Absence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease

Parkinson’s disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursorl-3,4-dihydroxyphenylalanine (l-DOPA), but its prolonged use causes dyskinesias referred to asl-DOPA–induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PDl-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson’s symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronicl-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine–treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect ofl-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.

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7-nitroindazole attenuates 6-hydroxydopamine-induced spatial learning deficits and dopamine neuron loss in a presymptomatic animal model of Parkinson's disease.

Experimental and Clinical Psychopharmacology ◽

10.1037/1064-1297.16.2.178 ◽

2008 ◽

Vol 16 (2) ◽

pp. 178-189 ◽

Cited By ~ 16

Author(s):

Kristi L. Haik ◽

Deborah A. Shear ◽

Chad Hargrove ◽

Jared Patton ◽

Michelle Mazei-Robison ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Model ◽

Spatial Learning ◽

Dopamine Neuron ◽

Learning Deficits ◽

Neuron Loss ◽

6 Hydroxydopamine

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G-protein coupled receptor 88knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson’s disease

10.1101/617456 ◽

2019 ◽

Cited By ~ 1

Author(s):

Benjamin Galet ◽

Manuela Ingallinesi ◽

Jonathan Pegon ◽

Anh Do Thi ◽

Philippe Ravassard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

G Protein ◽

Rat Model ◽

Psychiatric Symptoms ◽

Symptomatic Relief ◽

Protein Signaling ◽

G Protein Coupled Receptor ◽

Motor Disability ◽

G Protein Coupled

ABSTRACTBeyond the motor disability, Parkinson’s disease (PD) is also characterized by an early appearance of psychiatric symptoms such as apathy, depression, anxiety and cognitive deficits, which can entail dementia and psychosis in later stages. While current treatments may provide some level of symptomatic relief, their use is limited by the development of adverse effects such as impulse-control disorders. There is thus a medical need for targets with novel modes of action to treat these aspects of PD. In this context, we investigated GPR88, an orphan G-protein coupled receptor that is associated with psychiatric disorders and highly enriched in the striatum, where it exerts an inhibitory control over neurotransmitter systems that are compromised in PD. To evaluate the potential of GPR88 as a target for the treatment of the psychiatric symptoms of PD, we knocked-down (KD) its expression in sensorimotor (dorsolateral, DLS) or associative (dorsomedial, DMS) striatal areas in a translational rat model of early PD. Our findings indicate thatGpr88-KD in the DMS, but not DLS, reduced the alterations in mood, motivation and cognition that characterized the model, through modulation of the expression ofregulator of G-protein signaling 4(Rgs4) and of transcription factor ΔFosB. Furthermore, the rat model of PD exhibited allostatic changes in striatal activity markers that may be related to patterns observed in patients, and which were reduced byGpr88-KD. Taken together, these results thus highlight the relevance of GPR88 as a therapeutic target for the psychiatric symptoms of PD.

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Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

10.1101/246595 ◽

2018 ◽

Cited By ~ 1

Author(s):

Stephen V Mahler ◽

Zachary D Brodnik ◽

Brittney M Cox ◽

William C Buchta ◽

Brandon S Bentzley ◽

...

Keyword(s):

Ventral Tegmental Area ◽

G Protein ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Response Strategy ◽

Neuron Activity ◽

G Protein Signaling ◽

Protein Signaling ◽

Cocaine Seeking ◽

Ventral Tegmental

AbstractVentral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine’s reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.Significance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamine’s complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

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