Effects of cocaine self‐administration and extinction on D₂‐like and A_2A receptor recognition and D₂‐like/G_i protein coupling in rat striatum

Abstract

Striatal adenosine (A)2 -dopamine (D)2 receptor (R) heteromers exist with antagonistic interactions. We have studied these Rs and their interactions during cocaine self-administration and extinction using a 'yoked' protocol to understand the role of motivational mechanisms behind the adaptive observed. In the ventral striatum, a significant increase in the A2A R density was observed in rats that received 'yoked' cocaine during maintenance phase and following its extinction while this significant increase was only observed after extinction from cocaine self-administration. In the dorsal striatum, a significant increase in the affinity of A2A Rs was determined in the two groups of rats that received cocaine during maintenance. D2 -like Rs were significantly increased in the dorsal striatum of animals that received 'yoked' cocaine during maintenance. In the rat dorsal, but not the ventral, striatum significant reductions in the EC50 values for dopamine and increases in the guanosine5'-([γ]-thio)triphosphate (GTPγS) accumulation were observed following active and passive cocaine injections during maintenance. After 10-day extinction, a significant reduction of the Bmax value of GTPγS accumulation was demonstrated in the dorsal striatum of rats previously self-administered cocaine, while a significant reduction of the EC50 value for dopamine in the ventral striatum was found in the 'yoked' cocaine group. By comparing the cocaine self-administration group with the 'yoked' cocaine group, evidence for the existence of motivational mechanisms that guide adaptive changes in the A2A R and D2 R and in the D2 -Gi coupling differentially developed in the ventral and dorsal striatum during cocaine maintenance and its extinction has been demonstrated.