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

Abstract

Psychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1and 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 (D1 barr2-KO ) or D2 (D2 barr2-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. We found that eliminating barr2 attenuated the ability of DA to inhibit D2-MSNs but had little effect on the DA response of D1-MSNs. While D1 barr2-KO mice had mostly normal drug responses, D2 barr2-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 barr2-KO and D1 barr2-KO mice displayed an enhanced conditioned place preference for the highest dose of morphine. These results indicate that D2-derived barr2 functionally contributes to the ability of DA to inhibit D2-MSNs and multiple behavioral responses to psychostimulants and opioids, while loss of barr2 in D1 neurons has little impact on D1-MSN excitability or drug-induced behaviors.

Glycogen synthase kinase-3 inhibitors suppress morphine-induced Straub’s tail via a centrally acting mechanism

“…GSK-3β and phosphorylated GSK-3β protein expression in the striatum and nucleus accumbens blotting was employed to observe protein expression levels of GSK-3β, phosphorylated GSK-3β Ser9 , and phosphorylated GSK-3β Tyr216 in the striatum and nucleus accumbens. These brain regions were chosen because morphine-induced excitation is induced mainly in the striatum and nucleus accumbens [34,35].…”

Disrupted circadian expression of β‐arrestin 2 affects reward‐related µ‐opioid receptor function in alcohol dependence

“…High levels of bArr2 thus lead to increased alcohol intake, whereas eliminating the protein reduces alcohol consumption. When specifically assessing the rewarding properties of alcohol, bArr2‐KO mice also display an enhanced conditioned place preference for low doses of alcohol (Li et al, 2013), a sensitized dopamine release in the Acb, an increased reward upon low doses of alcohol (Bjork et al, 2013), and altered excitability of accumbal D2 receptor medium spiny neurons (Porter‐Stransky et al, 2020). Despite these observations, the role of bArr2 in the development of AUD is less clear.…”