scholarly journals Amperometric measurements of cocaine cue and novel context-evoked glutamate and nitric oxide release in the nucleus accumbens core

2019 ◽  
Author(s):  
BM Siemsen ◽  
JA McFaddin ◽  
K Haigh ◽  
AG Brock ◽  
MN Leath ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nucleus Accumbens ◽  
Temporal Dynamics ◽  
Glutamate Release ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Nitric Oxide Release ◽  
Cocaine Seeking ◽  
No Release ◽  
Accumbens Core

AbstractCue-induced reinstatement of cocaine seeking after self-administration (SA) and extinction relies on glutamate release in the nucleus accumbens core (NAcore), which in turn activates neuronal nitric oxide synthase (nNOS) interneurons. Nitric oxide (NO) is required for structural plasticity in NAcore medium spiny neurons (MSNs), as well as cued cocaine seeking. However, NO release in the NAcore during reinstatement has yet to be directly measured. Further, the temporal relationship between glutamate release, and the induction of a NO response also remains unknown. Using wireless amperometric recordings in awake behaving rat, we quantified the magnitude and temporal dynamics of novel context- and cue-induced reinstatement-evoked glutamate and NO release in the NAcore. We found that re-exposure to cocaine-conditioned stimuli following SA and extinction increased extracellular glutamate, leading to release of NO in the NAcore. In contrast, exposing drug-naïve rats to a novel context led to a lower magnitude rise in glutamate in the NAcore relative to cue-induced reinstatement. Interestingly, novel context exposure evoked a higher magnitude NO response relative to cue-induced reinstatement. Despite differences in magnitude, novel context evoked-NO release in the NAcore was also temporally delayed when compared to glutamate. These results demonstrate a dissociation between the magnitude of cocaine cue- and novel context-evoked glutamate and NO release in the NAcore, yet similarity in the temporal dynamics of their release. Together, these data contribute to a greater understanding of the relationship between glutamate and NO, two neurotransmitters implicated in encoding the valence of distinct contextual stimuli.

scholarly journals A subset of nucleus accumbens neurons receiving dense and functional prelimbic cortical input are required for cocaine seeking

2021 ◽  
Author(s):  
Benjamin M. Siemsen ◽  
Sarah M. Barry ◽  
Kelsey Vollmer ◽  
Lisa M. Green ◽  
Ashley G. Brock ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Glutamate Release ◽  
Sprague Dawley ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Cortical Input ◽  
Cortical Projections ◽  
Cocaine Seeking ◽  
Accumbens Core

AbstractBackgroundPrelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown.MethodsMale Sprague-Dawley rats underwent cocaine or sucrose self-administration, extinction, and cue-induced reinstatement. Pathway-specific chemogenetics, patch-clamp electrophysiology, in vivo electrochemistry, and high-resolution confocal microscopy were used to identify and characterize a small population of nucleus accumbens core neurons that receive dense prelimbic cortical input to determine their role in regulating cue-induced cocaine and natural reward seeking.ResultsChemogenetic inhibition of prelimbic cortical projections to the nucleus accumbens core suppressed cue-induced cocaine relapse and normalized real-time cue-evoked increases in accumbens glutamate release to that of sucrose seeking animals. Furthermore, chemogenetic inhibition of the population of nucleus accumbens core neurons receiving the densest prelimbic cortical input suppressed cocaine, but not sucrose seeking. These neurons also underwent morphological plasticity during the peak of cocaine seeking in the form of dendritic spine expansion and increased ensheathment by astroglial processes at large spines.ConclusionsWe identified and characterized a unique subpopulation of nucleus accumbens neurons that receive dense prelimbic cortical input. The functional specificity of this subpopulation is underscored by their ability to mediate cue-induced cocaine relapse, but not sucrose seeking. This subset of cells represents a novel target for addiction therapeutics revealed by anterograde targeting to interrogate functional circuits imbedded within a known network.

scholarly journals Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats

2021 ◽  
Author(s):  
Amy Chan ◽  
Alexis Willard ◽  
Sarah Mulloy ◽  
Noor Ibrahim ◽  
Allegra Sciaccotta ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Female Rats ◽  
Therapeutic Effects ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Male And Female ◽  
Male And Female Rats ◽  
Cocaine Seeking ◽  
Ampk Activity ◽  
Accumbens Core

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder, but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.

scholarly journals Amperometric measurements of cocaine cue and novel context‐evoked glutamate and nitric oxide release in the nucleus accumbens core

2020 ◽  
Vol 153 (5) ◽  
pp. 599-616 ◽  
Author(s):  
Benjamin M. Siemsen ◽  
John A. McFaddin ◽  
Keiana Haigh ◽  
Ashley G. Brock ◽  
Mary Nan Leath ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nucleus Accumbens ◽  
Nucleus Accumbens Core ◽  
Nitric Oxide Release ◽  
Accumbens Core

scholarly journals Heroin Cues Reveal Astroglial Heterogeneity in the Nucleus Accumbens Core

2020 ◽  
Author(s):  
Anna Kruyer ◽  
Peter W. Kalivas
Keyword(s):  
Nucleus Accumbens ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Surface Expression ◽  
Actin Binding ◽  
Synapsin I ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Distinct Subpopulation ◽  
Accumbens Core

ABSTRACTBACKGROUNDCues 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.

scholarly journals AMPK signaling in the nucleus accumbens core mediates cue-induced reinstatement of cocaine seeking

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Xue-Jiao Gao ◽  
Kai Yuan ◽  
Lu Cao ◽  
Wei Yan ◽  
Yi-Xiao Luo ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Nucleus Accumbens Core ◽  
Ampk Signaling ◽  
Cocaine Seeking ◽  
Accumbens Core

scholarly journals Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cue‐induced cocaine seeking

2020 ◽  
Author(s):  
Allison R. Bechard ◽  
Carly N. Logan ◽  
Javier Mesa ◽  
Yasmin Padovan‐Hernandez ◽  
Harrison Blount ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Nucleus Accumbens Core ◽  
Cocaine Seeking ◽  
Accumbens Core

scholarly journals Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

2016 ◽  
Vol 113 (20) ◽  
pp. E2861-E2870 ◽  
Author(s):  
Shelly B. Flagel ◽  
Sraboni Chaudhury ◽  
Maria Waselus ◽  
Rebeca Kelly ◽  
Salima Sewani ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Protective Factor ◽  
Dopamine D2 Receptor ◽  
Genetic Difference ◽  
Epigenetic Modifications ◽  
Mrna Levels ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
The Core ◽  
Cocaine Seeking

This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with “temperament,” including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor.

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