Abstract
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 alcohol dependence. To this end, the effects of chronic ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA) subunit variant and kainate (GRIK) subunit mRNA expression were studied in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) of male cynomolgus monkeys. In DLPFC, total AMPA splice variant expression and total kainate receptor subunit expression were significantly decreased in alcohol drinking monkeys. Expression levels of GRIA3 flip and flop and GRIA4 flop mRNAs in this region were positively correlated with daily ethanol intake and blood ethanol concentrations (BEC) averaged over the 6 months prior to necropsy. In OFC, AMPA subunit splice variant expression was reduced in the alcohol treated group. GRIA2 flop mRNA levels in this region were positively correlated with daily ethanol intake and BEC averaged over the 6 months prior to necropsy. Results from these studies provide further evidence of transcriptional regulation of iGluR subunits in the primate brain following chronic alcohol self-administration. Additional studies examining the cellular localization of such effects in the framework of primate prefrontal cortical circuitry are warranted.
Highlights
Alcohol abuse is characterized in part by short-term and longterm biochemical alterations in brain regions that affect subsequent intake, withdrawal, relapse, and cognition
There were no significant differences in PICK1 or GRIP1 between the alcohol and control groups in this region (Figure 4B) and no DISCUSSION The current findings indicate that chronic ethanol selfadministration decreased the expression of mRNAs that encode specific Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunits
Significant decreases were observed in AMPA subunit splice variant expression and kainate subunit expression in dorsolateral prefrontal cortex (DLPFC)
Summary
Alcohol abuse is characterized in part by short-term and longterm biochemical alterations in brain regions that affect subsequent intake, withdrawal, relapse, and cognition. Prefrontal AMPA/kainate expression and ethanol non-human primate cortex exhibits significant anatomical and biochemical similarities with human cortex that facilitate the translation of findings to humans (Preuss, 2001) Previous studies using this model have found marked alterations in GABA-A and NMDA receptor subunit mRNA expression in the DLPFC and OFC but not in anterior cingulate cortex (ACC; Hemby et al, 2006; Acosta et al, 2010), suggesting region specific GABA/glutamate imbalances in the primate prefrontal cortex. To further investigate the potential contribution of AMPA and kainate receptor subunit expression in the prefrontal cortical dysfunction characteristic of alcoholism, we examined AMPA and kainate receptor subunit mRNA expression, including AMPA flip/flop variants in the DLPFC, OFC, and ACC of cynomolgus monkeys following chronic ethanol self-administration
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