Key role of the dopamine D₄ receptor in the modulation of corticostriatal glutamatergic neurotransmission.

Polymorphic variants of the dopamine D₄ receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D₄ 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 D₄ 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 D₄ receptor, the expanded intracellular domain of the humanized D₄ 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 D₄ receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D₄ receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.

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