Heteromerization of Dopamine D2 and Oxytocin Receptor in Adult Striatal Astrocytes

Abstract

The ability of oxytocin (OT) to interact with the dopaminergic system through facilitatory D2-OT receptor (OTR) receptor-receptor interaction in the limbic system is increasingly considered to play roles in social or emotional behavior, and suggested to serve as a potential therapeutic target. Although roles of astrocytes in the modulatory effects of OT and dopamine in the central nervous system are well recognized, the possibility of D2-OTR receptor-receptor interaction in astrocytes has been neglected. In purified astrocyte processes from adult rat striatum, we assessed OTR and dopamine D2 receptor expression by confocal analysis. The effects of activation of these receptors were evaluated in the processes through a neurochemical study of glutamate release evoked by 4-aminopyridine; D2-OTR heteromerization was assessed by co-immunoprecipitation and proximity ligation assay (PLA). The structure of the possible D2-OTR heterodimer was estimated by a bioinformatic approach. We found that both D2 and OTR were expressed on the same astrocyte processes and controlled the release of glutamate, showing a facilitatory receptor-receptor interaction in the D2-OTR heteromers. Biochemical and biophysical evidence confirmed D2-OTR heterodimers on striatal astrocytes. The residues in the transmembrane domains four and five of both receptors are predicted to be mainly involved in the heteromerization. In conclusion, roles for astrocytic D2-OTR in the control of glutamatergic synapse functioning through modulation of astrocytic glutamate release should be taken into consideration when considering interactions between oxytocinergic and dopaminergic systems in striatum.

Functional activation of dorsal striatum astrocytes improves movement deficits in hemi-parkinsonian mice

“…3e-h). Our current data does not distinguish whether these results are due to loss of direct action of dopamine on striatal astrocytes or indirectly through known changes in local neuronal function and synaptic inputs [48][49][50] . Striatal astrocytes express dopamine receptors in their distal processes, potentially within the range of neuronal synapses [2][3][4] .…”

“…Locomotion in the open field is driven partly by exploration and subsides as animals habituate to the novel environment 49 . In agreement with previous work demonstrating that dopamine signaling is important for exploratory behavior 51 , we found that lesioned animals showed a pronounced deficit in the early phase of the open field when the exploratory drive is the highest ( Fig.…”

Modulation of Neuron and Astrocyte Dopamine Receptors via Receptor–Receptor Interactions

“…In neurons [105], oxytocin, via the allosteric RRI established in the heterocomplex, markedly increased D 2 receptor recognition (increased affinity of the high-affinity state) and increased the coupling of G i/o to the receptor. The D 2 -OTR heterodimer was recently identified in astrocytes as well [106], and the activation of OTR was shown to have a facilitatory effect on the response of D 2 receptors, causing them to be activated by subthreshold D 2 agonist concentrations and leading to an inhibition of glutamate release by the cells.…”

“…In this context, extensive available data indicate that RRIs may play a significant role. Relevant examples include the heterodimers A 2A -D 2 and D 2 -OTR [96,106], formed by the association of the dopamine D 2 receptor with the adenosine A 2A or the oxytocin receptor, respectively. These receptor complexes are present in astrocytes and regulate the release of glutamate from these cells [106,127], a process relevant for the control of glutamatergic transmission in striatum and with potential roles in the dysregulation of glutamatergic transmission in various neuropsychiatric diseases (see [176] for a specific review on this topic).…”