Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the striatum. Relevance for cocaine use disorder.
In the current study behavioral and biochemical experiments were performed to study changes in the allosteric A2AR-D2R interactions in the ventral and dorsal striatum after cocaine self-administration versus corresponding yoked saline control. By using ex vivo [(3)H]-raclopride/quinpirole competition experiments, the effects of the A2AR agonist CGS 21680 (100 nM) on the KiH and KiL values of the D2-like receptor (D2-likeR) were determined. One major result was a significant reduction in the D2-likeR agonist high affinity state observed with CGS 21680 after cocaine self-administration in the ventral striatum compared with the yoked saline group. The results therefore support the hypothesis that A2AR agonists can at least in part counteract the motivational actions of cocaine. This action is mediated via the D2-likeR by targeting the A2AR protomer of A2AR-D2-like R heteroreceptor complexes in the ventral striatum, which leads to the reduction of D2-likeR protomer recognition through the allosteric receptor-receptor interaction. In contrast, in the dorsal striatum the CGS 21680-induced antagonistic modulation in the D2-likeR agonist high affinity state was abolished after cocaine self-administration versus the yoked saline group probably due to a local dysfunction/disruption of the A2AR-D2-like R heteroreceptor complexes. Such a change in the dorsal striatum in cocaine self-administration can contribute to the development of either locomotor sensitization, habit-forming learning and/or the compulsive drug seeking by enhanced D2-likeR protomer signaling. Potential differences in the composition and stoichiometry of the A2AR-D2R heteroreceptor complexes, including differential recruitment of sigma 1 receptor, in the ventral and dorsal striatum may explain the differential regional changes observed in the A2A-D2-likeR interactions after cocaine self-administration.
['Pintsuk|Julia|J|', 'Borroto-Escuela|Dasiel O|DO|', 'Pomierny|Bartosz|B|', 'Wydra|Karolina|K|', 'Zaniewska|Magdalena|M|', 'Filip|Malgorzata|M|', 'Fuxe|Kjell|K|']
D000494:Allosteric Regulation D000818:Animals D003042:Cocaine D019970:Cocaine-Related Disorders D003342:Corpus Striatum D008297:Male D011485:Protein Binding D051381:Rats D017208:Rats, Wistar D043705:Receptor, Adenosine A2A D017448:Receptors, Dopamine D2 D012646:Self Administration
Cocaine self-administration Heteroreceptor complex Allosteric receptor-receptor interactions Addiction Adenosine A2A receptor Dopamine D2 receptor