Heteromerization between α adrenoceptors and different polymorphic variants of the dopamine D receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

Polymorphic alleles of the human dopamine D receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D receptor variant and attention deficit hyperactivity disorder (ADHD). The α adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α adrenoceptor (αR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D receptor (DR) and αR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of DR to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the αR forms functional heteromers with DR and weather these heteromers show different properties depending on the DR variant involved. Using cortical brain slices from hDR knock-in and wild-type mice, here, we demonstrate that αR and DR heteromerize and constitute a significant functional population of cortical αR and DR. Moreover, in cortical slices from wild-type mice and in cells transfected with αR and DR, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hDR knock-in mice and in cells expressing the DR polymorphic variant. We also show a lack of efficacy of DR ligands to promote G protein activation and signaling only within the αR-DR heteromer. Taken together, our results suggest that αR-DR heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.