CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context

AbstractPreclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 μl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 μl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.

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

10.1101/2021.09.03.458762 ◽

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.

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Alcohol consumption increases basal extracellular glutamate in the nucleus accumbens core of Sprague-Dawley rats without increasing spontaneous glutamate release

European Journal of Neuroscience ◽

10.1111/ejn.13284 ◽

2016 ◽

Vol 44 (2) ◽

pp. 1896-1905 ◽

Cited By ~ 28

Author(s):

Dipanwita Pati ◽

Kyle Kelly ◽

Bethany Stennett ◽

Charles J. Frazier ◽

Lori A. Knackstedt

Keyword(s):

Nucleus Accumbens ◽

Alcohol Consumption ◽

Glutamate Release ◽

Sprague Dawley ◽

Nucleus Accumbens Core ◽

Extracellular Glutamate ◽

Sprague Dawley Rats ◽

Accumbens Core

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

10.1101/826677 ◽

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.

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Faculty Opinions recommendation of Differential control over cocaine-seeking behavior by nucleus accumbens core and shell.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1018246.206702 ◽

2004 ◽

Author(s):

Eric Nestler

Keyword(s):

Nucleus Accumbens ◽

Nucleus Accumbens Core ◽

Cocaine Seeking ◽

Seeking Behavior ◽

Differential Control ◽

Accumbens Core

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Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

Neural Plasticity ◽

10.1155/2017/4526417 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Hua Yang ◽

Mengjie Zhang ◽

Jiahao Shi ◽

Yunhe Zhou ◽

Zhipeng Wan ◽

...

Keyword(s):

Cerebral Cortex ◽

Mouse Model ◽

Glutamate Release ◽

Critical Role ◽

Conditional Knockout ◽

Snare Complex ◽

Extracellular Glutamate ◽

Glutamate Level

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

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

Scientific Reports ◽

10.1038/s41598-017-01043-5 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 5

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

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Sensitization of Rapid Dopamine Signaling in the Nucleus Accumbens Core and Shell After Repeated Cocaine in Rats

Journal of Neurophysiology ◽

10.1152/jn.00413.2010 ◽

2010 ◽

Vol 104 (2) ◽

pp. 922-931 ◽

Cited By ~ 32

Author(s):

Nii A. Addy ◽

David P. Daberkow ◽

Jeremy N. Ford ◽

Paul A. Garris ◽

R. Mark Wightman

Keyword(s):

Nucleus Accumbens ◽

Dopamine Release ◽

Cocaine Exposure ◽

Sprague Dawley ◽

Nucleus Accumbens Core ◽

Fast Scan Cyclic Voltammetry ◽

Uptake Inhibition ◽

Sprague Dawley Rats ◽

Dopamine Signaling

Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine pre-exposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent Km of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects.

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The Effects of Exposure to Mephedrone During Adolescence on Brain Neurotransmission and Neurotoxicity in Adult Rats

Neurotoxicity Research ◽

10.1007/s12640-018-9908-0 ◽

2018 ◽

Vol 34 (3) ◽

pp. 525-537 ◽

Cited By ~ 4

Author(s):

Katarzyna Kamińska ◽

Karolina Noworyta-Sokołowska ◽

Anna Górska ◽

Joanna Rzemieniec ◽

Agnieszka Wnuk ◽

...

Keyword(s):

Nucleus Accumbens ◽

Glutamate Release ◽

Cortical Cell ◽

Synaptic Cleft ◽

In Vivo Microdialysis ◽

Male Rats ◽

Adolescent Male ◽

Turnover Rates ◽

Adult Rats

Abstract According to the European Drug Report (2016), the use of synthetic cathinones, such as mephedrone, among young people has rapidly increased in the last years. Studies in humans indicate that psychostimulant drug use in adolescence increases risk of drug abuse in adulthood. Mephedrone by its interaction with transporters for dopamine (DAT) and serotonin (SERT) stimulates their release to the synaptic cleft. In animal studies, high repeated doses of mephedrone given to adolescent but not adult mice or rats induced toxic changes in 5-hydroxytryptamine (5-HT) neurons. The aim of our study was to investigate the effects of mephedrone given in adolescence on brain neurotransmission and possible neuronal injury in adult rats. Adolescent male rats were given mephedrone (5 mg/kg) for 8 days. In vivo microdialysis in adult rats showed an increase in dopamine (DA), 5-HT, and glutamate release in the nucleus accumbens and frontal cortex but not in the striatum in response to challenge dose in animals pretreated with mephedrone in adolescence. The 5-HT and 5-hydroxyindoleacetic acid contents decreased in the striatum and nucleus accumbens while DA turnover rates were decreased in the striatum and nucleus accumbens. The oxidative damage of DNA assessed with the alkaline comet assay was found in the cortex of adult rats. Therefore, the administration of repeated low doses of mephedrone during adolescence does not seem to induce injury to 5-HT and DA neurons. The oxidative stress seems to be responsible for possible damage of cortical cell bodies which causes maladaptive changes in serotonergic and dopaminergic neurons.

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