Locomotor Sensitization to Ethanol Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Nucleus Accumbens and Increases Ethanol Self-Administration

Abstract Learning associations between environmental cues and rewards is a fundamental adaptive function. Via such learning, reward-predictive cues come to activate approach to locations where reward is available. The nucleus accumbens (NAc) is essential for cued approach behavior in trained subjects, and cue-evoked excitations in NAc neurons are critical for the expression of this behavior. Excitatory synapses within the NAc undergo synaptic plasticity that presumably contributes to cued approach acquisition, but a direct link between synaptic plasticity within the NAc and the development of cue-evoked neural activity during learning has not been established. Here we show that, with repeated cue-reward pairings, cue-evoked excitations in the NAc emerge and grow in the trials prior to the detectable expression of cued approach behavior. We demonstrate that the growth of these signals requires NMDA receptor-dependent plasticity within the NAc, revealing a neural mechanism by which the NAc participates in learning of conditioned reward-seeking behaviors.

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Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity

Brain ◽

10.1093/brain/awt036 ◽

2013 ◽

Vol 136 (4) ◽

pp. 1216-1230 ◽

Cited By ~ 49

Author(s):

Livia Curcio ◽

Maria V. Podda ◽

Lucia Leone ◽

Roberto Piacentini ◽

Alessia Mastrodonato ◽

...

Keyword(s):

Synaptic Plasticity ◽

Nucleus Accumbens ◽

Nmda Receptor

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Targeted over-expression of brain-derived neurotrophic factor in the nucleus accumbens increases goal tracking and nicotine locomotor sensitization, but reduces nicotine self-administration in rats

Drug and Alcohol Dependence ◽

10.1016/j.drugalcdep.2016.08.091 ◽

2017 ◽

Vol 171 ◽

pp. e28

Author(s):

Russell W. Brown ◽

Lauren A. Beuttel ◽

Sara A. Dean ◽

Curtis A. Bradley ◽

James Wherry ◽

...

Keyword(s):

Nucleus Accumbens ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Locomotor Sensitization ◽

Self Administration ◽

Over Expression ◽

Goal Tracking

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Cocaine Self-Administration and Abstinence Modulate NMDA Receptor Subunits and Active Zone Proteins in the Rat Nucleus Accumbens

Molecules ◽

10.3390/molecules25153480 ◽

2020 ◽

Vol 25 (15) ◽

pp. 3480 ◽

Cited By ~ 1

Author(s):

Irena Smaga ◽

Karolina Wydra ◽

Małgorzata Frankowska ◽

Fabio Fumagalli ◽

Marek Sanak ◽

...

Keyword(s):

Nucleus Accumbens ◽

Nmda Receptor ◽

Active Zone ◽

Receptor Subunit ◽

Self Administration ◽

Nmda Receptor Subunit ◽

Nmda Receptor Subunits ◽

Cocaine Seeking ◽

Seeking Behavior ◽

Rat Nucleus Accumbens

Cocaine-induced plasticity in the glutamatergic transmission and its N-methyl-d-aspartate (NMDA) receptors are critically involved in the development of substance use disorder. The presynaptic active zone proteins control structural synaptic plasticity; however, we are still far from understanding the molecular determinants important for cocaine seeking behavior. The aim of this study was to investigate the effect of cocaine self-administration and different conditions of cocaine forced abstinence on the composition of the NMDA receptor subunits and on the levels of active zone proteins, i.e., Ras-related protein 3A (Rab3A), Rab3 interacting molecules 1 (RIM1) and mammalian uncoordinated protein 13 (Munc13) in the rat nucleus accumbens. We found an up-regulation of the accumbal levels of GluN1 and GluN2A following cocaine self-administration that was paralleled by an increase of Munc13 and RIM1 levels. At the same time, we also demonstrated that different conditions of cocaine abstinence abolished changes in NMDA receptor subunits (except for higher GluN1 levels after cocaine abstinence with extinction training), while an increase in the Munc13 concentration was shown in rats housed in an enriched environment. In conclusion, cocaine self-administration is associated with the specific up-regulation of the NMDA receptor subunit composition and is related with new presynaptic targets controlling neurotransmitter release. Moreover, changes observed in cocaine abstinence with extinction training and in an enriched environment in the levels of NMDA receptor subunit and in the active zone protein, respectively, may represent a potential regulatory step in cocaine-seeking behavior.

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A Model of Δ9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens

Biological Psychiatry ◽

10.1016/j.biopsych.2018.04.016 ◽

2018 ◽

Vol 84 (8) ◽

pp. 601-610 ◽

Cited By ~ 23

Author(s):

Sade Spencer ◽

Daniela Neuhofer ◽

Vivian C. Chioma ◽

Constanza Garcia-Keller ◽

Danielle J. Schwartz ◽

...

Keyword(s):

Synaptic Plasticity ◽

Nucleus Accumbens ◽

Self Administration

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Faculty Opinions recommendation of Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.

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

10.3410/f.1019172.253673 ◽

2004 ◽

Author(s):

Michael Ehlers

Keyword(s):

Synaptic Plasticity ◽

Nmda Receptor ◽

Receptor Subtypes ◽

Hippocampal Synaptic Plasticity

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The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

Neurochemical Research ◽

10.1007/s11064-021-03238-9 ◽

2021 ◽

Author(s):

Zhanglei Dong ◽

Bingwu Huang ◽

Chenchen Jiang ◽

Jiangfan Chen ◽

Han Lin ◽

...

Keyword(s):

Nucleus Accumbens ◽

D2 Receptor ◽

Fixed Ratio ◽

Receptor Activation ◽

Addictive Behaviors ◽

Self Administration ◽

A2a Receptors ◽

Mediated Effects ◽

Seeking Behavior ◽

Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

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Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz050 ◽

2019 ◽

Vol 22 (11) ◽

pp. 710-723 ◽

Cited By ~ 8

Author(s):

Atul P Daiwile ◽

Subramaniam Jayanthi ◽

Bruce Ladenheim ◽

Michael T McCoy ◽

Christie Brannock ◽

...

Keyword(s):

Sex Differences ◽

Nucleus Accumbens ◽

Fixed Ratio ◽

Female Rats ◽

Male Rats ◽

Mrna Levels ◽

Self Administration ◽

Male And Female ◽

Orexin Receptors ◽

Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

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Targeted disruption to NMDA receptor dependent synaptic plasticity in area CA1 of the hippocampus

Experimental Neurology ◽

10.1016/j.expneurol.2021.113808 ◽

2021 ◽

pp. 113808

Author(s):

Alejandra Arias-Cavieres ◽

Ateh Fonteh ◽

Carolina I. Castro-Rivera ◽

Alfredo J. Garcia

Keyword(s):

Synaptic Plasticity ◽

Nmda Receptor ◽

Targeted Disruption ◽

Area Ca1

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