Abstract
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 in situ PLA, in situ 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.
Highlights
There is significant evidence for the involvement of mesolimbic and striatal dopamine (DA) transmission in mediating different aspects of reward, as well as aversion, with particular importance for the nucleus accumbens (NAc)
The Proximity Ligation Assay (PLA) performed with the well-validated primary antibodies (Lee et al, 2004; Perreault et al, 2010, 2016; present study) to D1 receptor (D1R) (Rat, Sigma D2944) and D2 receptor (D2R) (Rabbit, Millipore AB5084) showed PLA signals visualized as clear fluorescent red signals at the cell body, suggesting a close proximity of D1R and D2R in medium spiny neurons (MSNs) of rat caudate putamen (CPu), NAc-core and NAc-shell (Figures 1A2–A4)
Using a second set of antibodies which consisted of the same anti-D1R and an antibody generated against D2R by that group (Frederick et al, 2015) and commercialized by Millipore (ABN 462), we detected a clear PLA signal in rat NAc (Figure 1A6) indicating the presence of D1-D2 heteromers
Summary
There is significant evidence for the involvement of mesolimbic and striatal dopamine (DA) transmission in mediating different aspects of reward, as well as aversion, with particular importance for the nucleus accumbens (NAc) (reviewed in Salamone and Correa, 2012). There is, a significant subpopulation of neurons that coexpress both D1R and D2R (Meador-Woodruff et al, 1991; Deng et al, 2006; Gangarossa et al, 2013; Gagnon et al, 2017) to form a D1-D2 receptor complex in the NAc (Hasbi et al, 2009; Perreault et al, 2010, 2016; Rico et al, 2017) The involvement of these MSNs and the role of the D1-D2 heteromer complex activation in the modulation of brain reward functions and addiction mechanisms have not been studied. The neurons expressing dopamine D1-D2 receptor heteromer in the NAc were able to influence neurotransmission within the ventral tegmental area (VTA) and substantia nigra (Perreault et al, 2012)
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