The role of D2-autoreceptors in regulating dopamine neuron activity and transmission

Abstract

Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine. These Gi/o-coupled inhibitory receptors play a major part in shaping dopamine transmission. Found at both somatodendritic and axonal sites, autoreceptors regulate the firing patterns of dopamine neurons and control the timing and amount of dopamine released from their terminals in target regions. Alterations in the expression and activity of autoreceptors are thought to contribute to Parkinson's disease as well as schizophrenia, drug addiction and attention-deficit hyperactivity disorder (ADHD), which emphasizes the importance of D2-autoreceptors in regulating the dopamine system. This review will summarize the cellular actions of dopamine autoreceptors and discuss recent advances that have furthered our understanding of the mechanisms by which D2-receptors control dopamine transmission.

Keywords: GPCR; VTA; cocaine; psychostimulants; substantia nigra.

Fig 1

Schematic illustrating D2-autoreceptor signaling and regulation of dopamine transmission at axon terminals in the striatum. At presynaptic terminals D2-receptors regulate the release, uptake and synthesis of dopamine. (1) Autoreceptors inhibit the probability of dopamine vesicle release by activating K_v1.2 channels and also potentially secondarily by inhibiting calcium entry through of voltage-gated calcium channels (VGCC). (2) Presynaptically D2-receptors increase the rate of dopamine uptake by increasing the plasma membrane expression of DAT and also by direct interactions that increase the activity of existing DATs. (3) Long-term activation of D2-autoreceptors leads to decreased PKA-mediated phosphorylation of TH leading to decreased synthesis and packaging of dopamine in vesicles.

Fig 2

Somatodendritic activation of D2-receptors mediates an inhibitory post-synaptic current that hyperpolarizes dopamine cells and causes a pause in firing. (A) Schematic illustrating the somatodendritic activation of D2-autoreceptors and GIRK2 channels in the VTA and SNc. GIRK2 channel activation and the associated efflux of potassium occurs though a G-protein βγ-mediated membrane delimited mechanism. (B) A train of extracellular stimuli evokes the local release of dopamine (modified from Courtney et al., 2012). The high concentration of dopamine activating D2-receptors leads to rapid activation of a D2-IPSC that is sufficient to cause a temporary pause in the firing of a VTA dopamine neuron.