Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice

Bagalkot, Tarique Rajasaheb; Jin, Hongmei; Prabhu, Vishwanath Vasudev; Muna, Sushma Shrestha; Cui, Yin; Yadav, Binod Kumar; Chae, Han-Jung; Chung, Young‐Chul

doi:10.1016/j.neuroscience.2015.10.024

Cited by 33 publications

(21 citation statements)

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“…The exact procedure for inducing social defeat stress has been described in previous articles from our research group [ 21 , 38 ]. Briefly, C57BL/6N mice were introduced into the home cage of an unfamiliar CD1 aggressor mouse and they were allowed to interact for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…In the postmortem brains of patients with schizophrenia, there are changes in the mRNA levels of both D2S and D2L: increased expression of D2S in the dorsolateral prefrontal cortex (DLPFC) [ 19 ] and mixed results on D2L in the DLPFC and frontal cortex [ 19 , 20 ]. However, to date, no studies have investigated the effects of social defeat stress on D2L or D2S except for one study from our research group [ 21 ], which found increased expression of D2S and D2L in the prefrontal cortex (PFC) of susceptible mice compared to controls. Dopamine and cyclic adenosine 3′,5′-monophosphate-regulated phosphoprotein-32 (DARPP-32) play central roles in mediating the effects of dopamine and glutamate [ 22 , 23 ] and their expression can be altered by acute stress [ 24 ] and electroconvulsive stimulation [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of social defeat stress on dopamine D2 receptor isoforms and proteins involved in intracellular trafficking

et al. 2018

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BackgroundChronic social defeat stress induces depression and anxiety-like behaviors in rodents and also responsible for differentiating defeated animals into stress susceptible and resilient groups. The present study investigated the effects of social defeat stress on a variety of behavioral parameters like social behavior, spatial learning and memory and anxiety like behaviors. Additionally, the levels of various dopaminergic markers, including the long and short form of the D2 receptor, and total and phosphorylated dopamine and cyclic adenosine 3′,5′-monophosphate regulated phosphoprotein-32, and proteins involved in intracellular trafficking were assessed in several key brain regions in young adult mice.MethodsMouse model of chronic social defeat was established by resident-intruder paradigm, and to evaluate the effect of chronic social defeat, mice were subjected to behavioral tests like spontaneous locomotor activity, elevated plus maze (EPM), social interaction and Morris water maze tests.ResultsMice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. The susceptible group exhibited greater decreases in time spent in the open and closed arms compared to the control group on the EPM. In the social interaction test, the susceptible group showed greater increases in submissive and neutral behaviors and greater decreases in social behaviors relative to baseline compared to the control group. Furthermore, increased expression of D2L, D2S, Rab4, and G protein-coupled receptor associated sorting protein-1 was observed in the amygdala of the susceptible group compared to the control group.ConclusionThese findings suggest that social defeat stress induce anxiety-like and altered social interacting behaviors, and changes in dopaminergic markers and intracellular trafficking-related proteins.Electronic supplementary materialThe online version of this article (10.1186/s12993-018-0148-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of social defeat stress on dopamine D2 receptor isoforms and proteins involved in intracellular trafficking

et al. 2018

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“…In line with this, a recent study found that SD reduces the expression of D1R in the medial prefrontal cortex (mPFC) only in susceptible mice (Shinohara et al., ). On the other hand, a number of studies have failed to find differences in the regulation of D1R after SD (Bagalkot et al., ; Burke et al., ; Jin et al., ; Lucas et al., ). Finally, data show that when SD occurs during adolescence, there is an increase in the levels of D1R in the caudate and putamen nucleus when the animals became adults (Novick, Forster, Tejani‐Butt, & Watt, ).…”

Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onmentioning

confidence: 99%

“…D2R are linked to different subtypes of impulsiveness (see review by Jentsch et al., ), with excessive eating in obese subjects (see review Wang, Volkow, & Fowler, ), and with the development of adequate social behavior (Manduca et al., ). SD has been shown to induce a long‐lasting increased expression of these receptors in the PFC and hippocampus of adult rodents (Bagalkot et al., ; Lucas et al., ; Montagud‐Romero, Reguilon et al., ). However, SD during adolescence undermines the maturation of cortical DA through D2R regulation of DA synthesis or the glucocorticoid‐facilitated pruning of cortical DA fibers (Burke & Miczek, ; Burke et al., ; Naneix, Marchand, Pichon, Pape, & Coutureau, ).…”

Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onmentioning

confidence: 99%

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Montagud‐Romero

Blanco-Gandía

Reguilón

et al. 2018

Eur J of Neuroscience

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Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces long-lasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short- and long-term consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

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“…Dopamine D 2 receptors (D 2 Rs), which belong to the family A of GPCRs, regulate a large number of physiological functions and are involved in a number of neuropsychiatric disorders including schizophrenia and Parkinson's disease. Along with numerous other GPCRs, D 2 Rs have been proven to form homodimers 8 9 and heterodimers 10 11 12 13 14 , and growing evidence indicates that altered D 2 R cooperativity may significantly contribute to CNS disorders 15 16 . Among receptors interacting with D 2 Rs in the CNS, the neurotensin receptor subtype 1 (NTS 1 R) together with its endogenous ligand, the tridecapeptide neurotensin, has gained substantial interest over the past decades.…”

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confidence: 99%

Structure-guided development of heterodimer-selective GPCR ligands

et al. 2016

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Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design of novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers. The compounds of types 1–3 consist of three different D2R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1R agonist NT(8-13). The bivalent ligands show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity (up to three orders of magnitude), compared with cells that only express D2Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated β-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells.

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Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice

Cited by 33 publications

References 37 publications

Effects of social defeat stress on dopamine D2 receptor isoforms and proteins involved in intracellular trafficking

Effects of social defeat stress on dopamine D2 receptor isoforms and proteins involved in intracellular trafficking

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Structure-guided development of heterodimer-selective GPCR ligands

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