Loss of β‐arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids

Psychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1 and D2 G protein‐coupled receptors. β‐arrestin2 (βarr2) desensitizes and internalizes these receptors and initiates G protein‐independent signaling. Previous work revealed that mice with a global or cell‐specific knockout of βarr2 have altered responses to certain drugs; however, the effects of βarr2 on the excitability of medium spiny neurons (MSNs), and its role in mediating the rewarding effects of drugs of abuse are unknown. D1‐Cre and D2‐Cre transgenic mice were crossed with floxed βarr2 mice to eliminate βarr2 specifically in cells containing either D1 (D1βarr2‐KO) or D2 (D2βarr2‐KO) receptors. We used slice electrophysiology to characterize the role of βarr2 in modulating D1 and D2 nucleus accumbens MSN intrinsic excitability in response to DA and tested the locomotor‐activating and rewarding effects of cocaine and morphine in these mice. Eliminating βarr2 attenuated the ability of DA to inhibit D2‐MSNs and altered the DA‐induced maximum firing rate in D1‐MSNs. While D1βarr2‐KO mice had mostly normal drug responses, D2βarr2‐KO mice 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. Both D2βarr2‐KO and D1βarr2‐KO mice displayed an enhanced conditioned place preference for the highest dose of morphine. These results indicate that D1‐ and D2‐derived βarr2 functionally contribute to DA‐induced changes in MSN intrinsic excitability and behavioral responses to psychostimulants and opioids dose‐dependently.