Abstract
BackgroundAntagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR–D2R interaction disappeared in the dorsal striatum.MethodsIn the current experiments, it was tested whether such modifications in the antagonistic A2AR–D2R receptor–receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc).ResultsMicrodialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R Ki, Low values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group.ConclusionsThe molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR–D2R receptor–receptor interactions may be an increased formation of higher-order complexes A2AR–D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR–D2R interaction in this receptor complex.
Highlights
Competition assays were performed in dorsal striatal membrane preparations from the control group with/without the adenosine A2A receptor agonist (CGS-21680) or A2A receptor agonist (CGS-21680) plus antagonist (ZM-241385) as indicated. (+)-Butaclamol 100 μM was used to determine the non-specific binding. a The curves based on the values of four rats with each determination performed in duplicates or triplicates are presented in percent of specific binding
The specific binding of the [3H]-raclopride without quinpirole was defined as one hundred percent. b The induced changes in the D2 receptor (D2R) affinities values by A2A receptor (A2AR) agonist CGS-21680 are presented in absolute values
Biochemical binding studies using the D2-like receptor radioligand [3H]-raclopride in competition with the D2-like receptor agonist quinpirole demonstrated that the percent increases of Ki, High and Ki, Low values induced by the A2AR agonist CGS-21680 were significantly more marked in membrane preparations from cocaine-injected rats
Summary
It is established that there exist antagonistic adenosine A2A receptor (A2AR)-dopamine (DA) D2 receptor (D2R) interactions in higher-order A2AR–D2R heteroreceptor complexes in cellular models and in the rat dorsal striatum, as Wilber Romero-Fernandez and Zilong Zhou have contributed to this work.Extended author information available on the last page of the article demonstrated with biochemical binding techniques using D2R radioligands and proximity ligation assay [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. It is of interest that following cocaine self-administration, the A2AR agonist-induced antagonistic modulation of the dorsal striatal D2-likeR agonist high-affinity binding site no longer develops [7]. Antagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Conclusions The molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR– D2R receptor–receptor interactions may be an increased formation of higher-order complexes A2AR–D2R-sigma1R in which cocaine by binding to the sigma1R protomer allosterically enhances the inhibitory A2AR–D2R interaction in this receptor complex
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