Ventral striatal D3 receptors and Parkinson's Disease
Section snippets
D2 Receptors are functionally relevant in PD
Parkinson's disease (PD) is a neurodegenerative disorder with an insidious onset and a prolonged course over many years. The primary cause of the symptoms of this illness is the neuronal death of dopamine (DA)-producing neurons of the substantia nigra (SN) and the resultant depletion of DA in the striatum [1]. The therapeutic intervention for PD is based on the assumption that activation of postsynaptically located DA receptors will provide some return of balance to the system. The preferred
Changes in expression of D3 receptors in PD
In vivo imaging by PET and SPECT in PD has shown a reduction in D2-like receptor binding of radioligands with increased disease duration [37], [38], [39] and/or complicated response to l-dopa [40], [41], [42]. This has led to the speculation that the loss of D2 receptors contributes to a deteriorated response to l-dopa in PD [41]. We [43] and others [44], [45], [46] have observed 25–35% increase of D2 receptors in post-mortem studies of PD regardless of the duration of illness. As the
Acknowledgements
Funded by Federal Grant NS40669 and Arizona Alzheimers Disease Research Grant to JNF, and Mayo Foundation Grant to CHA.
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Current concepts in treating mild cognitive impairment in Parkinson's disease
2022, NeuropharmacologyCitation Excerpt :D3Rs can be activated by tonic levels of DA and sustain spontaneous activity for a prolonged period of time suggesting they may play a more significant role in motor and cognitive dysfunction in PD than previously appreciated (Richtand et al., 2001; Nakajima et al., 2013; Sokoloff and Le Foll, 2017). Further, the localization of D3Rs in both mesolimbic and mesocortical pathways imply a role in reward-based cognitive processes and in regulating attention, memory and emotional reactivity (Murray et al., 1994; Gurevich and Joyce, 1999; Joyce et al., 2001; Sokoloff and Le Foll, 2017). Several D3R modulating agents with functional effects varying from partial agonists to antagonists have been developed and tested pre-clinically in a variety of cognitive tasks in PD models in rodents, non-human primate models of PD, and in PD patients (Nakajima et al., 2013 for review).
Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?
2020, Ageing Research ReviewsCitation Excerpt :Having PD with an additional diagnosis of dementia correlated with lower D3 receptor density. Correspondingly, non-demented PD cases have elevated levels of D3R binding (Joyce et al., 2001). When pramipexole was used to treat mild-moderate AD individuals, 13/16 patients showed improved cognition (Bennett et al., 2016).
Changes in firing rate and pattern of GABAergic neurons in subregions of the substantia nigra pars reticulata in rat models of Parkinson's disease
2010, Brain ResearchCitation Excerpt :The “indirect pathway” in the limbic striatum is regulated by the mesolimbic DA system through action on the D2 receptors similar with the indirect pathway in the sensorimotor striatum. In contrast, the D3 receptor is highly enriched within the limbic “direct pathway” and appears to be a primary target of the dopaminergic afferents in the limbic striatum, which imply that the limbic “direct pathway” is regulated by DA activity in a way different from that of the sensorimotor striatum (Joyce et al., 2001). In PD, it has been reported that the number of D2 receptors increase but the level of D3 receptors is reduced in the limbic striatum after the striatal DA depletion (Lévesque et al., 1995; Schwarting and Huston, 1996).
G protein-coupled receptor kinase 5, overexpressed in the α-synuclein up-regulation model of Parkinson's disease, regulates bcl-2 expression
2010, Brain ResearchCitation Excerpt :The subsequent binding of arrestins shield the cytoplasmic surface of the receptors precluding further G protein-coupled signaling from persistent stimulation (Krupnick and Benovic, 1998). The dysregulation of DA receptor signaling in the basal ganglia implicated in Parkinson's disease plays a role in generating motor deficits (Guigoni et al., 2005; Joyce et al., 2001; Muriel et al., 1999; Ryoo et al., 1998). Therefore, we think that dopaminergic dysfunction may determine the changes in GRK5 concentrations seen in our study.
Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia
2008, Neurobiology of AgingCitation Excerpt :Neurobiological mechanisms responsible for motor symptoms produced by the degeneration of dopaminergic neurons in PD are poorly understood. It is generally believed that dysregulation of DA receptor signaling in the basal ganglia plays a role in generating motor deficits (Guigoni et al., 2005; Joyce et al., 2001; Muriel et al., 1999; Ryoo et al., 1998), but the underlying molecular events are not known. DA receptors belong to the G protein-coupled receptor (GPCR) superfamily.
Central dopaminergic receptors (Part II): Pathophysiological and therapeutic considerations
2004, Revue Neurologique