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

Abstract

Typical neuroleptic drugs elicit their antipsychotic effects mainly by acting as antagonists at dopamine D2 receptors. Much of this activity is thought to occur in the cerebral cortex, where D2 receptors are found largely in inhibitory GABAergic neurons. Here we confirm this localization at the electron microscopic level, but additionally show that a subset of cortical interneurons with low or undetectable expression of D2 receptor isoforms are surrounded by astrocytic processes that strongly express D2 receptors. Ligand binding of isolated astrocyte preparations indicate that cortical astroglia account for approximately one-third of the total D2 receptor binding sites 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 Ca 2؉ elevation in isolated cortical astrocytes in a pharmacologically reversible manner, thus implicating this receptor in the signaling mechanisms by which astrocytes communicate with each other as well as with neurons. The discovery of D2 receptors in astrocytes with a selective anatomical relationship to interneurons represents a neuron͞glia substrate for cortical dopamine action in the adult cerebral cortex and a previously unrecognized site of action for antipsychotic drugs with affinities at the D2 receptor. The circuit basis of all cortical functions involve a balance between excitation and inhibition, and recent studies in this laboratory have begun to reveal the mechanisms by which interneurons exert control on cognitive processes mediated by prefrontal circuits (1, 2). D2 family receptors are among the neurotransmitter receptors through which inhibitory actions are signaled in the cortex (3-6). Previous light microscopic investigations have revealed that prefrontal cortical neurons express the D2S and D2L isoforms (4). Here, we report the ultrastructural localization of these D2 receptor isoforms. Knowledge of the precise cellular disposition of these receptors could have relevance to the differential effects of typical and atypical neuroleptic drugs as well as the modulation of cognitive processes carried out by prefrontal circuits. Materials and MethodsImmunocytochemistry. Affinity-purified anti-D2 polyclonal antibodies were used for anatomical studies at both light and electron microscopic levels, as described in detail in ref. 4. The specificity of these antibodies to both the short and long isoforms of the dopamine D2 receptor has been demonstrated (4). In brief, sections from four perfused monkey brains were incubated with anti-D2 antibodies and further processed by incubation with either biotinylated goat anti-rabbit antibodies (Jackson Immuno-Research) or goat anti-rabbit antibodies coupled to 1.4-nm gold particles (Nanoprobes, Stony Brook, NY). The bound anti-D2 antibodies were visualized by the immunoperoxidase method using the ABC Elite kit (Vector Laboratories) or by silver enhancement of gold particles (Nanoprobes). Double-label immunof luorescence studie...

Microdomains for Dopamine Volume Neurotransmission in Primate Prefrontal Cortex

“…The SSCs were almost exclusively localized in the perisomatic region of pyramidal cells, whereas they occurred rarely in perikarya and were virtually absent from the proximal processes of interneurons (see Materials and Methods for identification criteria). These rarely occurring SSCs in nonpyramidal neurons were never seen in association with DARs [see Khan et al (2001) for D 2 R, Muly et al (1998) for D 1 R]. In addition, both the D 5 R protein and D 5 R mRNA are localized predominantly in pyramidal neurons (Bergson et al, 1995a;Ariano et al, 1997;Ciliax et al, 2000).…”

Serum S100B is increased during early treatment with antipsychotics and in deficit schizophrenia

“…Thus, the data suggest that antipsychotics increase serum concentrations of S100B. Astrocytes may actively secrete S100B (Pinto et al, 2000) and possess D 2 receptors, at least in specific brain regions (Khan et al, 2001). Because particularly typical antipsychotics act via D 2 receptors (Kapur and Seeman, 2001), they may trigger elevations of the intracellular messenger cyclic adenosine 3V ,5V -monophosphate (cAMP) (Siegel et al, 1999).…”

Ciliary Neurotrophic Factor Mediates Dopamine D2Receptor-Induced CNS Neurogenesis in Adult Mice

“…This suggested that reduced cAMP could increase CNTF expression. Dopamine D 2 receptors are G-protein-coupled inhibitory receptors that reduce cAMP (Vallar and Meldolesi, 1989) and are present in astrocytes (Bal et al, 1994;Khan et al, 2001). In the SVZ, the D 2 type is the most abundant dopamine receptor (Araki et al, 2007).…”

“…Conversely, dopamine D 2 receptors are inhibitory G-protein-coupled receptors that after activation cause rapid reduction of the intracellular cAMP (Vallar and Meldolesi, 1989), suggesting that D 2 stimulation might increase CNTF expression. D 2 receptors are known to be present in astrocytes (Bal et al, 1994;Khan et al, 2001). Together, this raised the possibility that dopaminergic projections from the midbrain regulate forebrain neurogenesis via a D 2 -CNTF pathway.…”