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Impact of an Adenosine A(2A) Receptor Agonist and Antagonist on Binding of the Dopamine D(2) Receptor Ligand [(11)C]raclopride in the Rodent Striatum

[Image: see text] Adenosine A(2A) and dopamine D(2) receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A(2A) receptor-mediated modulation of D(2) receptor binding in vivo...

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Detalles Bibliográficos
Autores principales: Prasad, Kavya, de Vries, Erik F. J., Sijbesma, Jürgen W. A., Garcia-Varela, Lara, Vazquez-Matias, Daniel A., Moraga-Amaro, Rodrigo, Willemsen, Antoon T. M., Dierckx, Rudi A. J. O., van Waarde, Aren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346611/
https://www.ncbi.nlm.nih.gov/pubmed/35849844
http://dx.doi.org/10.1021/acs.molpharmaceut.2c00450
Descripción
Sumario:[Image: see text] Adenosine A(2A) and dopamine D(2) receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A(2A) receptor-mediated modulation of D(2) receptor binding in vivo using positron emission tomography (PET) with the D(2) antagonist tracer [(11)C]raclopride. Healthy male Wistar rats (n = 8) were scanned (60 min dynamic scan) with [(11)C]raclopride at baseline and 7 days later following an acute administration of the A(2A) agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BP(ND)) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [(11)C]raclopride BP(ND) (p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BP(ND) from the k(3)/k(4) ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [(11)C]raclopride scans after pretreatment with a vehicle (n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A(2A) antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k(3)/k(4) ratio (p < 0.01), but k(3) and k(4) estimates may be less reliable. The BP(ND) (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (p = 0.080) or 1.961 ± 0.11 (p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A(2A) agonist CGS21680, but not the antagonist KW6002, may reduce the D(2) receptor availability in the striatum.