Effects of adenosine A2A receptor stimulation in vivo on dopamine D3 receptor agonist binding in the rat brain

doi:10.1016/S0006-2952(99)00276-2

Biochemical Pharmacology

Volume 58, Issue 12, 15 December 1999, Pages 1961-1964

https://doi.org/10.1016/S0006-2952(99)00276-2 Get rights and content

Abstract

To investigate if adenosine A_2A receptor stimulation in vivo modulates dopamine D₃ receptor binding, we analyzed the effects of 2-[p-(carboxyethyl)-phenylethylamino]-5′-N-ethylcarboxyamidoadenosine (CGS 21680) on the binding properties of the selective D₃ receptor agonist [N-propyl-2,3,-³H]4aR,10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl2H,5H-[1]benzopyrano[4,3-b]1,4-oxazin-9-ol ([³H]PD 128907) in the rat forebrain using quantitative autoradiography. Intraperitoneally administered CGS 21680 (0.1–3 mg/kg) increased the K_dand B_maxvalues of [³H]PD 128907 binding in the islands of Calleja and in subregions of the caudate-putamen. These results suggest that stimulation of adenosine A_2Areceptors in vivo causes alterations in the binding characteristics of dopamine D₃ receptors in the basal ganglia, and that this effect may relate to the neuroleptic-like effect of adenosine A_2A receptor agonists.

Section snippets

Materials and methods

Male specific pathogen-free Sprague–Dawley rats (250 g; about 45 days old; Alab) were used. The rats were injected intraperitoneally (i.p.; 1.25 mL/rat) with CGS 21680 (0.1–3 mg/kg; Research Biochemicals Inc.) or with 0.9% sodium chloride alone one hour before decapitation. All experimental treatments were approved by the Swedish Committee for Ethical Experiments on Laboratory Animals. Some of the rats had also been used in a previous study [10]. After decapitation with a guillotine, the brains

Results and discussion

[³H]PD 128907 binding was localized to the islands of Calleja, islands of Calleja major, accumbens nucleus (core and shell), and caudate-putamen (Fig. 1). The binding of [³H]PD 128907 in the cerebral cortex was too low to be analyzed with regard to ic₅₀ values, B₀ values of the control group being 2.6 ± 0.7 fmol/mg protein, N = 5. The binding in the caudate-putamen was measured in two subregions as defined by the marked differences in binding levels. The caudate-putament subregion 1 may

Acknowledgements

This work was supported by the Swedish MRC (Grants 10377 and 12593) and grants from the Karolinska Institutet. P.B. H. was supported by the Swedish Brain Foundation.

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Adenosine is a neuroregulatory nucleoside that acts through four G protein-coupled receptors (GPCRs), A₁, A_2A, A_2B and A₃, which are widely expressed in cells of the nervous system. The A_2A receptor (A_2AR), the GPCR with the highest expression in the striatum, has a similar role to that of receptors for dopamine, one of the main neurotransmitters. Neuronal and glial A_2ARs participate in the modulation of dopaminergic transmission and act in almost any action in which the basal ganglia is involved. This chapter revisits the expression of the A_2AR in the basal ganglia in health and disease, and describes the diversity of signalling depending on whether the receptors are expressed as monomer or as heteromer. The A_2AR can interact with other receptors as adenosine A₁, dopamine D₂, or cannabinoid CB₁ to form heteromers with relevant functions in the basal ganglia. Heteromerization, with these and other GPCRs, provides diversity to A_2AR-mediated signalling and to the modulation of neurotransmission. Thus, selective A_2AR antagonists have neuroprotective potential acting directly on neurons, but also through modulation of glial cell activation, for example, by decreasing neuroinflammatory events that accompany neurodegenerative diseases. In fact, A_2AR antagonists are safe and their potential in the therapy of Parkinson’s disease has already led to the approval of one of them, istradefylline, in Japan and United States. The receptor also has a key role in reward circuits and, again, heteromers with dopamine receptors, but also with cannabinoid CB₁ receptors, participate in the events triggered by drugs of abuse.
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Citation Excerpt :
Antagonists specific to the D3 receptor have been suggested for treatment of psychotic and cognitive symptoms of schizophrenia (Gross et al., 2013; Sokoloff et al., 2013) and drug addiction (Heidbreder and Newman, 2010). Previous reports have shown that the A2A receptor modulates the ligand binding affinity of the D3 receptor (Hillefors et al., 1999). In addition, fluorescence resonance energy transfer (FRET) studies demonstrated that A2A receptor forms heteromeric complex with D3 receptor in which it antagonistically modulates signaling of D3 receptor (Torvinen et al., 2005).
G protein-coupled receptors (GPCRs) are transmembrane receptors that mediate a large number of cellular responses. The organization of GPCRs into dimers and higher-order oligomers is known to allow a larger repertoire of downstream signaling events. In this context, a crosstalk between the adenosine and dopamine receptors has been reported, indicating the presence of heterodimers that are functionally relevant. In this paper, we explored the effect of membrane cholesterol on the adenosine_2A (A_2A) and dopamine D₃ (D₃) receptors using coarse-grain molecular dynamics simulations. We analyzed cholesterol interaction sites on the A_2A receptor and were able to reproduce the sites indicated by crystallography and previous atomistic simulations. We predict novel cholesterol interaction sites on the D₃ receptor that could be important in the reported cholesterol sensitivity in receptor function. Further, we analyzed the formation of heterodimers between the two receptors. Our results suggest that membrane cholesterol modulates the relative population of several co-existing heterodimer conformations. Both direct receptor-cholesterol interaction and indirect membrane effects contribute toward the modulation of heterodimer conformations. These results constitute one of the first examples of modulation of GPCR hetero-dimerization by membrane cholesterol, and could prove to be useful in designing better therapeutic strategies.
Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A<inf>2A</inf> receptor ligands in rat, mouse and pig brain and first ex vivo results
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Biochemical Pharmacology

Abstract

Section snippets

Materials and methods

Results and discussion

Acknowledgements

References (19)

RDC8 codes for an adenosine A₂ receptor with physiological constitutive activity

Biochem Biophys Res Commun

The cellular localization of adenosine receptors in rat neostriatum

Neuroscience

Adenosine A_2a receptors in the nucleus accumbens mediate locomotor depression

Brain Res Bull

Stimulation of adenosine A₂ receptors induces catalepsy

Neurosci Lett

Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia

Trends Neurosci

Adenosine A_2A receptors modulate the binding characteristics of dopamine D₂ receptors in stably cotransfected fibroblast cells

Eur J Pharmacol

Effects of CGS 21680 in vivo on dopamine D₂ agonist binding in the rat brain

Brain Res

Prominent binding of the dopamine D₃ agonist [³H]PD 128907 in the caudate-putamen of the adult rat

Brain Res

Characterization of binding of [³H]PD 128907, a selective dopamine D₃ receptor agonist ligand, to CHO-K1 cells

Life Sci

Cited by (13)

The adenosine A<inf>2A</inf> receptor in the basal ganglia: Expression, heteromerization, functional selectivity and signalling

Role of cholesterol-mediated effects in GPCR heterodimers

Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A<inf>2A</inf> receptor ligands in rat, mouse and pig brain and first ex vivo results

Evidence for protein–protein interaction between dopamine receptors and the g protein-coupled receptor 143

Adenosine receptors as a paradigm to identify dimer/oligomers of G-protein-coupled receptors and as targets in parkinson’s disease and schizophrenia

Targeting the dopamine D3 receptor: an overview of drug design strategies

NeuroscienceEffects of adenosine A2A receptor stimulation in vivo on dopamine D3 receptor agonist binding in the rat brain

Abstract

Section snippets

Materials and methods

Results and discussion

Acknowledgements

Biochem Biophys Res Commun

Neuroscience

Brain Res Bull

Neurosci Lett

Trends Neurosci

Eur J Pharmacol

Brain Res

Brain Res

Life Sci

Neuroscience
Effects of adenosine A_2A receptor stimulation in vivo on dopamine D₃ receptor agonist binding in the rat brain