Dopamine D₁-D₂ receptor heteromer regulates signaling cascades involved in addiction: potential relevance to adolescent drug susceptibility.

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.