Key role of the dopamine D(4) receptor in the modulation of corticostriatal glutamatergic neurotransmission

Polymorphic variants of the dopamine D(4) receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D(4) receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D(4) receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D(4) receptor, the expanded intracellular domain of the humanized D(4) receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D(4) receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D(4) receptor–mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.