D5 Dopamine Receptors are Required for Dopaminergic Activation of Phospholipase C

Dopamine activates phospholipase C in discrete regions of the mammalian brain, and this action is believed to be mediated through a D-1-like receptor. Although multiple lines of evidence exclude a role for the D-1 subtype of D-1-like receptors in the phosphoinositide response, the D-5 subtype has not been similarly examined. Here, mice lacking D-5 dopamine receptors were tested for dopamine agonist-induced phosphoinositide signaling both in vitro and in vivo. The results show that hippocampal, cortical, and striatal tissues of D-5 receptor knockout mice significantly or completely lost the ability to produce inositol phosphate or diacylglycerol messengers after stimulation with dopamine or several selective D-1-like receptor agonists. Moreover, endogenous inositol-1,4,5-trisphosphate stimulation by the phospholipase C-selective D-1-like agonist 3-methyl-6chloro- 7,8-dihydroxy-1-[3methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) was robust in wild-type animals but undetectable in the D-5 receptor mutants. Hence, D-5 receptors are required for dopamine and selective D-1-like agonists to induce phospholipase C-mediated phosphoinositide signaling in the mammalian brain.