Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants

Gross, Joshua; Kaski, Shane W; Schroer, Adam B.; Wix, Kimberley A; Siderovski, David P.; Setola, Vincent

doi:10.1177/0269881117742100

Cited by 15 publications

(40 citation statements)

References 66 publications

(91 reference statements)

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“…RGS12 also appears to play a unique role in the actions of psychostimulants as RGS12 knockout mice show decreased amphetamine and cocaine-mediated hyperlocomotion; however, they do not show any deficits in locomotor sensitization and place preference (Gross et al 2018). These actions of RGS12 were found to involve regulation of the dopamine transporter in the ventral striatum.…”

Section: A Role Of Rgs Proteins In Amphetamine Addiction-related Behamentioning

confidence: 99%

Regulators of G Protein Signaling in Analgesia and Addiction

et al. 2020

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Regulators of G protein signaling (RGS) are multifunctional proteins expressed in peripheral and neuronal cells, playing critical roles in development, physiological processes, and pharmacological responses. RGS proteins primarily act as GTPase accelerators for activated Gα subunits of Gprotein coupled receptors (GPCRs), but they may also modulate signal transduction by several other mechanisms. Over the last two decades, preclinical work identified members of the RGS family with unique and critical roles in intracellular responses to drugs of abuse. New information

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Section: A Role Of Rgs Proteins In Amphetamine Addiction-related Behamentioning

confidence: 99%

Regulators of G Protein Signaling in Analgesia and Addiction

et al. 2020

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“…We recently found [40] that RGS12 is enriched in the ventral striatum (vSTR) of the mesolimbic dopamine (DA) system which contributes to reward and affect [41,42]. RGS12 loss reduces psychostimulant-induced hyperlocomotion and elevates dopamine transporter (DAT) expression and DA uptake in the vSTR, but not dorsal striatum (dSTR) [40]. We hypothesized that RGS12 loss could elevate vSTR KOR activity/sensitivity, as KOR is highly expressed in the mesolimbic DA system and enriched on presynaptic terminals of the nucleus accumbens (NAc) (terminals that originate from ventral tegmental area (VTA) DAergic projections [1,43]).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…KOR-mediated DA decrease occurs by inhibition of exocytotic DA release [46,47] and increased DAT-mediated DA reuptake via Gα i/o and MAPK-dependent signaling [48,49]. Here, we examined whether augmented vSTR DA uptake and reduced psychostimulant-induced hyperlocomotion in RGS12null mouse strains [40] results from enhanced KOR action, given that RGS12 is an established inhibitor of Gα i/o signaling [32]. Our investigation revealed that RGS12 more robustly affects KOR-mediated signaling than it does other opioid receptors, RGS12 differentially modulates G protein-dependent versus independent KOR signaling, and RGS12 loss differentially affects KOR-mediated behaviors, likely contingent upon which KORinitiated signaling cascade is required to elicit the particular behavioral outcome.…”

Section: Introductionmentioning

confidence: 99%

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Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior

Gross

Kaski

Schmidt

et al. 2019

Neuropsychopharmacol.

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Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KORdependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia-G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G proteindependent and-independent signaling downstream of KOR activation.

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“…Locomotor activity was assessed using a 16 X 16 open-field infrared photobeam activity system (PAS) from San Diego Instruments (San Diego, CA), as described previously (Gross et al, 2018). Briefly, locomotion was quantified as total beam breaks in the x and y coordinates in five minute bins.…”

Section: -Locomotionmentioning

confidence: 99%

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

Kaski¹

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Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder Shane West Kaski Endogenous opioids mediate both analgesic and affective responses to stress. While the mu opioid receptor (MOR) produces the reinforcing euphoric effects responsible for the high abuse potential of traditional opioid analgesics, the kappa opioid receptor (KOR) is hypothesized to mediate the dysphoric component of stress. With increasing rates of opioid addiction, extensive research efforts are focused on better understanding each of these systems and how they interact, with the goal of developing less addictive pain management strategies and better approaches to addiction treatment. With this in mind, we conducted both clinical and preclinical studies aimed at developing better treatment strategies for opioid use and the management of patients with opioid use disorder (OUD). First, we assessed a local cohort of patients with (OUD) for a collection of single nucleotide polymorphisms (SNPs) related to reward processing, with the goal of furthering efforts to develop a gene-based screening mechanism for OUD risk assessment. Second, we conducted preclinical assessments of the G protein-biased KOR agonist nalfurafine as a potential adjuvant medication for increasing the therapeutic efficacy of opioid-based analgesia. Genetic analysis of OUD patients identified two SNPs within the gene encoding the mu opioid receptor, one SNP within the gene encoding the serotonin 2B (5-HT2B) receptor, and one SNP within the gene encoding Regulator of G protein Signaling 2 (RGS2), with the frequency of each SNP varying significantly from that observed in reference populations of European descent. Preclinical investigations with nalfurafine use in mice demonstrated a greater analgesic synergy when co-administered with morphine than morphine co-administered with the unbiased KOR agonist U50,488. As G protein-biased KOR agonists are hypothesized to produce less dysphoria (a therapeutically limiting side effect of KOR agonists), they may present a viable method for reducing the dose of MOR-targeting analgesic necessary for adequate pain relief, thereby reducing the likelihood of developing OUD. Further research is necessary to identify any antitherapeutic effects of co-administering these two classes of drugs, as well as the range of pain modalities for which this approach is efficacious.

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Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants

Cited by 15 publications

References 66 publications

Regulators of G Protein Signaling in Analgesia and Addiction

Regulators of G Protein Signaling in Analgesia and Addiction

Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

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