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SFN 2004 Abstracts
THE SCRIPPS RESEARCH INSTITUTE, LA JOLLA
NEUROADAPTATIONS OF NMDA RECEPTORS IN RAT CENTRAL AMYGDALA AFTER CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL
Roberto M., Bajo M., Madamba S.G., de Lecea L. and Siggins G.R.
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
We recently reported that chronic ethanol treatment (CET; 2-3 weeks via ethanol inhalation) and early withdrawal (2-8 hours) led to neuroadaptations of glutamatergic transmission at both pre- and postsynaptic sites in central amygdala (CeA), suggesting that glutamatergic synapses in CeA play an important role in ethanol dependence. The ability of acute ethanol (44 mM) and ifenprodil, an antagonist of NMDARs containing the NR2B subunit, in blocking NMDA-EPSP/Cs was enhanced in CeA neurons from CET rats (Roberto et al., 2004, J. Neurosci. 24:1594), suggesting that CET sensitizes NMDA receptors to ethanol. To determine the persistence of these effects of CET, we recorded intracellularly in rat CeA slices taken from rats withdrawn for 1 and 2- weeks. At these times, acute ethanol decreased the NMDA-EPSP/C amplitudes to the same extent (by 20%) as in naïve rats, indicating that the effects of chronic ethanol were totally reversed after 1 week of cessation of CET. We also used quantitative real-time PCR and Western blot analysis to examine the effects of CET on the gene and protein expression of the more ethanol-sensitive NMDAR subunits (NR2A and B). CeA slices from CET rats showed a significant increase in NR1, NR2A and NR2B subunit protein levels. As in the electrophysiological study, this increase returned to control levels at 1 week withdrawal. Real-time PCR analysis revealed a significant increase in the mRNA level of the NR1 subunit and a tendency to increase NR2A and B compared to control rats. At 1 week of withdrawal mRNA for the 3 subunits decreased but at 2 weeks withdrawal mRNA was back to control levels. These combined data suggest that prolonged ethanol exposure changes the synaptic function, gene and protein composition of NMDA receptors and support the hypothesis that neuroadaptations at glutamatergic synapses in CeA play an important role in ethanol dependence. Supported by grants from NIH (AA013517, AA06420, DA03665).
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