Dysregulation of Dopamine Transporters via Dopamine D2 Autoreceptors Triggers Anomalous Dopamine Efflux Associated with Attention-Deficit Hyperactivity Disorder

The neurotransmitter dopamine (DA) modulates brain circuits involved in attention, reward, and motor activity. Synaptic DA homeostasis is primarily controlled via two presynaptic regulatory mechanisms, DA D-2 receptor (D2R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D(2)Rs can physically associate with DAT and regulate DAT function, linking DA release and reuptake to a common mechanism. We have established that the attention-deficit hyperactivity disorder-associated human DAT coding variant Ala559Val (hDAT A559V) results in anomalous DA efflux (ADE) similar to that caused by amphetamine-like psychostimulants. Here, we show that tonic activation of D2R provides support for hDAT A559V-mediated ADE. We determine in hDAT A559V a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports D2R-driven DA efflux. These studies identify a signaling network downstream of D2R activation, normally constraining DA action at synapses, that may be altered by DAT mutation to impact risk for DA-related disorders.