Effects of Prenatal and Early Postnatal Ethanol Exposure on [H]MK-801 Binding in Rat Cortex and Hippocampus

Abstract

The effects of prenatal and/or early postnatal exposure to ethanol at high concentrations on N-methyl-D-aspartate (NMDA) receptor number and functioning in the weanling rat were examined. The binge-like exposure protocol was used in an animal model of acute ethanol effects at two critical periods of development. [3H]MK-801 binding parameters for the internal channel phencyclidine site were assessed in the presence of 10 microM glutamate and 10 microM glycine activation. Four treatment groups were included: (1) animals exposed to ethanol both prenatal and postnatal; (2) animals exposed only prenatal; (3) animals exposed early postnatal only; and (4) control animals with no exposure to ethanol. The results of the [3H]MK-801 binding experiments showed that both prenatal and postnatal exposure to ethanol resulted in a significant decrease in the density of NMDA receptors. In addition, data indicated an apparent increase in the percentage of high-affinity state (open channel state) relative to low-affinity state (close channel state) receptors in the ethanol-treated groups. These results show that both prenatal and postnatal ethanol exposure decrease NMDA receptor density in the cortex and hippocampus. The findings are consistent with previous observations by our laboratory and others that NMDA-mediated calcium influx is reduced in these regions, as well as in whole brain by prenatal ethanol exposure. It is suggested that after ethanol exposure, the remaining functional NMDA receptors might have altered sensitivity to coagonist activation with an increased probability of channel opening.

Prenatal ethanol exposure enhances NMDAR‐dependent long‐term potentiation in the adolescent female dentate gyrus

“…CPP application completely blocked LTP induction following PNEE, suggesting that prenatal ethanol exposure causes LTP to become solely reliant upon NMDARs. This is surprising because PNEE reduces [ 3 H]MK-801 binding, NMDARmediated calcium entry, and expression of NR2A and NR2B NMDAR subunits in males (Lee et al, 1994;Diaz-Granados et al, 1997;Spuhler-Phillips et al, 1997) and activation of intracellular pathways that contribute to LTP (Samudio-Ruiz et al, 2009). Prenatal stress can also reduce NMDAR subunit expression in the hippocampus (Son et al, 2006;Yaka et al, 2007) indicating that altered expression and/or function of NMDARs following prenatal ethanol or prenatal stress might affect NMDAR contribution to synaptic plasticity in the adolescent hippocampus.…”

Enhancement of NMDA-induced functional responses without concomitant NMDA receptor changes following chronic ethanol exposure in cerebellar granule cells

“…For example, although Snell and colleagues (1993) observed an increased number of [ 3 H]MK-801and [ 3 H]glutamate binding sites to brain membranes in ethanol-treated mice, they found no difference in the binding characteristics for either [ 3 H]glycine or competitive NMDA receptor antagonist [ 3 H]CGS 19755. Furthermore, several researchers have not been able to detect any changes in the number of [ 3 H]MK-801 binding sites even following extensive periods of in vivo ethanol treatment (Tremwel et al 1994;Carter et al 1995;Diaz-Granados et al 1997;Rudolph et al 1997). These controversies are extended to corresponding ligand binding data from the brains of human alcoholics (Michaelis et al 1990;Freund and Anderson 1996).…”

“…However, in the same animal model for ethanol dependence, Snell and colleagues (1993) observed no changes in the binding parameters of the NMDA receptor co-agonist, [ 3 H]glycine, or the competitive NMDA receptor antagonist, [ 3 H]CGS19755. Other researchers, using various chronic ethanol administration regimens in vivo, have generally failed to observe changes in the binding parameters of NMDA receptor ligands (Tremwel et al 1994;Carter et al 1995;Ulrichsen et al 1996;Diaz-Granados et al 1997;Rudolph et al 1997). Similarly, in vitro studies in neuronal cultures have also provided conflicting observations.…”

Chronic Prenatal Ethanol Exposure Alters Ionotropic Glutamate Receptor Subunit Protein Levels in the Adult Guinea Pig Cerebral Cortex

“…A decreased number of NMDAR binding sites has been detected in hippocampal preparations from the rat and guinea pig (Abdollah and Brien, 1995;Savage et al, 1991). Region-specific alterations in the binding of the noncompetitive NMDAR antagonist [ 3 H]MK-801 have been observed in the brain of the rat and guinea pig exposed to ethanol prenatally, postnatally, or both (Chiu et al, 1999;Diaz-Granados et al, 1997;Naassila and Daoust, 2002). Modifications in the developmental patterns of NMDAR subunit messenger RNA and protein content have been documented in several studies (Hughes et al, 1998;Naassila and Daoust, 2002;Spuhler-Phillips et al, 1997).…”