Interactive reportDopamine D1 receptor expression in human basal ganglia and changes in Parkinson’s disease1
Introduction
Parkinson’s disease results from the progressive degeneration of pigmented nuclei of the brainstem, notably dopaminergic neurons of the substantia nigra pars compacta (SNc) [22]. The resulting decrease in striatal dopamine levels mainly underlies the motor deficits (akinesia, bradykinesia, rigidity) which characterize the disease, although decreased dopamine levels in extrastriatal regions may also contribute [23]. Dopamine replacement therapy using l-DOPA is the mainstay of treatment, but direct acting dopamine receptor agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole) are also widely used to treat the early symptoms [37]. However, after 2–5 years of treatment a significant proportion of patients treated with l-DOPA develop disabling side-effects (including dyskinesias and a loss of drug efficacy) [33]. The mechanisms responsible for these long-term treatment complications are not understood but may in part result from alterations in striatal dopamine receptor expression in response to the drug treatment and a resulting imbalance between striatal output pathways [5]. Striatal output pathways are broadly divided into: (a) GABAergic neurons of the direct pathway which innervate the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi), predominantly express dopamine D1 receptors and co-localize substance P and dynorphin and (b) GABAergic neurons of the indirect pathway which project to the external segment of the globus pallidus (GPe) then onto the SNr, predominantly express dopamine D2 receptors and co-localize with enkephalin. While it is generally agreed that striatal D2 receptor expression increases in untreated Parkinson’s disease and returns to near normal levels following l-DOPA treatment, there have been reports of increases, decreases and no change in striatal D1 dopamine receptor density [6], [9], [11], [28], [29], [42], [43], [44], [45], [46], [47], [48]. These conflicting results may reflect differences in the duration and severity of disease and/or the extent of drug treatment of individuals used in these investigations [28], [47]. Much less is known about alterations in dopamine receptor expression occurring in extrastriatal areas in Parkinson’s disease. A reduction in dopamine D1 and D2 receptors in the SNc, which corresponds to the loss of dopaminergic neurons, has been described [6], [9], [44], while other studies have found no change in striatal or extrastriatal dopamine D1 receptors [9], [11]. In addition to the substantia nigra, there is evidence for dopamine receptors in areas of basal ganglia which are not traditionally considered dopaminergic such as the globus pallidus, subthalamic nucleus and cerebellum [3], [24], [39] and again it is unknown whether alterations of dopamine receptor expression in these areas contribute to benefit or/and side-effects produced by dopamine replacement therapy.
Drugs currently used to treat Parkinson’s disease act largely on D2 receptors and the ability of D1 receptor agonists to control motor disturbances in Parkinson’s disease has largely been overlooked. The first D1 agonist studied, SKF38393, proved ineffective in the treatment of Parkinson’s disease and MPTP-treated marmosets, but was later found to be a weak partial agonist with poor brain penetration [7], [10]. In contrast, newer full D1 agonists, ABT-431, CY-208-243 and dihydrexidine, were effective at reducing parkinsonian motor deficits in humans [16], [51], [57] and in MPTP-treated primates [2], [4], [14], [18], [20], [25], [40], [41], [49], [51], [52], [56], [58] showing the importance of D1 receptors to the control of motor function. So, again it is important to delineate the expression of D1 receptors in both striatal and extrastriatal regions of the basal ganglia and to assess the changes that occur in Parkinson’s disease following chronic dopaminergic drug treatment.
In this study we examined the status of D1 receptor protein (identified as specific [3H]-SCH23390 binding sites) and mRNA expression in the striatum and extrastriatal regions of brain taken from patients dying with treated Parkinson’s disease and age-matched control subjects using radioligand binding and reverse transcription polymerase chain reaction (RT-PCR) techniques. The aim was to resolve the controversy over striatal D1 receptor expression in Parkinson’s disease. In addition, the level of dopamine D1 receptor mRNA expression was examined in extrastriatal brain regions because previous studies have not examined dopamine D1 receptor mRNA expression in areas outside of the striatum in Parkinson’s disease.
Section snippets
Human brain tissue
This study was performed on brain tissue from 16 patients who died with a clinical diagnosis of idiopathic Parkinson’s disease and 14 control subjects who died with no known neurological or psychiatric disease. Details of each case are given in Table 1. It should be noted that tissue was not available from all regions for each case. The two groups were not significantly different for age at death (mean±S.E.M. years: control, 73.6±3.3; Parkinson’s disease, 77.6±2.0; F=1.10, P=0.302) or the time
RT-PCR
RT-PCR and radioligand binding were used to investigate the expression of dopamine D1 receptor mRNA in post-mortem brain. Preliminary experiments were conducted to determine the optimum Mg2+ concentration for the primers and the number of PCR cycles required that kept the reactions within the exponential phase of amplification (data not shown). The relative amounts of D1 receptor mRNA (corrected for genomic DNA contamination) were calculated as a percentage of β-actin mRNA levels measured in
Discussion
In this study the expression of the dopamine D1 receptor mRNA and protein (specific [3H]-SCH23390 binding sites) was examined in parkinsonian human brain by RT-PCR and radioligand binding using [3H]-SCH23390. Increased D1 receptor mRNA and protein levels were found within the striatum, whereas decreased expression occurred in extrastriatal areas. Parkinsonian patients were receiving dopaminergic agonists at the time of death. The alterations observed in this study may therefore reflect the
Acknowledgements
This work was supported by the National Parkinson Foundation Inc., Miami. Human brain tissue was provided by the National Parkinson Foundation/University of Miami Brain Endowment Bank and the Brain Tissue Resource Center of Harvard Medical School. Technical assistance was provided by M. Basile M.S. (brain tissue handling) and Q. Ouyang M.S. (radioligand binding).
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2019, NeuronCitation Excerpt :Therefore, DA tightly regulated ChI activity to reduce and compress the dynamic frequency range in normal mice (Bamford et al., 2008; Wang et al., 2013) while increasing and normalizing ChI activity in progressive DA-deficient mice. Similar findings are reported in PD: increased D2R density, mRNA, and protein are found in untreated patients, and increased D1R density and LID occur in late-stage PD (Hurley et al., 2001; Seeman et al., 1987). Additional studies will be needed to determine the precise mechanisms underlying the observed changes in DA receptor efficiency.
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2018, NeuroscienceCitation Excerpt :In PD patients, no clear results concerning D1 receptor density in the CPu were found. Striatal D1 receptor density were described to be unaltered (Shinotoh et al., 1993; Corvol et al., 2004), decreased (Turjanski et al., 1997) or increased (Hurley et al., 2001). In hemi-PD rats we found a slightly elevated D1 receptor density in the CPu early post lesion that decreased with increasing post lesion survival.
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2015, Progress in NeurobiologyCitation Excerpt :Studies in experimental models of PD indicate that the number and affinity of D1R is unchanged following DA depletion (Aubert et al., 2005; Breese et al., 1987; Joyce, 1991; Marshall et al., 1989; Savasta et al., 1988). Similar results were obtained in post-mortem samples from parkinsonian patients (Hurley et al., 2001; Pimoule et al., 1985; Shinotoh et al., 1993). However, the loss of DAergic input to the striatum and the development of dyskinetic behaviour in response to chronic administration of L-dopa are accompanied by increased recruitment of D1R at the plasma membrane of MSNs, which may be caused by impaired receptor internalization and trafficking (Berthet et al., 2009; Guigoni et al., 2007).
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Published on the World Wide Web on 30 January 2001.