β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol

Abstract

Rationale The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens. Objectives Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge. Methods Alcohol-evoked (0.375, 0.75 and 1.5 g/kg intraperitoneally, i.p.) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [35S]GTP-γ-S autoradiography. Results In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice. Conclusions Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.

Arresting the Development of Addiction: The Role ofβ-Arrestin 2 in Drug Abuse

“…The reinforcing effects of alcohol are thought to be mediated by dopamine release in striatal regions as well as endogenous opioid systems. Consistent with this theory, barr2-KO mice had enhanced alcohol-evoked dopamine release in the nucleus accumbens shell (Björk et al, 2013), which may contribute to the alcohol hypersensitivity. However, barr2-KO mice lacked the alcohol-induced elevations in c-fos in the nucleus accumbens shell seen in control animals (Björk et al, 2008).…”

“…However, barr2-KO mice lacked the alcohol-induced elevations in c-fos in the nucleus accumbens shell seen in control animals (Björk et al, 2008). Although m-opioid receptor binding and function did not differ between barr2-KO and wild-type mice in drug-naïve conditions (likely due to low levels of receptor activation), alcohol induced greater m-opioid receptor agonist stimulation in the dorsal striatum and amygdala of barr2-KO mice (Björk et al, 2013). These differences in m-opioid receptor function may contribute to the altered behavioral responses to alcohol in barr2-KO mice.…”

“…Whereas one study found that mice completely lacking barr2 consumed significantly less alcohol at low doses and had a reduced preference for alcohol in a two-bottle choice procedure compared with controls (Björk et al, 2008), another laboratory observed that barr2-KO mice consumed more alcohol, especially at higher doses (Li et al, 2013). However, both studies reported that barr2-KO mice had enhanced CPP for low doses of alcohol (Björk et al, 2013;Li et al, 2013), possibly indicating that the lack of barr2 conferred hypersensitivity to the rewarding properties of alcohol. barr2-KO mice also had attenuated alcohol-induced locomotor responses compared with wild-type animals (Björk et al, 2008;Li et al, 2013).…”

Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis

“…Given diminished MORs during withdrawal and protracted abstinence, a pharmacological blockade would be expected to worsen the condition and eventually precipitate relapse. Thus, there must be other, still unknown mechanisms in place-for example, augmented signaling from enhanced G-protein-MOR coupling (Bjork et al, 2013) or other molecular downstream effects-that explain the mode of action of opioid receptor antagonist treatment in alcoholism.…”

Morphine-induced trafficking of a mu-opioid receptor interacting protein in rat locus coeruleus neurons

“…In heterologous models over-expressing GRK2 or brain areas, such as the striatum, which contain high level of these proteins (GRK, beta-arrestins), this kinase effector system may enable morphine-induced MOR endocytosis (Bohn et al, 2004, Haberstock-Debic et al, 2005). Even within the striatum variability of GRK2 expression exists between specialized subpopulations of neurons (Bychkov, 2012) and beta-arrestin knockout mice have increased MOR signaling and reward responses (Bjork, 2013). The delicate balance between PKC membrane desensitization and GRK/beta-arrestin internalization pathways for MOR and the relative regulatory protein levels (GRK2, beta-arrestin-1 and −2) between the LC and striatum are increasingly complicated by nucleus-specific expression changes observed following acute, chronic, and withdrawal from morphine exposure (Fan, 2002; Fan, 2003).…”