Angiotensin II and Dopamine 4 Receptor Interaction in Neurons from ADHD Rats

Grant Winners

Deans

Abstract

Background: Attention deficit hyperactivity disorder (ADHD) is a common neuro-developmental childhood disorder, and it can continue through adolescence and adulthood. Currently available therapeutic treatments focus on reducing the symptoms of ADHD and improving quality of life, but the medications do not cure the underlying disorder. The long-term objective of these studies is to better understand the molecular pathways that are involved in ADHD and to identify druggable targets for the treatment of the disorder. The Dopamine 4 receptor (D4 receptor) is currently of interest as a major player in the etiology of ADHD because of the high degree of functionally relevant variability in its gene, and the association of this gene with novelty seeking behavior. Thus, factors affecting D4 receptor function, such as dimerization of the receptor with another G protein-coupled receptor (GPCR), can affect the ability of the D4 receptor to provide attention.

Rationale: Studies in the kidney and vascular smooth muscle cells suggest that there is cross talk between the Renin Angiotensin System (RAS) and the dopaminergic system to regulate blood pressure. Interestingly, angiotensin AT1 receptors (AT1 receptors), the primary receptor for angiotensin II (Ang II), which is the major peptide produced by the RAS, are expressed in the prefrontal cortex. However, the cross talk between the AT1 receptor and the D4 receptor in the prefrontal cortex is not yet explored, especially in relation to ADHD.

Methods:  The spontaneously hypertensive rat (SHR) is a widely used model of ADHD, and it displays the major symptoms of this disorder. Neuronal cells isolated from the prefrontal cortex of the SHR will be used to investigate an interaction between the AT1 receptor and the D4 receptor for its influence on methylation-related signaling activity of the D4 receptor. We will measure the expression of the D4 receptor and the AT1 receptor at mRNA and protein levels using qPCR (quantitative polymerase chain reaction) and Western blotting techniques. We will also measure the effects of Ang II on the levels of the D4 receptor, as well as the downstream effect of the D4 receptor, including DNA methylation. Results from SHR samples will be statistically analysed and compared to controls.

Significance of the Study: Although medications are available to manage ADHD symptoms and improve the quality of everyday life, the number of children with ADHD continues to rise from 7.8% in 2003 to 11% in 2011. Further, 11% of children ages 4-17 years (~6.4 million) are diagnosed with ADHD. Thus, studies delineating changes that occur at the molecular level will be important in understanding the etiology of the disorder and will provide targets to design medications to treat the disorder.