Behavioral control by striatal adenosine A<sub>2A</sub>‐dopamine D<sub>2</sub> receptor heteromers

Taura, Jaume; Valle-León, Marta; Sahlholm, Kristoffer; Watanabe, Masahiko; Craenenbroeck, Kathleen Van; Fernández-Dueñas, Víctor; Ferré, Sergi; Ciruela, Francisco

doi:10.1111/gbb.12432

Cited by 27 publications

(39 citation statements)

References 55 publications

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“…Caesarean derived 1 (CD-1) mice (Janvier Labs, Le Genest-Saint-Isle, France), D 2 R knockout (D 2 R KO) CD-1, and M 1 R knockout (M 1 R KO) C57BL/6J mice were generated as described previously (Fisahn et al, 2002;Taura et al, 2017). Animals were housed and tested in compliance with the guidelines described in the Guide for the Care and Use of Laboratory Animals (Clark et al, 1997) and following the European Communities Council Directive (2010/63/EU), FELASA, and ARRIVE guidelines.…”

Section: Animalsmentioning

confidence: 99%

“…; Tocris Biosciences, Bristol, United Kingdom) 10 min before each locomotor activity test. The mice were evaluated for drug-induced locomotor activity as described previously (Taura et al, 2017). Briefly, non-habituated mice were placed in the center of an activity field apparatus (30 × 30 cm, surrounded by four 50-cm-high black walls) equipped with a camera above to record activity.…”

Section: Locomotor Activity Testsmentioning

confidence: 99%

“…and/or VU0255035 (10 mg/kg, i.p.) was administered, and 1.5 h later, catalepsy was measured as described previously (Massari et al, 2017;Taura et al, 2017). Briefly, using a stopwatch with a cutoff time of 120 s, the duration of an abnormal upright posture was measured, in which the forepaws of the mouse were placed on a horizontal wooden bar (0.6-cm diameter) that was located 4.5 cm above the floor.…”

Section: Horizontal Bar Testmentioning

confidence: 99%

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Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

et al. 2020

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor control deficits, which is associated with the loss of striatal dopaminergic neurons from the substantia nigra. In parallel to dopaminergic denervation, there is an increase of acetylcholine within the striatum, resulting in a striatal dopaminergiccholinergic neurotransmission imbalance. Currently, available PD pharmacotherapy (e.g., prodopaminergic drugs) does not reinstate the altered dopaminergic-cholinergic balance. In addition, it can eventually elicit cholinergic-related adverse effects. Here, we investigated the interplay between dopaminergic and cholinergic systems by assessing the physical and functional interaction of dopamine D 2 and muscarinic acetylcholine M 1 receptors (D 2 R and M 1 R, respectively), both expressed at striatopallidal medium spiny neurons. First, we provided evidence for the existence of D 2 R-M 1 R complexes via biochemical (i.e., co-immunoprecipitation) and biophysical (i.e., BRET 1 and NanoBiT R ) assays, performed in transiently transfected HEK293T cells. Subsequently, a D 2 R-M 1 R co-distribution in the mouse striatum was observed through doubleimmunofluorescence staining and AlphaLISA R immunoassay. Finally, we evaluated the functional interplay between both receptors via behavioral studies, by implementing the classical acute reserpine pharmacological animal model of experimental parkinsonism. Reserpinized mice were administered with a D 2 R-selective agonist (sumanirole) and/or an M 1 R-selective antagonist (VU0255035), and alterations in PD-related behavioral tasks (i.e., locomotor activity) were evaluated. Importantly, VU0255035 (10 mg/kg) potentiated the antiparkinsonian-like effects (i.e., increased locomotor activity and decreased catalepsy) of an ineffective sumanirole dose (3 mg/kg). Altogether, our data suggest the existence of putative striatal D 2 R/M 1 R heteromers, which might be a relevant target to manage PD motor impairments with fewer adverse effects.

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Section: Animalsmentioning

confidence: 99%

Section: Locomotor Activity Testsmentioning

confidence: 99%

Section: Horizontal Bar Testmentioning

confidence: 99%

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Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

et al. 2020

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“…However, as mentioned before, we now know that the canonical interaction requires receptor heteromerization ( Navarro et al, 2018 ). Therefore, we recently performed new studies on the behavioral effects of SCH 442416 upon genetic blockade of A2AR or D2R and upon administration of the A2AR agonist CGS 21680 and the D2R antagonist haloperidol, to reevaluate if they could all be explained within the framework of a predominant population of striatal postsynaptic A2AR-D2R heteromers ( Taura et al, 2017 ).…”

Section: Revisiting the Behavioral Effects Of Adenosine Receptor Ligamentioning

confidence: 99%

Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

et al. 2018

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The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson’s disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.

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“…One of the explanations for antagonistic interactions may be that the A1R activation within the heteromer changes the binding of dopamine to D1 receptors [31]. Similarly, A 2A R-D2Rs also display antagonistic interactions [32,33]. As a key modulator of striatal neuronal activity, the balance between A 2A R and D2R is essential for the function of heteromers.…”

Section: Introductionmentioning

confidence: 99%

Effects of 7-Methylxanthine on Deprivation Myopia and Retinal Dopamine Release in Chickens

Liu

Schaeffel

Trier³

et al. 2019

Ophthalmic Res

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Introduction: Intake of 7-methylxanthine (7-MX), an adenosine receptor (AR) antagonist, has been shown to inhibit school myopia in children and deprivation myopia in rhesus monkeys, but the underlying mechanisms are not known. Also retinal dopamine seems to be involved in the control of eye growth, and in the brain, ARs and dopamine receptors interact widely by heteromerization. We have studied whether 7-MX can inhibit deprivation myopia also in chickens and whether inhibition may involve the retinal dopamine system. Methods: 7-MX was applied by either tubefeeding (100 µg/g body weight, twice a day) or intravitreal injection (12.5 µg, every other day). Forty-eight 2-week-old chicks wore unilateral diffusers and were randomly assigned to either the tube-feeding group (involving 7-MX, vehicle [xanthan gum], or no feeding, for 13 days) or the intravitreal injection group (involving 7-MX, vehicle, or DMSO, for 8 days). Refractions (REs), ocular biometry (AL, VCD), and scleral and choroidal thickness (ChT) were measured before and after treatment. Dopamine and dihydroxyphenylacetic acid (DOPAC) content were determined in retina and vitreous by HPLC at the end of the experiments. Results: No matter how 7-MX was applied, it did not inhibit deprivation myopia in chicks. No significant differences were observed in RE, VCD, AL, and scleral fibrous layer thickness. Feeding 7-MX produced more choroidal thinning in the open contralateral eye compared to control eyes in the vehicle-fed group (-40 ± 14 vs. -1 ± 7 µm, unpaired t test, p < 0.05). DOPAC and dopamine concentration in vitreous and DOPAC concentration in retina did not change with 7-MX. Vitreal dopamine content was significantly decreased in deprived eyes in the groups fed with the vehicle xanthan gum (paired t test, p < 0.01) but not in 7-MX-treated eyes, perhaps indicating a small effect of 7-MX on dopamine. Conclusions: In our study, 7-MX had no effect on DM in chicks and only minor effects on ChT and retinal dopamine. It remains unclear whether 7-MX inhibits myopia through a retinal mechanism or whether it acts directly on choroid and sclera. In the latter case, the finding that myopia is suppressed in mammals but not birds might be explained by differences in scleral structure.

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Behavioral control by striatal adenosine A_2A‐dopamine D₂ receptor heteromers

Cited by 27 publications

References 55 publications

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

Effects of 7-Methylxanthine on Deprivation Myopia and Retinal Dopamine Release in Chickens

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Behavioral control by striatal adenosine A2A‐dopamine D2 receptor heteromers

Cited by 27 publications

References 55 publications

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

Effects of 7-Methylxanthine on Deprivation Myopia and Retinal Dopamine Release in Chickens

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Behavioral control by striatal adenosine A_2A‐dopamine D₂ receptor heteromers