the opioid peptide precursors PPE-A and PPE-B were assessed, following repeated vehicle, ropinirole, or L-DOPA administration in the 6-OHDA-lesioned rat model of Parkinson's disease. While repeated administration of L-DOPA significantly elevated PPE-B mRNA levels (313% cf. vehicle, 6-OHDA-lesioned rostral striatum; 189% cf. vehicle, 6-OHDA-lesioned caudal striatum) in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease, ropinirole did not. These data and previous studies suggest the involvement of enhanced opioid transmission in L-DOPA-induced dyskinesia and that part of the reason why D2/D3 dopamine receptor agonists have a reduced propensity to elicit dyskinesia may reside in their reduced ability to elevate opioid transmission.
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PMID:Ropinirole versus L-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia. 1469 17

The neurotoxin MPTP induces nigral dopaminergic cell death in primates and produces a partial model of Parkinson's disease (PD). Pramipexole is a D2/D3 dopamine receptor agonist used in the symptomatic treatment of PD, and which also protects neuronal cells against dopaminergic toxins in vitro. We now demonstrate that pramipexole partially prevents MPTP toxicity in vivo in a primate species. Common marmosets were repeatedly treated with pramipexole either before, coincidentally with, or after low-dose MPTP treatment designed to induce a partial lesion of the substantia nigra. Animals pretreated with pramipexole had a significantly greater number of surviving tyrosine hydroxylase (TH) positive neurones in the pars compacta of the substantia nigra. Pramipexole pretreatment also prevented degeneration of striatal dopamine terminals. Treatment with pramipexole concurrently with MPTP or following MPTP did not prevent TH-positive cell loss. Pramipexole pretreatment appears to induce adaptive changes that protect against dopaminergic cell loss in primates.
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PMID:Pramipexole protects against MPTP toxicity in non-human primates. 1646 39

Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptor-mediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.
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PMID:Behavioral sensitization, alternative splicing, and d3 dopamine receptor-mediated inhibitory function. 1685 31

The dopamine D3 receptor is believed to play an important role in regulation of rodent locomotor behavior, and has been proposed as a therapeutic target for substance abuse, psychotic disorders, and Parkinson's disease. One model of dopamine D3 receptor function, based on studies utilizing D3 receptor knockout mice and D3 receptor-preferring agonists, proposes that D3 receptor stimulation is inhibitory to psychostimulant-induced locomotion, in opposition to the effects of concurrent dopamine D1 and D2 receptor stimulation. Recent progress in medicinal chemistry has led to the development of highly-selective dopamine D3 receptor antagonists. In order to extend our understanding of D3 dopamine receptor's behavioral functions, we determined the effects of the highly-selective dopamine D3 receptor antagonist NGB 2904 on amphetamine-stimulated and spontaneous locomotion in wild-type and dopamine D3 receptor knockout mice. NGB 2904 (26.0 microg/kg s.c.) enhanced amphetamine-stimulated locomotion in wild-type mice, but had no measurable effect in dopamine D3 receptor knockout mice. Of a range of doses (0.026 microg-1.0 mg/kg) given acutely or once daily for seven days, the highest dose of NGB 2904 (1.0 mg/kg) stimulated spontaneous locomotion in wild-type mice, but was without measurable effect in dopamine D3 receptor knockout mice. These behavioral effects of NGB 2904 contrast with those described for other highly D3 receptor-selective antagonists, which have not previously demonstrated an effect on spontaneous locomotor activity. In combination, these data add to the behavioral profile of this novel D3 receptor ligand and provide further support for a role for dopamine D3 receptor inhibitory function in the modulation of rodent locomotion.
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PMID:The dopamine D3 receptor antagonist NGB 2904 increases spontaneous and amphetamine-stimulated locomotion. 1740 30


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