Upregulation of glutamate receptor subtypes during alcohol withdrawal in rats

Department of Psychiatry, University Hospital Rigshospitalet, Copenhagen, Denmark.
Alcohol and Alcoholism (Impact Factor: 2.89). 11/2004; 40(2):89-95. DOI: 10.1093/alcalc/agh117
Source: PubMed


To investigate glutamate receptor subtypes during alcohol withdrawal.
Rats were exposed to severe alcohol intoxication for 84 h and then decapitated at 0, 12 and 36 h after the last alcohol dose (n = 7 per group). Alcohol was administered five times a day by intragastric intubation. The densities of N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were studied in membranes from the forebrain by using the specific ligands [3H]MK-801 and [3H]AMPA, respectively.
Although no change in the maximal density (B(max)) of [3H]MK-801 binding sites was observed at the time of withdrawal, [3H]MK-801 binding was increased by 49% 12 h into the withdrawal reaction compared with the control group. At 36 h post alcohol the B(max) of the [3H]MK-801 binding was still increased by 24% compared with the control group; however, this difference was not statistically significant. When investigated at the time of withdrawal from chronic alcohol intoxication, no significant alterations in the B(max) of the [3H]AMPA binding was detected, but 12 h into the withdrawal reaction the [3H]AMPA binding was markedly increased by 94%. At 36 h post alcohol the [3H]AMPA binding had returned to control levels. No significant alterations in the dissociation constant (K(D)) of either [3H]MK-801 or [3H]AMPA binding was observed at any time point.
NMDA and AMPA receptors are involved in the cerebral hyperactivity of alcohol withdrawal.

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Available from: Steven Haugbøl, Aug 21, 2015
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    • "Our results differ in that we examine NMDARs in a specific region, the VTA, rather than in the whole brain. Also, our studies involved a relatively brief period of EtOH intake relative to previous work (Chen et al., 1997; Haugbøl et al., 2005). "
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    ABSTRACT: Background: Corticotropin releasing factor (CRF) and urocortin play an important role in many stress responses and also can regulate ethanol (EtOH) intake. Adaptations in CRF signaling in the central amygdala promote EtOH consumption after long-term EtOH intake in dependent animals and also after brief periods of binge EtOH intake. Thus, even brief episodes of EtOH consumption can alter the function of the CRF system, allowing CRF to regulate EtOH intake. Here, we examined whether brief binge EtOH consumption leads to CRF receptor adaptations within the ventral tegmental area (VTA), a structure involved in signaling rewarding and aversive events and important in the development and expression of drug and alcohol addiction. Methods: We utilized a mouse model of binge drinking known as drinking in the dark (DID), where C57BL/6J mice drink approximately 6 g/kg in 4 hours and achieve blood EtOH concentrations of approximately 100 mg/dl, which is equivalent to binge drinking in humans. We used ex vivo whole-cell recordings from putative VTA dopamine (DA) neurons to examine CRF regulation of NMDA receptor (NMDAR) currents. We also examined the impact of CRF receptor antagonist injection in the VTA on binge EtOH intake. Results: Ex vivo whole-cell recordings from putative VTA DA neurons showed enhanced CRF-mediated potentiation of NMDAR currents in juvenile mice that consumed EtOH in the DID procedure. CRF-induced potentiation of NMDAR currents in EtOH-drinking mice was blocked by administration of CP-154,526 (3 μM), a selective CRF1 receptor antagonist. Furthermore, intra-VTA infusion of CP-154,526 (1 μg) significantly reduced binge EtOH consumption in adult mice. These results were not due to alterations of VTA NMDAR number or function, suggesting that binge drinking may enhance signaling through VTA CRF1 receptors onto NMDARs. Conclusions: Altered CRF1 receptor-mediated signaling in the VTA promotes binge-like EtOH consumption in mice, which supports the idea that CRF1 receptors may therefore be a promising pharmacological target for reducing binge drinking in humans.
    Alcoholism Clinical and Experimental Research 06/2013; 37(10). DOI:10.1111/acer.12153 · 3.21 Impact Factor
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    • "Chronic exposure of animals to alcohol can lead to a compensatory increase in NMDAR functionality through increased expression of NMDAR subunits; however, the experimental paradigm used can greatly influence which subunit is affected and the magnitude of the change. The largest alteration in expression occurs during withdrawal following a constant exposure or repeated deprivation protocol (Gulya et al., 1991; Darstein et al., 2000; Nixon et al., 2004; Haugbol et al., 2005; Nelson et al., 2005; Raeder et al., 2008). The influence of sex on molecular changes has not been extensively studied in human brain, despite its vulnerability (Harper et al., 1990). "
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    ABSTRACT: The aim of this study was to assess whether chronic alcohol misuse affects N-methyl-d-aspartate (NMDA) receptor subunit concentrations in human cases, and whether male and female subjects respond differently. Real-time RT-PCR normalized to GAPDH was used to assay NR1, NR2A and NR2B subunit mRNA in superior frontal (SFC) and primary motor (PMC) cortex tissue obtained at autopsy from chronic alcoholics with and without comorbid cirrhosis of the liver, and from matched controls. The expression of all three subunits was significantly lower in both areas of cirrhotic alcoholics than in either controls or alcoholics without comorbid disease, who did not differ significantly. Values were also influenced by the subject's sex and genotype. The mu-opiate receptor C1031G polymorphism selectively modulated NMDA transcript expression in cirrhotic-alcoholic SFC, an effect that was more marked for NR1 and NR2A than for NR2B subunit transcripts. Contrasting 5HT1B genotypes affected NMDA mRNA expression differently in male and female SFC, but not PMC, in cirrhotic alcoholics. NMDA receptor subunit expression may differentially influence male and female cirrhotic alcoholics' susceptibility to brain damage.
    Alcohol and Alcoholism 10/2009; 44(6):594-601. DOI:10.1093/alcalc/agp052 · 2.89 Impact Factor
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    • "[Color figure can be viewed in the online issue, which is available at] 2003; Haugbøl et al., 2005). The hippocampal formation is important in regulating cerebral neuronal hyperexcitability (McIntyre and Gilby, 2008), and, because NPY suppresses hyperexcitability in this region (Baraban et al., 1997; Klapstein and Colmers, 1997; Woldbye et al., 1997; Vezzani et al., 1999), decreases in hippocampal NPY could participate in mediating decreased inhibitory neurotransmission during chronic ethanol intoxication and subsequent withdrawal, leading to tolerance and withdrawal hyperexcitability, respectively (Bison and Crews, 2003; Olling et al., 2007). "
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    ABSTRACT: Previous studies show that chronic ethanol treatment induces prominent changes in brain neuropeptide Y (NPY). The purpose of the present study was to explore ethanol effects at a deeper NPY-system level, measuring expression of NPY and its receptors (Y1, Y2, Y5) as well as NPY receptor binding and NPY-stimulated [(35)S]GTPgammaS functional binding. Rats received intragastric ethanol repeatedly for 4 days, and the NPY system was studied in the hippocampal dentate gyrus (DG), CA3, CA1, and piriform cortex (PirCx) and neocortex (NeoCx) during intoxication, peak withdrawal (16 hr), late withdrawal (3 days), and 1 week after last ethanol administration. NPY mRNA levels decreased during intoxication and at 16 hr in hippocampal regions but increased in the PirCx and NeoCx at 16 hr. NPY mRNA levels were increased at 3 days and returned to control levels in most regions at 1 week. Substantial changes also occurred at the receptor level. Thus Y1, Y2, and Y5 mRNA labelling decreased at 16 hr in most regions, returning to control levels at 3 days, except for PirCx Y2 mRNA, which increased at 3 days and 1 week. Conversely, increases in NPY receptor binding occurred in hippocampal regions during intoxication and in functional binding in the DG and NeoCx during intoxication and at 16 hr and in PirCx during intoxication and at 1 week. Thus this study shows that ethanol intoxication and withdrawal induce complex plastic changes in the NPY system, with decreased/increased gene expression or binding occurring in a time- and region-specific manner. These changes may play an important role in mediating ethanol-induced changes in neuronal excitability.
    Journal of Neuroscience Research 08/2009; 87(10):2386-97. DOI:10.1002/jnr.22049 · 2.59 Impact Factor
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