Beta-arrestin 1 regulation of reward-motivated behaviors and glutamatergic function

Abstract

The two highly homologous non-visual arrestins, beta-arrestin 1 and 2, are ubiquitously expressed in the central nervous system, yet knowledge of their disparate roles is limited. While beta-arrestin 2 (βarr2) has been implicated in several aspects of reward-related learning and behavior, very little is known about the behavioral function of beta-arrestin 1 (βarr1). Using mice lacking βarr1, we focused on the role of this scaffolding and signal transduction protein in reward-motivated behaviors and in striatal glutamatergic function. We found that βarr1 KO mice were both slower in acquiring cocaine self-administration and in extinguishing this behavior. They also showed deficits in learning tasks supported by a natural food reward, suggesting a general alteration in reward processing. We then examined glutamatergic synaptic strength in WT and KO medium spiny neurons (MSNs) of the Nucleus Accumbens (NAc) shell in naïve animals, and from those that underwent cocaine self-administration. An increase in the AMPA/NMDA (A/N) ratio and a relative lack of GluN2B-enriched NMDARs was found in naïve KO vs WT MSNs. Applying Lim Domain Kinase (LIMK1), the kinase that phosphorylates and inactivates cofilin, to these cells, showed that both βarr1 and LIMK regulate the A/N ratio and GluN2B-NMDARs. Cocaine self-administration increased the A/N ratio and GluN2B-NMDARs in WT MSNs and, although the A/N ratio also increased in KO MSNs, this was accompanied by fewer GluN2B-NMDARs and an appearance of calcium-permeable AMPARs. Finally, to examine the consequences of reduced basal GluN2B-NMDARs in reward-processing seen in KO mice, we chronically infused ifenprodil, a GluN2B antagonist, into the NAc shell of WT mice. This intervention substantially reduced food-motivated behavior. Together these findings identify a previously unknown role of βarr1 in regulating specific reward-motivated behaviors and glutamatergic function.

Environmental temperature variation affects brain protein expression and cognitive abilities in adult zebrafish (Danio rerio): A proteomic and behavioural study

“…The down-regulation of the arrestin pathway at 18°C and 34°C could provoke alterations of ZF cognitive abilities in analogy to β arrestin 1 KO-mice that showed deficits in learning tasks suggesting spatial learning deficiencies and general alteration in reward processing [76].…”

Hijacking the Progress of Addiction: Looking at β-Arrestin 1 and β-Arrestin 2 to Cognize Drugs of Abuse

“…The researcher observed that self-administration of cocaine augmented the AMPA/NMDA ratio and GluN2B-NMDARs in spinal medium neurons of WT mice. But for KO spinal medium neurons, an increase in AMPA/NMDA ratio was detected accompanied by fewer GluN2B-NMDARs and a presence of calcium-penetrable AMPARs [8]. The study suggested that ifenprodil is an inhibitor of NMDA receptor specifically of glycine-binding NMDA receptor (GluN1) and glutamate-binding NMDA receptor subunit 2 (GluN2B) [10].…”

“…In a study, Mittal et al examined the key mechanisms involved in behavioural performances mediated by β-arrestin 1 [8]. Using a mice model lacking β-arrestin 1, they studied the role of this scaffolding protein in reward-driven behaviours and striatal glutamatergic role.…”

“…They observed that mice lacking the β-arrestin 1 were slow responses to self-administration of cocaine and quenching of the response. The researchers revealed the difficulty in learning advocated by natural food reward, proposing distortion in the reward system [8]. It has been observed that glutamate plays a major role in processes (i.e., reinforcement, sensitization, context conditioning, habit and reinforcement learning, craving and relapse) facilitating development and managing of addiction [9].…”

“…They finally concluded that lack of β-arrestin 1 result in specific deficits in cocaine and food-related behaviours and in glutamatergic synaptic asset and subunit construction [8].…”