The physiological relevance of functional selectivity in dopamine signalling.

We sought to determine the role of functionally selective dopamine (DA) signalling pathways (G protein or β-arrestin) in DA-dependent behaviours. Mice that were globally deficient for β-arrestins or mice deficient in GSK3β in D2 receptor (D2R)-expressing neurons were used to investigate the role of functional selectivity in DA-dependent behaviours such as locomotor activity and conditioned place preference (CPP). Wild-type or knockout mice were injected with drugs such as morphine and amphetamine, which are known to increase DA levels in the brain and to induce a hyper-locomotor response and CPP. Unlike β-arrestin1 (βarr1)-deficient mice, mice globally deficient for β-arrestin2 (βarr2) mount a reduced hyperlocomotor response to either morphine or amphetamine. However, mice deficient in GSK3β in D2R-expressing neurons show a significantly reduced locomotor response to only amphetamine but not morphine. Interestingly, all mice tested show a normal CPP response to either morphine or amphetamine. β-arrestin-mediated DA receptor signalling has an important role in the locomotor response, but not CPP, to drugs such as morphine and amphetamine, demonstrating a functional selectivity of DA-dependent behaviours in mice. It is likely that G-protein-dependent signalling through DA receptors mediates the CPP response.