Dopamine D₁-D₂ Receptor Heteromer Regulates Signaling Cascades Involved in Addiction: Potential Relevance to Adolescent Drug Susceptibility

Abstract

Adolescence is a developmental period that has been associated with heightened sensitivity to psychostimulant-induced reward, thus placing adolescents at increased risk to develop drug addiction. Although alterations in dopamine-induced synaptic plasticity are perhaps the most critical factor in mediating addiction processes, developmental differences in the cell signaling mechanisms that contribute to synaptic plasticity, and their contribution to adolescent reward sensitivity, has been grossly understudied. The most abundant dopamine receptors, the D₁ and D₂ receptors, as well as the dopamine D₁-D₂ receptor heteromer, exhibit age-dependent and brain region-specific changes in their expression and function and are responsible for regulating cell signaling pathways known to significantly contribute to the neurobiological mechanisms underlying addiction. The D₁-D₂ receptor heteromer, for instance, has been associated with calcium calmodulin kinase IIα, brain-derived neurotrophic factor and glycogen synthase kinase 3 (GSK-3) signaling, three proteins highly implicated in the regulation of glutamate transmission and synaptic plasticity and which regulate addiction to amphetamine, opioids and cocaine. Therefore, in this review the importance of these signaling proteins as potential mediators of addiction susceptibility in adolescence will be highlighted, and the therapeutic potential of the D₁-D₂ receptor heteromer in addiction will be discussed. It is the overall goal of this review to draw attention to the research gap in dopamine-induced cell signaling in the adolescent brain - knowledge that would provide much-needed insights into adolescent addiction vulnerability.

Prediction of alcohol drinking in adolescents: Personality-traits, behavior, brain responses, and genetic variations in the context of reward sensitivity

“…Although the present study implicates a strong influence of rs1800497 and rs7713917 on alcohol drinking behavior it has to be prospectively examined via which routes, particularly on a molecular level, their genetic influence becomes manifest. Especially those pathways including D1 and D2 receptors regulating reward would be of great interest for further studies as they have been shown to enhance the brain's reactivity to drug cues (Volkow and Morales, 2015) especially in adolescents (Perreault et al, 2014). The previously mentioned points emphasize the fact that our findings of genetic and personality-related effects have to be considered within the context of our specific model.…”

Sex difference in dopamine D1-D2 receptor complex expression and signaling affects depression- and anxiety-like behaviors

“…Activation of the dopamine D2 receptor (D2R) leads to dephosphorylation and inactivation of Akt [31,32], through a complex consisting of βarrestin2-Akt-protein phosphatase 2A [βarr2-Akt-PP2A] [33], which results in activation and reduced phosphorylation of GSK3 [31][32][33]. Further, GSK3 is constitutively active, and its inhibition by phosphorylation can also be mediated by other kinases, such as PKA, PKC, CaMKII, CDK5 (reviewed, [27,34]). Modulation of GSK3 activity, notably its β subunit, through the βarr2-Akt-PP2A complex is mediated essentially through D2R, to a lesser extent through D3R and did not involve D1R directly [31,33,35,36].…”

Pharmacology of Ultrasonic Vocalizations in adult Rats: Significance, Call Classification and Neural Substrate

“…This finding is relevant to earlier reports indicating that D1 and D2 dopamine receptors can form hetero-oligomers and work in tandems in a synergistic manner, including the ventral striatum [ 120 , 121 ]. The D1-D2 receptor oligomers have distinct signaling properties and were also found in the nucleus accumbens and ventral tegmental area [ 122 , 123 ].…”