Differential alterations of GABA sub(A) receptor ( alpha 1, beta 2, gamma 2 subunit) expression and increased seizure susceptibility in rat offspring from morphine-addicted mothers: Beneficial effect of dextromethorphan

Although prenatal morphine exposure experimentally induces seizures in rat offspring, underlying mechanisms remain unclear. This study addresses whether prenatal morphine exposure altered subunit compositions of gamma -aminobutyric acid receptor subtype A (GABA sub(A)R) in the hippocampal CA1 area and temporal cortex and increased seizure susceptibility of young rat offspring, at a representative age (postneonatal days 14; P14). Therapeutic efficacy of dextromethorphan (a noncompetitive antagonist of N-methyl-d-aspartate receptors (NMDARs)), in such offspring was also evaluated. From P7 to 14, Sprague-Dawley rat offspring were intraperitoneally (ip) injected a representative dose of dextromethorphan (3 mg/kg) twice a day. At P14, some offspring were ip injected pentylenetetrazol to estimate seizure susceptibility, while the others were studied for GABA sub(A)R subunit ( alpha 1, beta 2, gamma 2) expression. Prenatal morphine exposure caused the up-regulated alpha 1 subunit and down-regulated beta 2/ gamma 2 subunit expression of GABA sub(A)R within hippocampus and temporal cortex in rat offspring associated to increase seizure susceptibility. The magnitudes of upregulated alpha 1 subunit and downregulated beta 2 subunit expression in the hippocampus were greater than which in the temporal cortex. The use of dextromethorphan markedly reversed the prenatal morphine-induced alterations, indicating the possible therapeutic actions of dextromethorphan. These results suggest that the altered subunit compositions ( alpha 1, beta 2, gamma 2) of GABA sub(A)R in the hippocampal CA1 area and temporal cortex may contribute, at least in part, to the increased seizure susceptibility of rat offspring subjected to prenatal morphine exposure. More importantly, dextromethorphan may be a promising clinical agent acting against these alterations.