AbstractThe functional role of the dopamine D₄ receptor (D₄R) and its main polymorphic variants has become more evident with the demonstration of heteromers of D₄R that control the function of frontal cortico-striatal neurons. Those include heteromers with the α_2A adrenoceptor (α_2AR) and with the D₂R, localized in their cortical somato-dendritic region and striatal nerve terminals, respectively. By using biophysical and cell-signaling methods and heteromer-disrupting peptides in mammalian transfected cells and rat brain slice preparations, here we provide evidence for a new functionally relevant D₄R heteromer, the α_1AR-D₄R heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of α_1AR with the D_4.4R and D_4.7R polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between α_1AR and D₄R ligands could be demonstrated for both α_1AR-D_4.4R and α_1AR-D_4.7R heteromers on G protein-independent signaling, but only for α_1AR-D_4.4R on G protein-dependent signaling. From these functional differences, it is proposed that the D_4.4R variant provides a gain of function of the α_1AR-mediated noradrenergic stimulatory control of cortico-striatal glutamatergic neurotransmission, which could result in a decrease in the vulnerability for impulse control-related neuropsychiatric disorders and increase in the vulnerability for posttraumatic stress disorder.