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bioRxiv · 10.1101/685719

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

Porter-Stransky, K. A.·Petko, A. K.·Karne, S. L.·Liles, L. C.·Urs, N. M.·Caron, M. G.·Paladini, C. A.·Weinshenker, D.
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Abstract

Psychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1 and D2 G protein-coupled receptors. {beta}-arrestin2 ({beta}arr2) desensitizes and internalizes these receptors and initiates G protein-independent signaling. Previous work revealed that mice with a global or cell-specific knockout of {beta}arr2 have altered responses to certain drugs; however, the effects of {beta}arr2 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 {beta}arr2 mice to eliminate {beta}arr2 specifically in cells containing either D1 (D1{beta}arr2-KO) or D2 (D2{beta}arr2-KO) receptors. We used slice electrophysiology to characterize the role of {beta}arr2 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. We found that eliminating {beta}arr2 attenuated the ability of DA to inhibit D2-MSNs but had little effect on the DA response of D1-MSNs. While D1{beta}arr2-KO mice had mostly normal drug responses, D2{beta}arr2-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 D2{beta}arr2-KO and D1{beta}arr2-KO mice displayed an enhanced conditioned place preference for the highest dose of morphine. These results indicate that D2-derived {beta}arr2 functionally contributes to the ability of DA to inhibit D2-MSNs and multiple behavioral responses to psychostimulants and opioids, while loss of {beta}arr2 in D1 neurons has little impact on D1-MSN excitability or drug-induced behaviors.

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Porter-Stransky, K. A., Petko, A. K., Karne, S. L., Liles, L. C., Urs, N. M., Caron, M. G., Paladini, C. A., Weinshenker, D.. 2019-06-28. Loss of β-arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids. https://doi.org/10.1101/685719

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