Generation and characterization of hD5 and C-terminal Mutant hD(5m) transgenic rats

Dopamine D1-like receptors play important roles in many brain activities such as cognition and emotion. We have generated human hD5 and mutant human hD5 (hD(5m)) transgenic rats. The C-terminal juxtamembrane domain of mutant hD5 was identical to that of hD5 pseudogenes. The transgenes were driven by the CAMKII promoter that led the expression mainly in the cerebral cortex and hippocampus. We have used different dopamine receptor agonists to compare the pharmacological profiles of the human hD5 and hD(5m) receptors. The results showed that they exhibited distinct pharmacological properties. Our results of pharmacological studies indicated that the C-terminal of D5 receptor could play important roles in agonist binding affinity. Hippocampal long-term potentiation (LTP) evoked by tetanic stimulation was significantly reduced in both transgenic rats. In addition, we found that the overexpression of dopamine hD5 and hD(5m) receptors in the rat brain resulted in memory impairments. Interestingly, an atypical D1-like receptor agonist, SKF83959, could induce anxiety in hD(5m) receptor transgenic rats but had no effect on the anxiety-like behavior in D5 receptor transgenic and wild-type rats.