Dopamine receptor signaling in the forebrain

Dopamine (DA) is an important modulator of neuronal activity and synaptic plasticity throughout the CNS. The actions of DA are mediated by D₁- and D₂-type receptors, which are distributed presynaptically, postsynaptically, and extrasynaptically, in projection and interneurons. These receptors utilize phosphorylation cascades or direct membrane interactions to affect the function of voltage- and neurotransmitter-gated channels, cytosolic enzymes, and transcription factors. Via these mechanisms, DA receptors have complex effects on neurotransmitter release, neuronal excitability, synaptic integration, synaptic plasticity, and circuit interactions. D₁- and D₂-type receptors may also form complexes with each other and with other receptors, which adds to the complexity and flexibility of dopaminergic signaling. In the CNS, DA receptors are primarily distributed in the striatum and frontal cortex, where they affect action selection, exertion of effort, attention and working memory, behavioral activation, and learning from both rewarding and aversive events. Abnormal DA signaling in these circuits is associated with Parkinson disease (PD), dystonia, schizophrenia, drug addiction, and attention-deficit disorders. The manifestations of these conditions reflect both the direct effects of impaired DA receptor signaling and DA receptor-triggered plastic changes in striatal and cortical synapses. The physiology, signaling, and pharmacology of DA receptors and their involvement in disease have been the subject of several reviews.^1–8