Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains

Background: The Spontaneously Hypertensive Rat (SHR) shows a number of behaviours that closely parallel those seen in children with attention-deficit hyperactivity disorder. These include motor hyperactivity, excessive responses under a fixed-interval/extinction schedule, difficulty in acquiring operant tasks and increased sensitivity to immediate behavioural reinforcement. As in children with ADHD, the behavioural and cognitive deficits in the SHR are responsive to stimulants, including d-amphetamine and d,l-methylphenidate. The non-hyperactive Wistar Kyoto (WKY) rat strain is often used as a control in behavioural studies of the SHR, and WKY itself has been suggested to be a useful animal model of depression. Numerous studies have shown that dopaminergic neurotransmission is altered between the two strains. Human genetic studies have found associations between several dopaminergic genes and both ADHD and depression. Methods: We sequenced three candidate dopaminergic genes (Drd2, Drd4, and Dat1) in the SHR and WKY to identify between-strain sequence differences. Results: No between-strain sequence differences were found in either Drd2 or Drd4, but several variations were found in the Dat1 gene that encodes the dopamine transporter. Conclusion: It is plausible that DNA sequence changes in the Dat1 gene account for some of the behavioural differences observed between the SHR and WKY strains. Future work will focus on elucidating the functional effects of the observed polymorphisms.