Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

Abstract

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyperand hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G proteincoupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.arrestin | antipsychotics | biased signaling | dopamine D2R | fast-spiking interneurons G protein-coupled receptors (GPCRs) represent the largest family of receptors in the human genome and are one of the most common targets of pharmaceutical drugs (1, 2). Upon ligand binding, GPCRs activate downstream G protein-dependent signaling pathways followed by phosphorylation of the receptor by G protein-coupled receptor kinases (GRKs) (3). Phosphorylation enhances association of the GPCR with β-arrestins (βarrs), and this combined process mediates desensitization of G-protein signaling (4) and internalization of GPCRs (5-7). Two isoforms of βarrs, βarr1 and βarr2, are widely coexpressed in most tissues in mammals and are 80% identical, but they can have either overlapping or distinct functions (8, 9). It is now firmly established that GPCRs activate downstream signaling pathways through not only canonical G-protein pathways but also, the ability of βarrs to scaffold distinct intracellular signaling complexes (10-12). Elucidation of these distinct G-protein and βarr signaling pathways has provided support for the concept of functional selectivity or biased signaling, wherein each signaling pathway has the ability to mediate distinct physiological responses (13). There are now several physiologically relevant examples of selective engagement of signaling pathways or selective GPCR ligands that target these different signaling pathways (13-15). Therefore, leveraging the concept of GPCR functional selectivity holds promise for the development of more selective therapeutic approaches. Dopamine (DA) is a catecholamine neurotransmitter that has been implicated in movement, reward, and cognition (16-19) as well as CNS disorders, such as schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, and obsessive-compulsive disorder (20-23). DA mediates its effects via GPCRs belonging to two major ...

Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway

“…The infusion of dopamine D2 receptor (D2R) agonists and antagonists into the PFC modulates working memory and set-shifting in rodents (Druzin et al, 2000;Floresco et al, 2006;St Onge et al, 2011). In nonhuman primates, prefrontal D2Rs are specifically necessary for neural activity associated with memory-guided saccades (Wang et al, 2004). Consistent with these animal studies, genetic variation in D2Rs modulates prefrontal activity and working memory in humans (Zhang et al, 2007).…”

“…D2Rs have classically been assumed to inhibit neuronal excitability via G i signaling (e.g., in indirect pathway medium spiny neurons and dopaminergic terminals) (Bonci and Hopf, 2005). However, other studies have described novel mechanisms whereby D2Rs can signal through G ␤␥ subunits or interactions with ␤-arrestin (Beaulieu et al, 2005), including in prefrontal interneurons (Urs et al, 2016). These results enlarge the family of possible signaling pathways downstream of D2R activation.…”

“…There has also been controversy about whether D2Rs might form heteroreceptors with D1Rs in the cortex (Beaulieu and Gainetdinov, 2011;Zhang et al, 2011). Findings like these suggest that D2Rs exist in heterogeneous forms, which may explain how D2Rs can couple to various intracellular signaling pathways, giving rise to distinct effects on neuronal excitability, in different neuronal populations.…”

“…In nonhuman primates, prefrontal D2Rs are specifically necessary for neural activity associated with memory-guided saccades (Wang et al, 2004). Consistent with these animal studies, genetic variation in D2Rs modulates prefrontal activity and working memory in humans (Zhang et al, 2007). Prefrontal D2Rs have also been hypothesized to contribute to schizophrenia (Winterer and Weinberger, 2004;Durstewitz and Seamans, 2008), Tourette syndrome (Simonic et al, 1998;Minzer et al, 2004;Yoon et al, 2007;Steeves et al, 2010), and bipolar disorder (Minton et al, 2009).…”

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

“…Similarly, mice lacking β-arrestin 2 show augmented morphine-induced dopamine release in the striatum with respect to controls [12]. In a study Urs et al tested morphine CPP and locomotion in order to study the role of β-arrestin 2 in D1-comprising neurons in conditional KO mice that absence β-arrestin 2 only in D1-comprising cells [13]. Although β-arrestin 2 interactions with dopamine receptors may change effects of opioid, staffing of µ-opioid receptor by β-arrestin 2 could also be imperative due to morphine's great magnetism for µ-opioid receptors.…”