The physiological relevance of functional selectivity in dopamine signalling

Abstract

We sought to determine the role of functionally selective dopamine (DA) signalling pathways (G protein or b-arrestin) in DA-dependent behaviours. Mice that were globally deficient for b-arrestins or mice deficient in GSK3b in D2 receptor (D2R)-expressing neurons were used to investigate the role of functional selectivity in DA-dependent behaviours such as locomotor activity and conditioned place preference (CPP). Wild-type or knockout mice were injected with drugs such as morphine and amphetamine, which are known to increase DA levels in the brain and to induce a hyper-locomotor response and CPP. Unlike b-arrestin1 (barr1)-deficient mice, mice globally deficient for b-arrestin2 (barr2) mount a reduced hyperlocomotor response to either morphine or amphetamine. However, mice deficient in GSK3b in D2R-expressing neurons show a significantly reduced locomotor response to only amphetamine but not morphine. Interestingly, all mice tested show a normal CPP response to either morphine or amphetamine. b-arrestin-mediated DA receptor signalling has an important role in the locomotor response, but not CPP, to drugs such as morphine and amphetamine, demonstrating a functional selectivity of DA-dependent behaviours in mice. It is likely that G-protein-dependent signalling through DA receptors mediates the CPP response.

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

“…barr2 signaling, particularly in D2-containing MSNs, mediates amphetamine-induced locomotion (Peterson et al, 2015;Urs et al, 2016); however, whether this mechanism also mediates amphetamine reward is currently unknown. By contrast, barr2 in D1-containing neurons is proposed to mediate morphine-induced locomotion but not reward (Urs et al, 2011;Urs and Caron, 2014). While a simplistic model whereby barr2 mediates all psychomotor drug effects would be convenient, the data indicate that barr2 is likely modulating different drug effects in different brain regions through interactions with various GPCRs and intracellular molecules.…”

“…Indeed, mice lacking barr2 but not barr1 have altered behavioral responses to addictive drugs, including morphine (Bohn et al, 2003;Urs and Caron, 2014), amphetamine (Urs and Caron, 2014), and alcohol (Li et al, 2013) (Table 1); therefore, barr2 is a likely candidate for modulating the effects of drugs of abuse. The purpose of this review is to catalog what is currently known about the role of barr2 in mediating the behavioral effects of various drugs of abuse and to discuss the questions that remain and what techniques are needed to properly answer these questions.…”

Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists

“…The G-protein-independent pathway is initiated by the ligand binding event, followed by phosphorylation of the receptor by the G-protein coupled receptor kinases (GRKs), which further leads to the recruitment of β-arrestin-2 and activation of the glycogen synthase kinase 3β (GSK3β)-mediated pathway . The endogenous neurotransmitter dopamine signals through both the G-protein and β-arrestin-mediated/G-dependent pathways, leading to the downstream effects of mitogen-activated protein-independent pathways kinase (MAPK) activation . However, synthetic ligands that mimic dopamine’s signaling action of activating multiple pathways cause undesirable side effects, which has led to the design of a new class of dopaminergic agents that have a biased signaling profile through either the G-protein-dependent or β-arrestin-mediated/G-protein-independent pathways. , Some known chemotypes with D2R biased signaling profile include antipsychotic drugs such as aripiprazole and its analogues, which recruit and signal through the β-arrestin-mediated pathway .…”

“…The endogenous neurotransmitter dopamine signals through both the G-protein and β-arrestin-mediated/G-dependent pathways, leading to the downstream effects of mitogen-activated protein-independent pathways kinase (MAPK) activation . However, synthetic ligands that mimic dopamine’s signaling action of activating multiple pathways cause undesirable side effects, which has led to the design of a new class of dopaminergic agents that have a biased signaling profile through either the G-protein-dependent or β-arrestin-mediated/G-protein-independent pathways. , Some known chemotypes with D2R biased signaling profile include antipsychotic drugs such as aripiprazole and its analogues, which recruit and signal through the β-arrestin-mediated pathway . Similarly, several other clinically used antipsychotic agents have been shown to signal via the β-arrestin-mediated pathway at the D2R, suggesting a common mechanism of action .…”

The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation

“…Functionally selective drugs are predicted to have increased specificity of action by only engaging the therapeutically relevant pathway, while avoiding activation of potential side-effect inducing pathways (14)(15)(16). For the dopamine D2 receptor (D2R), selective targeting of the D2R/barr signaling pathway may improve drugs used to treat schizophrenia, Parkinson's disease, or other disorders (15,17,18).…”