Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ΔFosB

• Published in: Frontiers in pharmacology Vol. 8; p. 924
• Main Authors: Hasbi, Ahmed, Perreault, Melissa L, Shen, Maurice Y F, Fan, Theresa, Nguyen, Tuan, Alijaniaram, Mohammed, Banasikowski, Tomek J, Grace, Anthony A, O'Dowd, Brian F, Fletcher, Paul J, George, Susan R
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04.01.2018
• Subjects: addiction and addiction behaviors; DARPP-32; deltaFosB; dopamine D1-D2 heteromer; dopamine signaling; Pharmacology; proximity ligation assay; dopamine signaling; addiction treatment; addiction and addiction behaviors; DARPP-32; dopamine D1-D2 heteromer; FRET; proximity ligation assay; deltaFosB
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2017.00924

A significant subpopulation of neurons in rat nucleus accumbens (NAc) coexpress dopamine D1 and D2 receptors, which can form a D1-D2 receptor complex, but their relevance in addiction is not known. The existence of the D1-D2 heteromer in the striatum of rat and monkey was established using PLA, FRET and co-immunoprecipitation. In rat, D1-D2 receptor heteromer activation led to place aversion and abolished cocaine CPP and locomotor sensitization, cocaine intravenous self-administration and reinstatement of cocaine seeking, as well as inhibited sucrose preference and abolished the motivation to seek palatable food. Selective disruption of this heteromer by a specific interfering peptide induced reward-like effects and enhanced the above cocaine-induced effects, including at a subthreshold dose of cocaine. The D1-D2 heteromer activated Cdk5/Thr75-DARPP-32 and attenuated cocaine-induced pERK and ΔFosB accumulation, together with inhibition of cocaine-enhanced local field potentials in NAc, blocking thus the signaling pathway activated by cocaine: D1R/cAMP/PKA/Thr34-DARPP-32/pERK with ΔFosB accumulation. In conclusion, our results show that the D1-D2 heteromer exerted tonic inhibitory control of basal natural and cocaine reward, and therefore initiates a fundamental physiologic function that limits the liability to develop cocaine addiction.