Faculty Articles

Regulation of the Dopamine D4 Receptor by Angiotensin II in Rat Astrocytes



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The FASEB Journal





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Federation of American Societies for Experimental Biology (FASEB)




We investigated whether Angiotensin (Ang) II regulates the Dopamine D4 receptor (D4) protein expression and whether this interaction is dysregulated in astrocytes isolated from Spontaneously hypertensive rats (SHRs).


A role for the cerebellum in attention and cognitive control has recently been reported. Dysregulation of the D4 receptor function in the cerebellum has been linked to neurodevelopmental disorders such as Attention deficit hyperactivity disorder (ADHD). The mechanisms underlying the dysfunction of the D4 receptor are unknown. We proposed that the angiotensin type 1 receptor (AT1R) cross talks with the D4 receptors, and this interaction may be dysregulated in neurodevelopmental disorders such as ADHD. We used the SHR which is a widely accepted animal model for ADHD. Astrocytes were used as a model brain system to explore the interaction between the two receptors.


Cerebellar astrocytes were prepared from 2–3 days old Wistar and SHR pups. Quiescent cells were treated with 100nM Ang II (the major AT1R ligand) for 1–48 hours. Expression of the D4 receptor protein levels was determined by Western blotting.


There were no significant differences in basal protein levels of the D4 receptor in cerebellar SHR samples as compared to the Wistar controls. In Wistar rats, Ang II downregulated the D4 receptor expression relative to untreated controls. In SHR, Ang II decreased D4 receptor protein expression at most time points examined. There was no significant difference in the ability of Ang II to reduce the D4 receptor protein levels in SHR cerebellar astrocytes as compared to the effect observed in Wistar cerebellum astrocytes.


There is an interaction between the AT1R and the D4 receptor as demonstrated by the ability of Ang II to reduce the D4 receptor protein expression in both SHR and Wistar rat cerebellum samples. This Ang II-mediated effect was similar in cerebellum astrocytes from both Wistar and SHRs suggesting that these cells were similarly responsive to the peptide. This interaction between the AT1R and the D4 receptor will be further investigated as a potential therapeutic target for pathophysiological conditions mediated by these two systems in other areas of the brain where there is a higher expression of the D4 receptor, such as the prefrontal cortex.


Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences


angiotensin II, astrocytes, dopamine D4 receptor, protein, spontaneously hypertensive rats (SHRs)

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