An astroglia-linked dopamine D2-receptor action in prefrontal cortex

Typical neuroleptic drugs elicit their antipsychotic effects mainly by acti ng as antagonists at dopamine D2 receptors. Much of this activity is though t to occur in the cerebral cortex, where D2 receptors are found largely in inhibitory GABAergic neurons. Here we confirm this localization at the elec tron microscopic level, but additionally show that a subset of cortical int erneurons with low or undetectable expression of D2 receptor isoforms are s urrounded by astrocytic processes that strongly express D2 receptors. Ligan d binding of isolated astrocyte preparations indicate that cortical astrogl ia account for approximately one-third of the total D2 receptor binding sit es in the cortex, a proportion that we found conserved among rodent, monkey , and human tissues. Further, we show that the D2 receptor-specific agonist , quinpirole, can induce Ca2+ elevation in isolated cortical astrocytes in a pharmacologically reversible manner, thus implicating this receptor in th e signaling mechanisms by which astrocytes communicate with each other as w ell as with neurons. The discovery of D2 receptors in astrocytes with a sel ective anatomical relationship to interneurons represents a neuron/glia sub strate for cortical dopamine action in the adult cerebral cortex and a prev iously unrecognized site of action for antipsychotic drugs with affinities at the D2 receptor.