Understanding the Functional Plasticity in Neural Networks of the Basal Ganglia in Cocaine Use Disorder: A Role for Allosteric Receptor-Receptor Interactions in A2A-D2 Heteroreceptor Complexes

Figure 2

((a) Dorsal striatum) Yoked saline group. The high density of D2R-sigma1R [14, 15] leads to an increased formation of A2AR-D2R-sigma1R heterocomplexes which together with the A2AR-D2R heterocomplexes can be in dominance over D2 homoreceptor complexes. This can help explain the significant antagonistic A2AR-D2R interaction observed [16]. Cocaine self-administration (maintenance) group. Cocaine can bind to the sigma1R [17] but does not increase its recruitment to the plasma membrane in the dorsal striatum [18]. Instead, it is proposed that the major change induced by cocaine can be the increase in extracellular DA levels which is postulated to increase the formation of D2R homoreceptor complexes. Due to competition, this can reduce the number of A2AR-D2R and A2AR-D2R-sigma1R heteroreceptor complexes. As a result, the antagonistic allosteric A2AR-D2R interactions disappear [16]. ((b) Ventral striatum) Yoked saline group. The lower density of D2R-sigma-1R, especially in nuc accumbens core [14, 15], may lead to the preferential formation of D2R-sigma1R heterocomplexes in view of a possible higher affinity of sigma1R for D2R monomer-homoreceptor complexes versus the affinity for the A2AR-D2R heteroreceptor complexes. Due to competition, the A2AR-D2R heteroreceptor complexes will become reduced and only weak nonsignificant antagonistic A2AR-D2R interactions develop. Cocaine self-administration (maintenance) group. Upon cocaine self-administration, cocaine can here increase sigma1R expression [18] and increase its recruitment to the plasma membrane where it interacts with D2R potentially at several interfaces. In view of the marked increase of sigma1R in the plasma membrane increased formation of A2AR-D2R-sigma1R heteroreceptor complexes can develop with restoration of significant antagonistic A2AR-D2R interactions [16] in spite of increases in extracellular DA levels postulated to favour D2R homodimerization.

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