Abstract
Dopamine D2 autoreceptors (D(2)ARs), located in somatodendritic and axon terminal compartments of dopamine (DA) neurons, function to provide a negative feedback regulatory control on DA neuron firing, DA synthesis, reuptake and release. Dysregulation of D(2)AR-mediated DA signaling is implicated in vulnerability to substance use disorder (SUD). Due to the extreme low abundance of D(2)ARs compared to postsynaptic D(2) receptors (D(2)PRs) and the lack of experimental tools to differentiate the signaling of D(2)ARs from D(2)PRs, the regulation of D(2)ARs by drugs of abuse is poorly understood. The recent availability of conditional D(2)AR knockout mice and newly developed virus-mediated gene delivery approaches have provided means to specifically study the function of D(2)ARs at the molecular, cellular and behavioral levels. There is a growing revelation of novel mechanisms and new proteins that mediate D(2)AR activity, suggesting that D(2)ARs act cooperatively with an array of membrane and intracellular proteins to tightly control DA transmission. This review highlights D(2)AR-interacting partners including transporters, G-protein-coupled receptors, ion channels, intracellular signaling modulators, and protein kinases. The complexity of the D(2)AR interaction network illustrates the functional divergence of D(2)ARs. Pharmacological targeting of multiple D(2)AR-interacting partners may be more effective to restore disrupted DA homeostasis by drugs of abuse.