Dataset Information

Ethanol self-administration modulation of NMDA receptor subunit and related synaptic protein mRNA expression in prefrontal cortical fields in cynomolgus monkeys.

ABSTRACT:

Background

Functional impairment of the orbital and medial prefrontal cortex underlies deficits in executive control that characterize addictive disorders, including alcohol addiction. Previous studies indicate that alcohol alters glutamate neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting ionotropic glutamate receptor (iGluR) complexes. Glutamatergic transmission is integral to cortico-cortical and cortico-subcortical communication, and alcohol-induced changes in the abundance of the receptor subunits and/or their splice variants may result in critical functional impairments of prefrontal cortex in the alcohol-addicted state.

Methods and results

The effects of chronic ethanol self-administration on glutamate receptor ionotropic NMDA (GRIN), as well as GRIN1 splice variant mRNA expression was studied in the orbitofrontal cortex (OFC; Area 13), dorsolateral prefrontal cortex (DLPFC; Area 46) and anterior cingulate cortex (ACC; Area 24) of male cynomolgus monkeys. Chronic ethanol self-administration resulted in significant changes in the expression of NMDA subunit mRNA expression in the DLPFC and OFC, but not the ACC. In DLPFC, the overall expression of NMDA subunits was significantly decreased in ethanol treated monkeys. Slight but significant changes were observed for synaptic associated protein 102 kD (SAP102) and neuronal nitric oxide synthase (nNOS) mRNAs. In OFC, the NMDAR1 variant GRIN1-1 was reduced while GRIN1-2 was increased. Furthermore, no significant changes in GFAP protein levels were observed in either the DLPFC or OFC.

Conclusion

Results from these studies provide the first demonstration of posttranscriptional regulation of iGluR subunits in the primate brain following long-term ethanol self-administration. Furthermore, changes in these transcripts do not appear to reflect changes in glial activation or loss. Further studies examining the expression and cellular localization of subunit proteins and receptor pharmacology would shed more light on the findings reported here.

SUBMITTER: Acosta G

PROVIDER: S-EPMC3272763 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ethanol self-administration modulation of NMDA receptor subunit and related synaptic protein mRNA expression in prefrontal cortical fields in cynomolgus monkeys.

Acosta Glen G Hasenkamp Wendy W Daunais James B JB Friedman David P DP Grant Kathleen A KA Hemby Scott E SE

Brain research 20100104

<h4>Background</h4>Functional impairment of the orbital and medial prefrontal cortex underlies deficits in executive control that characterize addictive disorders, including alcohol addiction. Previous studies indicate that alcohol alters glutamate neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting ionotropic glutamate receptor (iGluR) complexes. Glutamatergic transmission is integral to cortico-cortical and cortico-subcortical co ...[more]

PMID: 20043891

Similar Datasets

Project description:BackgroundGenome-wide profiling to examine brain transcriptional features associated with excessive ethanol (EtOH) consumption has been applied to a variety of species including rodents, nonhuman primates (NHPs), and humans. However, these data were obtained from cross-sectional samples which are particularly vulnerable to individual variation when obtained from small outbred populations typical of human and NHP studies. In the current study, a novel within-subject design was used to examine the effects of voluntary EtOH consumption on prefrontal cortex (PFC) gene expression in a NHP model.MethodsTwo cohorts of cynomolgus macaques (n = 23) underwent a schedule-induced polydipsia procedure to establish EtOH self-administration followed by 6 months of daily open access to EtOH (4% w/v) and water. Individual daily EtOH intakes ranged from an average of 0.7 to 3.7 g/kg/d. Dorsal lateral PFC area 46 (A46) brain biopsies were collected in EtOH-naïve and control monkeys; contralateral A46 biopsies were collected from the same monkeys following the 6 months of fluid consumption. Gene expression changes were assessed using RNA-Seq paired analysis, which allowed for correction of individual baseline differences in gene expression.ResultsA total of 675 genes were significantly down-regulated following EtOH consumption; these were functionally enriched for immune response, cell adhesion, plasma membrane, and extracellular matrix. A total of 567 genes that were up-regulated following EtOH consumption were enriched in microRNA target sites and included target sites associated with Toll-like receptor pathways. The differentially expressed genes were also significantly enriched in transcription factor binding sites.ConclusionsThe data presented here are the first to use a longitudinal biopsy strategy to examine how chronic EtOH consumption affects gene expression in the primate PFC. Prominent effects were seen in both cell adhesion and neuroimmune pathways; the latter contained both pro- and antiinflammatory genes. The data also indicate that changes in miRNAs and transcription factors may be important epigenetic regulators of EtOH consumption.

Project description:BackgroundA clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA).MethodsWe conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor-expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA.ResultsPunishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor-expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing.ConclusionsThese findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.

Project description:Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

Dataset Information

Ethanol self-administration modulation of NMDA receptor subunit and related synaptic protein mRNA expression in prefrontal cortical fields in cynomolgus monkeys.

Background

Methods and results

Conclusion

Publications

Ethanol self-administration modulation of NMDA receptor subunit and related synaptic protein mRNA expression in prefrontal cortical fields in cynomolgus monkeys.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets