Loss Of β-ARRESTIN2 In D2 Cells Alters Neuronal Excitability And Behavioral Responses To Drugs Of Abuse
Drug abuse continues to be a major health crisis, with the opioid epidemic considered a public health emergency. Unfortunately, there is a paucity of effective pharmaceutical interventions to treat psychostimulant and opioid addictions. Previous work has shown that the protein β-arrestin2, which is involved in dopamine receptor internalization and signaling, alters certain drug responses; however, the cell-type specificity of these effects and whether β-arrestin2 can alter the rewarding effects of drugs was unknown. To fill in this gap, the present study generated mice lacking β-arrestin2 either in D1 or D2 dopamine receptor-containing cells, used slice electrophysiology to characterize the role of β-arrestin2 in these neurons' responses to dopamine, and tested the behavioral effects of cocaine and morphine in these mice. Eliminating β-arrestin2 in D2, but not D1, cells impaired electrophysiological responses to dopamine. While mice lacking β-arrestin2 in D1 neurons exhibited mostly normal drug responses, mice lacking β-arrestin2 in D2 cells showed dose-dependent reductions in acute locomotor responses to cocaine and morphine, attenuated locomotor sensitization to cocaine, and blunted cocaine reward measured with conditioned place preference. Together, these results indicate that D2-derived β-arrestin2 is critical for the ability of dopamine to inhibit D2 neurons and modulates multiple behavioral responses to psychostimulants and opioids. β-arrestin2 may be a beneficial target for future pharmacotherapies in the treatment of addiction.