Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

Kruyer, Anna; Parrilla-Carrero, Jeffrey; Powell, Courtney; Brandt, Lasse; Gutwinski, Stefan; Angelis, Ariana; Chalhoub, Reda M; Jhou, Thomas C.; Kalivas, Peter W.; Amato, Davide

doi:10.1038/s41380-021-01235-6

Cited by 21 publications

(27 citation statements)

References 82 publications

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“…Since astrocytes dampen synaptic potentiation via a number of mechanisms ( 20 , 44 ), we hypothesize that increased astrocyte insulation of D2-MSNs during cue-reinstated heroin seeking may reduce D2-MSN potentiation relative to the extinguished context ( 31 , 45 ). However, a number of reports indicate that subpopulations of D2-MSNs in the striatum promote, rather than inhibit, motivated behaviors ( 53 – 56 ). Moreover, cortical inputs linked to cued reinstatement ( 57 ) innervate D2-MSNs to a greater extent than D1-MSNs ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Plasticity in astrocyte subpopulations regulates heroin relapse

et al. 2022

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Opioid use disorder (OUD) produces detrimental personal and societal consequences. Astrocytes are a major cell group in the brain that receives little attention in mediating OUD. We determined how astrocytes and the astroglial glutamate transporter, GLT-1, in the nucleus accumbens core adapt and contribute to heroin seeking in rats. Seeking heroin, but not sucrose, produced two transient forms of plasticity in different astroglial subpopulations. Increased morphological proximity to synapses occurred in one subpopulation and increased extrasynaptic GLT-1 expression in another. Augmented synapse proximity by astroglia occurred selectively at D2-dopamine receptor–expressing dendrites, while changes in GLT-1 were not neuron subtype specific. mRNA-targeted antisense inhibition of either morphological or GLT-1 plasticity promoted cue-induced heroin seeking. Thus, we show that heroin cues induce two distinct forms of transient plasticity in separate astroglial subpopulations that dampen heroin relapse.

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Section: Discussionmentioning

confidence: 99%

Plasticity in astrocyte subpopulations regulates heroin relapse

et al. 2022

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“…In a situation of excessive dopaminergic neurotransmission, it also functions as a D2 receptor antagonist [ 154 ]. In schizophrenia, D2 signaling is considerably hyperactive [ 155 ], and in the prefrontal cortex, the D1 receptor is decreased [ 156 ].…”

Section: Gpcrs In Cnsmentioning

confidence: 99%

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

Rahman

Islam

Mim

et al. 2022

Oxidative Medicine and Cellular Longevity

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G protein-coupled receptors (GPCRs) are intricately involved in the conversion of extracellular feedback to intracellular responses. These specialized receptors possess a crucial role in neurological and psychiatric disorders. Most nonsensory GPCRs are active in almost 90% of complex brain functions. At the time of receptor phosphorylation, a GPCR pathway is essentially activated through a G protein signaling mechanism via a G protein-coupled receptor kinase (GRK). Dopamine, an important neurotransmitter, is primarily involved in the pathophysiology of several CNS disorders; for instance, bipolar disorder, schizophrenia, Parkinson’s disease, and ADHD. Since dopamine, acetylcholine, and glutamate are potent neuropharmacological targets, dopamine itself has potential therapeutic effects in several CNS disorders. GPCRs essentially regulate brain functions by modulating downstream signaling pathways. GPR6, GPR52, and GPR8 are termed orphan GPCRs because they colocalize with dopamine D1 and D2 receptors in neurons of the basal ganglia, either alone or with both receptors. Among the orphan GPCRs, the GPR52 is recognized for being an effective psychiatric receptor. Various antipsychotics like aripiprazole and quetiapine mainly target GPCRs to exert their actions. One of the most important parts of signal transduction is the regulation of G protein signaling (RGS). These substances inhibit the activation of the G protein that initiates GPCR signaling. Developing a combination of RGS inhibitors with GPCR agonists may prove to have promising therapeutic potential. Indeed, several recent studies have suggested that GPCRs represent potentially valuable therapeutic targets for various psychiatric disorders. Molecular biology and genetically modified animal model studies recommend that these enriched GPCRs may also act as potential therapeutic psychoreceptors. Neurotransmitter and neuropeptide GPCR malfunction in the frontal cortex and limbic-related regions, including the hippocampus, hypothalamus, and brainstem, is likely responsible for the complex clinical picture that includes cognitive, perceptual, emotional, and motor symptoms. G protein and GPCR-mediated signaling play a critical role in developing new treatment options for mental health issues, and this study is aimed at offering a thorough picture of that involvement. For patients who are resistant to current therapies, the development of new drugs that target GPCR signaling cascades remains an interesting possibility. These discoveries might serve as a fresh foundation for the creation of creative methods for pharmacologically useful modulation of GPCR function.

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“…Since astrocytes dampen synaptic potentiation via a number of mechanisms (20,40), we hypothesize that increased astrocyte insulation of D2-MSNs during cue-reinstated heroin seeking may reduce D2-MSN potentiation relative to the extinguished context (26,41). However, a number of reports indicate that subpopulations of D2-MSNs in the striatum promote, rather than inhibit motivated behaviors (49)(50)(51)(52). Moreover, cortical inputs linked to cued reinstatement (53) innervate D2-MSNs to a greater extent than D1-MSNs (54).…”

Section: Astroglial Adaptations Are Differentially Regulated Around D...mentioning

confidence: 99%

Plasticity in astrocyte subpopulations regulates heroin relapse

Kruyer

Kalivas

2020

Preprint

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BACKGROUNDCues predicting heroin delivery induce heroin seeking by initiating synaptic glutamate release in the nucleus accumbens core. The intensity of heroin seeking is negatively modulated by cue-induced increases in synaptic proximity of astrocytes. Glutamate-driven heroin seeking is also negatively regulated by compounds that promote glutamate uptake through the astrocytic transporter GLT-1. We hypothesized that the cue-induced increase in astrocyte synaptic proximity reduces heroin seeking by increasing GLT-1 synaptic proximity.METHODSRats were trained to self-administer heroin or sucrose before undergoing extinction and cued reinstatement of heroin or sucrose seeking. We used confocal microscopy to assess expression and co-registration of GLT-1 with the synaptic marker Synapsin I in the nucleus accumbens core.RESULTSExtinction from heroin, but not sucrose self-administration, downregulated GLT-1. Heroin cues increased surface expression of GLT-1 in parallel with heroin seeking, but counter to expectations, the increase was not proximal to synapses identified by Synapsin I. In fact, astroglia showing cue-induced increased surface expression of GLT-1 constituted a distinct subpopulation of astroglia from those showing increased synaptic proximity. Supporting discrete mechanisms, preventing cue-evoked increases in astrocyte synaptic proximity by knocking down the astroglial-selective actin binding protein ezrin did not impact cue-induced increases in GLT-1 surface expression.CONCLUSIONSOur data demonstrate that heroin-paired cues elicit two transient adaptations in astrocytes in the nucleus accumbens core, restoration of synaptic proximity and increased surface expression of GLT-1. Each adaptation occurs in largely non-overlapping subpopulations of astrocytes, but both adaptations appear to dampen reinstated heroin seeking.

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Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

Cited by 21 publications

References 82 publications

Plasticity in astrocyte subpopulations regulates heroin relapse

Plasticity in astrocyte subpopulations regulates heroin relapse

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

Plasticity in astrocyte subpopulations regulates heroin relapse

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